HLA-G 3′UTR Polymorphisms Predict Drug-Induced G3-4 Toxicity Related to Folinic Acid/5-Fluorouracil/Oxaliplatin (FOLFOX4) Chemotherapy in Non-Metastatic Colorectal Cancer

PubMed Central

Garziera, Marica; Virdone, Saverio; De Mattia, Elena; Scarabel, Lucia; Cecchin, Erika; Polesel, Jerry; D’Andrea, Mario; Pella, Nicoletta; Buonadonna, Angela; Favaretto, Adolfo; Toffoli, Giuseppe

2017-01-01

Polymorphisms in drug-metabolizing enzymes might not completely explain inter-individual differences in toxicity profiles of patients with colorectal cancer (CRC) that receive folinic acid/5-fluorouracil/oxaliplatin (FOLFOX4). Recent data indicate that the immune system could contribute to FOLFOX4 outcomes. In light of the immune inhibitory nature of human leukocyte antigen-G (HLA-G), a non-classical major histocompatibility complex (MHC) class I molecule, we aimed to identify novel genomic markers of grades 3 and 4 (G3-4) toxicity related to FOLFOX4 therapy in patients with CRC. We retrospectively analyzed data for 144 patients with stages II-III CRC to identify HLA-G 3′ untranslated region (3′UTR) polymorphisms and related haplotypes and evaluate their impact on the risk of developing G3-4 toxicities (i.e., neutropenia, hematological/non-hematological toxicity, neurotoxicity) with logistic regression. The rs1610696-G/G polymorphism was associated with increased risk of G3-4 neutropenia (OR = 3.76, p = 0.015) and neurotoxicity (OR = 8.78, p = 0.016); rs371194629-Ins/Ins was associated with increased risk of neurotoxicity (OR = 5.49, p = 0.027). HLA-G 3′UTR-2, which contains rs1610696-G/G and rs371194629-Ins/Ins polymorphisms, was associated with increased risk of G3-4 neutropenia (OR = 3.92, p = 0.017) and neurotoxicity (OR = 11.29, p = 0.009). A bootstrap analysis confirmed the predictive value of rs1610696 and rs371194629, but the UTR-2 haplotype was validated only for neurotoxicity. This exploratory study identified new HLA-G 3′UTR polymorphisms/haplotypes as potential predictive markers of G3-4 toxicities in CRC. PMID:28653974

Is Period3 Genotype Associated With Sleep and Recovery in Patients With Disorders of Consciousness?

PubMed

Bedini, Gloria; Bersano, Anna; Sebastiano, Davide Rossi; Sattin, Davide; Ciaraffa, Francesca; Tosetti, Valentina; Brenna, Greta; Franceschetti, Silvana; Ciusani, Emilio; Leonardi, Matilde; Vela-Gomez, Jesus; Boncoraglio, Giorgio B; Parati, Eugenio A

2016-06-01

Background Sleep evaluation is increasingly being used as prognostic tool in patients with disorders of consciousness, but, surprisingly, the role of Period3 (Per3) gene polymorphism has never been evaluated. Objective The aim of this study was to investigate the contribution of Per3 genotype on sleep quantity and consciousness recovery level in patients with disorders of consciousness (DOC). Methods In this observational study, we evaluated 71 patients with DOC classified as vegetative state/unresponsive wakefulness syndrome or minimally conscious state. Demographic and clinical data were collected and a standardised diagnostic workup, including a polysomnographic record, was applied. After informed consent provided by proxy, genomic DNA was obtained and Per3 polymorphism was analysed by polymerase chain reaction to identify 5/5, 4/5, or 4/4 genotype. Results Per3(5/5) genotype was found in 12.7% of our DOC patients. The median total Coma Recovery Scale-revised score in Per3(5/5) carriers was significantly higher than 4/4 genotype (10, range 5-16 vs 7, range 4-11; post hoc P = .036). Moreover, total sleep time seemed to be higher in 5/5 genotype (5/5, 221 minutes, range 88-515 minutes; 4/4, 151.5 minutes, range 36-477 minutes; and 4/5, 188 minutes, range 44-422 minutes). Conclusion For the first time we have shown a possible association between Per3 polymorphism and consciousness recovery level in DOC patients. Even though the exact molecular mechanism has not been defined, we speculate that its effect is mediated by higher total sleep time and slow wave sleep, which would improve the preservation of main cerebral connections. © The Author(s) 2015.

Prediction of sensitivity to warfarin based on VKORC1 and CYP2C9 polymorphisms in patients from different places in Colombia.

PubMed

Cifuentes, Ricardo A; Murillo-Rojas, Juan; Avella-Vargas, Esperanza

2016-03-03

In the search to prevent hemorrhages associated with anticoagulant therapy, a major goal is to validate predictors of sensitivity to warfarin. However, previous studies in Colombia that included polymorphisms in the VKORC1 and CYP2C9 genes as predictors reported different algorithm performances to explain dose variations, and did not evaluate the prediction of sensitivity to warfarin.  To determine the accuracy of the pharmacogenetic analysis, which includes the CYP2C9 *2 and *3 and VKORC1 1639G>A polymorphisms in predicting patients' sensitivity to warfarin at the Hospital Militar Central, a reference center for patients born in different parts of Colombia.  Demographic and clinical data were obtained from 130 patients with stable doses of warfarin for more than two months. Next, their genotypes were obtained through a melting curve analysis. After verifying the Hardy-Weinberg equilibrium of the genotypes from the polymorphisms, a statistical analysis was done, which included multivariate and predictive approaches.  A pharmacogenetic model that explained 52.8% of dose variation (p<0.001) was built, which was only 4% above the performance resulting from the same data using the International Warfarin Pharmacogenetics Consortium algorithm. The model predicting the sensitivity achieved an accuracy of 77.8% and included age (p=0.003), polymorphisms *2 and *3 (p=0.002) and polymorphism 1639G>A (p<0.001) as predictors.  These results in a mixed population support the prediction of sensitivity to warfarin based on polymorphisms in VKORC1 and CYP2C9 as a valid approach in Colombian patients.

DOE Office of Scientific and Technical Information (OSTI.GOV)

Chen, Pei-Chun; Chen, Yen-Ching; Research Center for Gene, Environment, and Human Health, College of Public Health, National Taiwan University, Taiwan

Purpose: To identify germline polymorphisms to predict concurrent chemoradiation therapy (CCRT) response in esophageal cancer patients. Materials and Methods: A total of 139 esophageal cancer patients treated with CCRT (cisplatin-based chemotherapy combined with 40 Gy of irradiation) and subsequent esophagectomy were recruited at the National Taiwan University Hospital between 1997 and 2008. After excluding confounding factors (i.e., females and patients aged {>=}70 years), 116 patients were enrolled to identify single nucleotide polymorphisms (SNPs) associated with specific CCRT responses. Genotyping arrays and mass spectrometry were used sequentially to determine germline polymorphisms from blood samples. These polymorphisms remain stable throughout disease progression,more » unlike somatic mutations from tumor tissues. Two-stage design and additive genetic models were adopted in this study. Results: From the 26 SNPs identified in the first stage, 2 SNPs were found to be significantly associated with CCRT response in the second stage. Single nucleotide polymorphism rs16863886, located between SGPP2 and FARSB on chromosome 2q36.1, was significantly associated with a 3.93-fold increase in pathologic complete response to CCRT (95% confidence interval 1.62-10.30) under additive models. Single nucleotide polymorphism rs4954256, located in ZRANB3 on chromosome 2q21.3, was associated with a 3.93-fold increase in pathologic complete response to CCRT (95% confidence interval 1.57-10.87). The predictive accuracy for CCRT response was 71.59% with these two SNPs combined. Conclusions: This is the first study to identify germline polymorphisms with a high accuracy for predicting CCRT response in the treatment of esophageal cancer.« less

Association between the CLOCK gene 3111 T > C polymorphism and an irregular menstrual cycle in Korean adolescents.

PubMed

Kim, Kye-Hyun; Kim, Yunsin; Ha, Juwon; Shin, Dong-Won; Shin, Young-Chul; Oh, Kang-Seob; Woo, Hee-Yeon; Lim, Se-Won

2015-01-01

The menstrual cycle is an example of a human infradian rhythm, but an altered sleep-wake cycle or a disrupted circadian rhythm can change the regularity of the menstrual cycle. In this study, we investigated whether an irregular menstrual cycle is associated with polymorphisms in the CLOCK (3111T > C) and/or PER3 (variable number tandem repeat, VNTR) genes, which are known to have an impact on the circadian rhythm. One hundred ninety-seven postmenarchal, adolescent girls from two girls' high schools in Seoul, Korea, were studied. All participants were requested to complete the Perceived Stress Scale (PSS), the State-Trait Anxiety Inventory (STAI), and the Beck Depression Inventory (BDI) to assess the emotional distress that might cause menstrual irregularity. Every participant donated a blood sample from which DNA was extracted and genotyped for the CLOCK 3111T > C and PER3 VNTR polymorphisms. A significant association was found between the CLOCK 3111T > C genotype and irregular menstrual cycles. Subjects with the 3111T > C genotype had a high risk of an irregular menstrual cycle compared with 3111T/T homozygous subjects (odds ratio [OR] = 2.88; 95% confidence interval [CI]: 1.26-6.55). When multivariate logistic regression analysis was performed to adjust for age, PSS, STAI, BDI and BMI, subjects with the 3111T > C polymorphism showed a significantly increased OR for irregular menstrual cycles (OR = 3.09; 95% CI: 1.32-7.21). There was no significant association between the PER3 VNTR polymorphism and the irregularity of the menstrual cycle (p > 0.05). The results of this study suggest that the CLOCK 3111T > C polymorphism could be an independent risk factor for irregular menstrual cycles, irrespective of psychological distress and endocrine or metabolic conditions, and could be used as a molecular marker for gynecological studies on this aspect.

Mutagen Sensitivity, Apoptosis, and Polymorphism in DNA Repair as Measures of Prostate Cancer Risk

DTIC Science & Technology

2006-02-01

replacement, energy, or high-protein beverages such as Instant Breakfast, Ensure, Slimfast, Sustacal or others? NEVER (GO TO QUESTION 7) 1 time per...other noodles ? NEVER (GO TO QUESTION 61) 1–6 times per year 2 times per week 7–11 times per year 3–4 times per week 1 time per month 5...other noodles , how much did you usually eat? Less than 1 cup 1 to 3 cups More than 3 cups 60b. How often did you eat your pasta, spaghetti

Common breast cancer susceptibility alleles and the risk of breast cancer for BRCA1 and BRCA2 mutation carriers: implications for risk prediction

PubMed Central

Antoniou, Antonis C; Beesley, Jonathan; McGuffog, Lesley; Sinilnikova, Olga M.; Healey, Sue; Neuhausen, Susan L.; Ding, Yuan Chun; Rebbeck, Timothy R.; Weitzel, Jeffrey N.; Lynch, Henry T.; Isaacs, Claudine; Ganz, Patricia A.; Tomlinson, Gail; Olopade, Olufunmilayo I.; Couch, Fergus J.; Wang, Xianshu; Lindor, Noralane M.; Pankratz, Vernon S.; Radice, Paolo; Manoukian, Siranoush; Peissel, Bernard; Zaffaroni, Daniela; Barile, Monica; Viel, Alessandra; Allavena, Anna; Dall’Olio, Valentina; Peterlongo, Paolo; Szabo, Csilla I.; Zikan, Michal; Claes, Kathleen; Poppe, Bruce; Foretova, Lenka; Mai, Phuong L.; Greene, Mark H.; Rennert, Gad; Lejbkowicz, Flavio; Glendon, Gord; Ozcelik, Hilmi; Andrulis, Irene L.; Thomassen, Mads; Gerdes, Anne-Marie; Sunde, Lone; Cruger, Dorthe; Jensen, Uffe Birk; Caligo, Maria; Friedman, Eitan; Kaufman, Bella; Laitman, Yael; Milgrom, Roni; Dubrovsky, Maya; Cohen, Shimrit; Borg, Ake; Jernström, Helena; Lindblom, Annika; Rantala, Johanna; Stenmark-Askmalm, Marie; Melin, Beatrice; Nathanson, Kate; Domchek, Susan; Jakubowska, Ania; Lubinski, Jan; Huzarski, Tomasz; Osorio, Ana; Lasa, Adriana; Durán, Mercedes; Tejada, Maria-Isabel; Godino, Javier; Benitez, Javier; Hamann, Ute; Kriege, Mieke; Hoogerbrugge, Nicoline; van der Luijt, Rob B; van Asperen, Christi J; Devilee, Peter; Meijers-Heijboer, E.J.; Blok, Marinus J; Aalfs, Cora M.; Hogervorst, Frans; Rookus, Matti; Cook, Margaret; Oliver, Clare; Frost, Debra; Conroy, Don; Evans, D. Gareth; Lalloo, Fiona; Pichert, Gabriella; Davidson, Rosemarie; Cole, Trevor; Cook, Jackie; Paterson, Joan; Hodgson, Shirley; Morrison, Patrick J.; Porteous, Mary E.; Walker, Lisa; Kennedy, M. John; Dorkins, Huw; Peock, Susan; Godwin, Andrew K.; Stoppa-Lyonnet, Dominique; de Pauw, Antoine; Mazoyer, Sylvie; Bonadona, Valérie; Lasset, Christine; Dreyfus, Hélène; Leroux, Dominique; Hardouin, Agnès; Berthet, Pascaline; Faivre, Laurence; Loustalot, Catherine; Noguchi, Tetsuro; Sobol, Hagay; Rouleau, Etienne; Nogues, Catherine; Frénay, Marc; Vénat-Bouvet, Laurence; Hopper, John L.; Daly, Mary B.; Terry, Mary B.; John, Esther M.; Buys, Saundra S.; Yassin, Yosuf; Miron, Alex; Goldgar, David; Singer, Christian F.; Dressler, Anne Catharina; Gschwantler-Kaulich, Daphne; Pfeiler, Georg; Hansen, Thomas V. O.; Jønson, Lars; Agnarsson, Bjarni A.; Kirchhoff, Tomas; Offit, Kenneth; Devlin, Vincent; Dutra-Clarke, Ana; Piedmonte, Marion; Rodriguez, Gustavo C.; Wakeley, Katie; Boggess, John F.; Basil, Jack; Schwartz, Peter E.; Blank, Stephanie V.; Toland, Amanda Ewart; Montagna, Marco; Casella, Cinzia; Imyanitov, Evgeny; Tihomirova, Laima; Blanco, Ignacio; Lazaro, Conxi; Ramus, Susan J.; Sucheston, Lara; Karlan, Beth Y.; Gross, Jenny; Schmutzler, Rita; Wappenschmidt, Barbara; Engel, Christoph; Meindl, Alfons; Lochmann, Magdalena; Arnold, Norbert; Heidemann, Simone; Varon-Mateeva, Raymonda; Niederacher, Dieter; Sutter, Christian; Deissler, Helmut; Gadzicki, Dorothea; Preisler-Adams, Sabine; Kast, Karin; Schönbuchner, Ines; Caldes, Trinidad; de la Hoya, Miguel; Aittomäki, Kristiina; Nevanlinna, Heli; Simard, Jacques; Spurdle, Amanda B.; Holland, Helene; Chen, Xiaoqing; Platte, Radka; Chenevix-Trench, Georgia; Easton, Douglas F.

2010-01-01

The known breast cancer (BC) susceptibility polymorphisms in FGFR2, TNRC9/TOX3, MAP3K1,LSP1 and 2q35 confer increased risks of BC for BRCA1 or BRCA2 mutation carriers. We evaluated the associations of three additional SNPs, rs4973768 in SLC4A7/NEK10, rs6504950 in STXBP4/COX11 and rs10941679 at 5p12 and reanalyzed the previous associations using additional carriers in a sample of 12,525 BRCA1 and 7,409 BRCA2 carriers. Additionally, we investigated potential interactions between SNPs and assessed the implications for risk prediction. The minor alleles of rs4973768 and rs10941679 were associated with increased BC risk for BRCA2 carriers (per-allele Hazard Ratio (HR)=1.10, 95%CI:1.03-1.18, p=0.006 and HR=1.09, 95%CI:1.01-1.19, p=0.03, respectively). Neither SNP was associated with BC risk for BRCA1 carriers and rs6504950 was not associated with BC for either BRCA1 or BRCA2 carriers. Of the nine polymorphisms investigated, seven were associated with BC for BRCA2 carriers (FGFR2, TOX3, MAP3K1, LSP1, 2q35, SLC4A7, 5p12, p-values:7×10−11-0.03), but only TOX3 and 2q35 were associated with the risk for BRCA1 carriers (p=0.0049, 0.03 respectively). All risk associated polymorphisms appear to interact multiplicatively on BC risk for mutation carriers. Based on the joint genotype distribution of the seven risk associated SNPs in BRCA2 mutation carriers, the 5% of BRCA2 carriers at highest risk (i.e. between 95th and 100th percentiles) were predicted to have a probability between 80% and 96% of developing BC by age 80, compared with 42-50% for the 5% of carriers at lowest risk. Our findings indicated that these risk differences may be sufficient to influence the clinical management of mutation carriers. PMID:21118973

DPYD*2A and MTHFR C677T predict toxicity and efficacy, respectively, in patients on chemotherapy with 5-fluorouracil for colorectal cancer.

PubMed

Nahid, Noor Ahmed; Apu, Mohd Nazmul Hasan; Islam, Md Reazul; Shabnaz, Samia; Chowdhury, Surid Mohammad; Ahmed, Maizbha Uddin; Nahar, Zabun; Islam, Md Siddiqul; Islam, Mohammad Safiqul; Hasnat, Abul

2018-01-01

Significant inter-individual variation in the sensitivity to 5-fluorouracil (5-FU) represents a major therapeutic hindrance either by impairing drug response or inducing adverse drug reactions (ADRs). This study aimed at exploring the cause behind this inter-individual alterations in consequences of 5-fluorouracil-based chemotherapy by investigating the effects of DPYD*2A and MTHFR C677T polymorphisms on toxicity and response of 5-FU in Bangladeshi colorectal cancer patients. Colorectal cancer patients (n = 161) receiving 5-FU-based chemotherapy were prospectively enrolled. DPYD and MTHFR polymorphisms were assessed in peripheral leukocytes. Multivariate analyses were applied to evaluate which variables could predict chemotherapy-induced toxicity and efficacy. Multivariate analyses showed that DPYD*2A polymorphism was a predictive factor (P = 0.023) for grade 3 and grade 4 5-fluorouracil-related toxicities. Although MTHFR C677T polymorphism might act as forecasters for grade 3 or grade 4 neutropenia, diarrhea, and mucositis, this polymorphism was found to increase significantly (P = 0.006) the response of 5-FU. DPYD*2A and MTHFR C677T polymorphisms could explain 5-FU toxicity or clinical outcome in Bangladeshi colorectal patients.

Evolutionary conservation analysis increases the colocalization of predicted exonic splicing enhancers in the BRCA1 gene with missense sequence changes and in-frame deletions, but not polymorphisms

PubMed Central

Pettigrew, Christopher; Wayte, Nicola; Lovelock, Paul K; Tavtigian, Sean V; Chenevix-Trench, Georgia; Spurdle, Amanda B; Brown, Melissa A

2005-01-01

Introduction Aberrant pre-mRNA splicing can be more detrimental to the function of a gene than changes in the length or nature of the encoded amino acid sequence. Although predicting the effects of changes in consensus 5' and 3' splice sites near intron:exon boundaries is relatively straightforward, predicting the possible effects of changes in exonic splicing enhancers (ESEs) remains a challenge. Methods As an initial step toward determining which ESEs predicted by the web-based tool ESEfinder in the breast cancer susceptibility gene BRCA1 are likely to be functional, we have determined their evolutionary conservation and compared their location with known BRCA1 sequence variants. Results Using the default settings of ESEfinder, we initially detected 669 potential ESEs in the coding region of the BRCA1 gene. Increasing the threshold score reduced the total number to 464, while taking into consideration the proximity to splice donor and acceptor sites reduced the number to 211. Approximately 11% of these ESEs (23/211) either are identical at the nucleotide level in human, primates, mouse, cow, dog and opossum Brca1 (conserved) or are detectable by ESEfinder in the same position in the Brca1 sequence (shared). The frequency of conserved and shared predicted ESEs between human and mouse is higher in BRCA1 exons (2.8 per 100 nucleotides) than in introns (0.6 per 100 nucleotides). Of conserved or shared putative ESEs, 61% (14/23) were predicted to be affected by sequence variants reported in the Breast Cancer Information Core database. Applying the filters described above increased the colocalization of predicted ESEs with missense changes, in-frame deletions and unclassified variants predicted to be deleterious to protein function, whereas they decreased the colocalization with known polymorphisms or unclassified variants predicted to be neutral. Conclusion In this report we show that evolutionary conservation analysis may be used to improve the specificity of an ESE prediction tool. This is the first report on the prediction of the frequency and distribution of ESEs in the BRCA1 gene, and it is the first reported attempt to predict which ESEs are most likely to be functional and therefore which sequence variants in ESEs are most likely to be pathogenic. PMID:16280041

Polymorphisms in arsenic(+III oxidation state) methyltransferase (AS3MT) predict gene expression of AS3MT as well as arsenic metabolism.

PubMed

Engström, Karin; Vahter, Marie; Mlakar, Simona Jurkovic; Concha, Gabriela; Nermell, Barbro; Raqib, Rubhana; Cardozo, Alejandro; Broberg, Karin

2011-02-01

Arsenic (As) occurs as monomethylarsonic acid (MMA) and dimethylarsinic acid (DMA) in humans, and the methylation pattern demonstrates large interindividual differences. The fraction of urinary MMA is a marker for susceptibility to As-related diseases. We evaluated the impact of polymorphisms in five methyltransferase genes on As metabolism in two populations, one in South America and one in Southeast Asia. The methyltransferase genes were arsenic(+III oxidation state) methyltransferase (AS3MT), DNA-methyltransferase 1a and 3b (DNMT1a and DNMT3b, respectively), phosphatidylethanolamine N-methyltransferase (PEMT), and betaine-homocysteine methyltransferase (BHMT). AS3MT expression was analyzed in peripheral blood. Subjects were women exposed to As in drinking water in the Argentinean Andes [n = 172; median total urinary As (U-As), 200 µg/L] and in rural Bangladesh (n = 361; U-As, 100 µg/L; all in early pregnancy). Urinary As metabolites were measured by high-pressure liquid chromatography/inductively coupled plasma mass spectrometry. Polymorphisms (n = 22) were genotyped with Sequenom, and AS3MT expression was measured by quantitative real-time polymerase chain reaction using TaqMan expression assays. Six AS3MT polymorphisms were significantly associated with As metabolite patterns in both populations (p ≤ 0.01). The most frequent AS3MT haplotype in Bangladesh was associated with a higher percentage of MMA (%MMA), and the most frequent haplotype in Argentina was associated with a lower %MMA and a higher percentage of DMA. Four polymorphisms in the DNMT genes were associated with metabolite patterns in Bangladesh. Noncoding AS3MT polymorphisms affected gene expression of AS3MT in peripheral blood, demonstrating that one functional impact of AS3MT polymorphisms may be altered levels of gene expression. Polymorphisms in AS3MT significantly predicted As metabolism across these two very different populations, suggesting that AS3MT may have an impact on As metabolite patterns in populations worldwide.

Age at cancer onset in germline TP53 mutation carriers: association with polymorphisms in predicted G-quadruplex structures

PubMed Central

Hainaut, Pierre

2014-01-01

Germline TP53 mutations predispose to multiple cancers defining Li-Fraumeni/Li-Fraumeni-like syndrome (LFS/LFL), a disease with large individual disparities in cancer profiles and age of onset. G-quadruplexes (G4s) are secondary structural motifs occurring in guanine tracks, with regulatory effects on DNA and RNA. We analyzed 85 polymorphisms within or near five predicted G4s in TP53 in search of modifiers of penetrance of LFS/LFL in Brazilian cancer families with (n = 35) or without (n = 110) TP53 mutations. Statistical analyses stratified on family structure showed that cancer tended to occur ~15 years later in mutation carriers who also carried the variant alleles of two polymorphisms within predicted G4-forming regions, rs17878362 (TP53 PIN3, 16 bp duplication in intron 3; P = 0.082) and rs17880560 (6 bp duplication in 3′ flanking region; P = 0.067). Haplotype analysis showed that this inverse association was driven by the polymorphic status of the remaining wild-type (WT) haplotype in mutation carriers: in carriers with a WT haplotype containing at least one variant allele of rs17878362 or rs17880560, cancer occurred ~15 years later than in carriers with other WT haplotypes (P = 0.019). No effect on age of cancer onset was observed in subjects without a TP53 mutation. The G4 in intron 3 has been shown to regulate alternative p53 messenger RNA splicing, whereas the biological roles of predicted G4s in the 3′ flanking region remain to be elucidated. In conclusion, this study demonstrates that G4 polymorphisms in haplotypes of the WT TP53 allele have an impact on LFS/LFL penetrance in germline TP53 mutation carriers. PMID:24336192

Computed crystal energy landscapes for understanding and predicting organic crystal structures and polymorphism.

PubMed

Price, Sarah Sally L

2009-01-20

The phenomenon of polymorphism, the ability of a molecule to adopt more than one crystal structure, is a well-established property of crystalline solids. The possible variations in physical properties between polymorphs make the reliable reproduction of a crystalline form essential for all research using organic materials, as well as quality control in manufacture. Thus, the last two decades have seen both an increase in interest in polymorphism and the availability of the computer power needed to make the computational prediction of organic crystal structures a practical possibility. In the past decade, researchers have made considerable improvements in the theoretical basis for calculating the sets of structures that are within the energy range of possible polymorphism, called crystal energy landscapes. It is common to find that a molecule has a wide variety of ways of packing with lattice energy within a few kilojoules per mole of the most stable structure. However, as we develop methods to search for and characterize "all" solid forms, it is also now usual for polymorphs and solvates to be found. Thus, the computed crystal energy landscape reflects and to an increasing extent "predicts" the emerging complexity of the solid state observed for many organic molecules. This Account will discuss the ways in which the calculation of the crystal energy landscape of a molecule can be used as a complementary technique to solid form screening for polymorphs. Current methods can predict the known crystal structure, even under "blind test" conditions, but such successes are generally restricted to those structures that are the most stable over a wide range of thermodynamic conditions. The other low-energy structures can be alternative polymorphs, which have sometimes been found in later experimental studies. Examining the computed structures reveals the various compromises between close packing, hydrogen bonding, and pi-pi stacking that can result in energetically feasible structures. Indeed, we have observed that systems with many almost equi-energetic structures that contain a common interchangeable motif correlate with a tendency to disorder and problems with control of the crystallization product. Thus, contrasting the computed crystal energy landscape with the known crystal structures of a given molecule provides a valuable complement to solid form screening, and the examination of the low-energy structures often leads to a rationalization of the forms found.

Epistatic interaction between FCRL3 and NFκB1 genes in Spanish patients with rheumatoid arthritis

PubMed Central

Martínez, A; Sánchez, E; Valdivia, A; Orozco, G; López‐Nevot, M A; Pascual‐Salcedo, D; Balsa, A; Fernández‐Gutiérrez, B; de la Concha, E G; García‐Sánchez, A; Koeleman, B P C; Urcelay, E; Martín, J

2006-01-01

Background A Japanese study has described a strong association between rheumatoid arthritis and several polymorphisms located in the Fc receptor‐like 3 (FCRL3) gene, a member of a family of genes related to Fc receptors located on chromosome 1q21–23. Objectives To evaluate the association between rheumatoid arthritis and FCLR3 polymorphisms in a large cohort of Caucasian patients with rheumatoid arthritis and healthy controls of Spanish origin. Owing to the described functional link between the FCRL3 polymorphisms and the transcription factor nuclear factor κB (NFκB), a functional polymorphism located in the NFκB1 gene was included. Methods 734 patients with rheumatoid arthritis from Madrid and Granada, Spain, were included in the study, along with 736 healthy controls. Polymorphisms in the FCRL3 gene were studied by TaqMan technology. The −94ins/delATTG NFκB1 promoter polymorphism was analysed by fragment analysis after polymerase chain reaction with labelled primers. Genotypes were compared using 3×2 contingency tables and χ2 values. Results No overall differences were found in any of the FCRL3 polymorphisms and in the NFκB1 promoter polymorphism when patients were compared with controls. However, when stratified according to NFκB1 genotypes, a susceptibility effect of FCRL3 polymorphisms was observed in patients who were heterozygotes for NFκB1 (pc = 0.003). Conclusions The FCRL3 polymorphisms associated with rheumatoid arthritis in a Japanese population are not associated per se with rheumatoid arthritis in a Spanish population. A genetic interaction was found between NFκB1 and FCRL3 in Spanish patients with rheumatoid arthritis. These findings may provide a general rationale for divergent genetic association results in different populations. PMID:16476711

Prevalence of combinatorial CYP2C9 and VKORC1 genotypes in Puerto Ricans: implications for warfarin management in Hispanics.

PubMed

Duconge, Jorge; Cadilla, Carmen L; Windemuth, Andreas; Kocherla, Mohan; Gorowski, Krystyna; Seip, Richard L; Bogaard, Kali; Renta, Jessica Y; Piovanetti, Paola; D'Agostino, Darrin; Santiago-Borrero, Pedro J; Ruaño, Gualberto

2009-01-01

Polymorphisms in the cytochrome P450 2C9 (CYP2C9) and vitamin K epoxide reductase complex subunit 1 (VKORC1) genes significantly alter the effective warfarin dose. We determined the frequencies of alleles, single carriers, and double carriers of single nucleotide polymorphisms (SNPs) in the CYP2C9 and VKORC1 genes in a Puerto Rican cohort and gauged the impact of these polymorphisms on warfarin dosage using a published algorithm. A total of 92 DNA samples were genotyped using Luminex x-MAP technology. The polymorphism frequencies were 6.52%, 5.43% and 28.8% for CYP2C9 *2, *3 and VKORC1-1639 C>A polymorphisms, respectively. The prevalence of combinatorial genotypes was 16% for carriers of both the CYP2C9 and VKORC1 polymorphisms, 9% for carriers of CYP2C9 polymorphisms, 35% for carriers of the VKORC1 polymorphism, and the remaining 40% were non-carriers for either gene. Based on a published warfarin dosing algorithm, single, double and triple carriers of functionally deficient polymorphisms predict reductions of 1.0-1.6, 2.0-2.9, and 2.9-3.7 mg/day, respectively, in warfarin dose. Overall, 60% of the population carried at least a single polymorphism predicting deficient warfarin metabolism or responsiveness and 13% were double carriers with polymorphisms in both genes studied. Combinatorial genotyping of CYP2C9 and VKORC1 can allow for individualized dosing of warfarin among patients with gene polymorphisms, potentially reducing the risk of stroke or bleeding.

A cross-sectional study on the relationships among the polymorphism of period2 gene, work stress, and insomnia.

PubMed

Li, Ju; Huang, Chan; Lan, Yajia; Wang, Yongwei

2015-12-01

Work-related stress factors are commonly considered to be increasing the risk of insomnia. But the association between circadian-rhythm gene period2 (per2) and insomnia remains unknown. The paper aimed to examine the relationships among the polymorphism in rs7602358 of Per2 gene, work stress, and insomnia. In the cross-sectional study of a total of 364 Chinese workers recruited, 218 had insomnia tested by the Athens Insomnia Scale (AIS-5). Work stress was assessed using the General Job Stress Questionnaire (GJSQ). Per2 genotypes were determined by SNaPshot technology. Unconditional logistic regression analysis was used to examine the interaction between polymorphism of Per2 and work stress in insomnia. The genotype AC or allele C of Per2 significantly increased the risk of insomnia (OR, 5.41; 95 % CI, 2.23-13.1) (OR, 3.29; 95 % CI, 1.55-6.98). Compared to low work stress, high work stress had a higher risk of insomnia (OR, 2.73; 95 % CI, 1.77-4.22). A significant interaction between Per2 and work stress in the risk of insomnia was found. Compared to workers with low work stress and genotype AA, those with high work stress and genotype AC had a higher risk of insomnia (OR, 15.12; 95 % CI, 3.46-66.09). The effect of genotype AC or allele C of Per2 on insomnia was relatively stronger than that of high work stress, suggesting that individual's susceptibility should be taken into consideration when intervening and controlling insomnia of workers.

Genetic polymorphisms in 5-Fluorouracil-related enzymes predict pathologic response after neoadjuvant chemoradiation for rectal cancer.

PubMed

Nelson, Bailey; Carter, Jane V; Eichenberger, Maurice R; Netz, Uri; Galandiuk, Susan

2016-11-01

Many patients with rectal cancer undergo preoperative neoadjuvant chemoradiation, with approximately 70% exhibiting pathologic downstaging in response to treatment. Currently, there is no accurate test to predict patients who are likely to be complete responders to therapy. 5-Fluorouracil is used regularly in the neoadjuvant treatment of rectal cancer. Genetic polymorphisms affect the activity of thymidylate synthase, an enzyme involved in 5-Fluorouracil metabolism, which may account for observed differences in response to neoadjuvant treatment between patients. Detection of genetic polymorphisms might identify patients who are likely to have a complete response to neoadjuvant therapy and perhaps allow them to avoid operation. DNA was isolated from whole blood taken from patients with newly diagnosed rectal cancer who received neoadjuvant therapy (n = 50). Response to therapy was calculated with a tumor regression score based on histology from the time of operation. Polymerase chain reaction was performed targeting the promoter region of thymidylate synthase. Polymerase chain reaction products were separated using electrophoresis to determine whether patients were homozygous for a double-tandem repeat (2R), a triple-tandem repeat (3R), or were heterozygous (2R/3R). A single nucleotide polymorphism, 3G or 3C, also may be present in the second repeat unit of the triple-tandem repeat allele. Restriction fragment length polymorphism assays were performed in patients with at least one 3R allele using HaeIII. Patients with at least 1 thymidylate synthase 3G allele were more likely to have a complete or partial pathologic response to 5-Fluorouracil neoadjuvant therapy (odds ratio 10.4; 95% confidence interval, 1.3-81.6; P = .01) than those without at least one 3G allele. Identification of rectal cancer patients with specific genetic polymorphisms in enzymes involved in 5-Fluorouracil metabolism seems to predict the likelihood of complete or partial pathologic response to preoperative neoadjuvant therapy. Copyright © 2016 Elsevier Inc. All rights reserved.

Regionally clustered ABCC8 polymorphisms in a prospective cohort predict cerebral oedema and outcome in severe traumatic brain injury.

PubMed

Jha, Ruchira Menka; Koleck, Theresa A; Puccio, Ava M; Okonkwo, David O; Park, Seo-Young; Zusman, Benjamin E; Clark, Robert S B; Shutter, Lori A; Wallisch, Jessica S; Empey, Philip E; Kochanek, Patrick M; Conley, Yvette P

2018-04-19

ABCC8 encodes sulfonylurea receptor 1, a key regulatory protein of cerebral oedema in many neurological disorders including traumatic brain injury (TBI). Sulfonylurea-receptor-1 inhibition has been promising in ameliorating cerebral oedema in clinical trials. We evaluated whether ABCC8 tag single-nucleotide polymorphisms predicted oedema and outcome in TBI. DNA was extracted from 485 prospectively enrolled patients with severe TBI. 410 were analysed after quality control. ABCC8 tag single-nucleotide polymorphisms (SNPs) were identified (Hapmap, r 2 >0.8, minor-allele frequency >0.20) and sequenced (iPlex-Gold, MassArray). Outcomes included radiographic oedema, intracranial pressure (ICP) and 3-month Glasgow Outcome Scale (GOS) score. Proxy SNPs, spatial modelling, amino acid topology and functional predictions were determined using established software programs. Wild-type rs7105832 and rs2237982 alleles and genotypes were associated with lower average ICP (β=-2.91, p=0.001; β=-2.28, p=0.003) and decreased radiographic oedema (OR 0.42, p=0.012; OR 0.52, p=0.017). Wild-type rs2237982 also increased favourable 3-month GOS (OR 2.45, p=0.006); this was partially mediated by oedema (p=0.03). Different polymorphisms predicted 3-month outcome: variant rs11024286 increased (OR 1.84, p=0.006) and wild-type rs4148622 decreased (OR 0.40, p=0.01) the odds of favourable outcome. Significant tag and concordant proxy SNPs regionally span introns/exons 2-15 of the 39-exon gene. This study identifies four ABCC8 tag SNPs associated with cerebral oedema and/or outcome in TBI, tagging a region including 33 polymorphisms. In polymorphisms predictive of oedema, variant alleles/genotypes confer increased risk. Different variant polymorphisms were associated with favourable outcome, potentially suggesting distinct mechanisms. Significant polymorphisms spatially clustered flanking exons encoding the sulfonylurea receptor site and transmembrane domain 0/loop 0 (juxtaposing the channel pore/binding site). This, if validated, may help build a foundation for developing future strategies that may guide individualised care, treatment response, prognosis and patient selection for clinical trials. © Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2018. All rights reserved. No commercial use is permitted unless otherwise expressly granted.

Can sudden cardiac death in the young be predicted and prevented? Lessons from autopsy for the emergency physician.

PubMed

White, Jennifer L; Chang, Anna Marie; Cesar, Sergi; Sarquella-Brugada, Georgia

2018-06-01

Sudden unexpected death in the young, though rare, is devastating for both the family and the community. Although only 1.3 to 8.5 cases of sudden cardiac death (SCD) occur per 100 000 young people, autopsy is often inconclusive. Many causes of SCD are related to autosomal dominant inherited risk, however; therefore, answers are important for survivors. Causes of autopsy-positive SCD in young patients include hypertrophic cardiomyopathy and arrhythmogenic right ventricular dysplasia. Autopsy-negative SCD has been related to inherited arrhythmogenic causes such as long QT syndrome, Brugada syndrome, catecholaminergic polymorphic ventricular tachycardia, Wolff- Parkinson-White syndrome, and idiopathic ventricular fibrillation. The important question for the emergency physician is how SCD can be predicted and prevented in the young so that there is no need for an autopsy.

First principles study of pressure induced polymorphic phase transition in KNO3

NASA Astrophysics Data System (ADS)

Yedukondalu, N.; Vaitheeswaran, G.

2015-06-01

We report the structural, elastic, electronic, and vibrational properties of polymorphic phases II and III of KNO3 based on density functional theory (DFT). Using semi-empirical dispersion correction (DFT-D2) method, we predicted the correct thermodynamic ground state of KNO3 and the obtained ground state properties of the polymorphs are in good agreement with the experiments. We further used this method to calculate the elastic constants, IR and Raman spectra, vibrational frequencies and their assignment of these polymorphs. The calculated Tran Blaha-modified Becke Johnson (TB-mBJ) electronic structure shows that both the polymorphic phases are direct band gap insulators with mixed ionic and covalent bonding. Also the TB-mBJ band gaps are improved over standard DFT functionals which are comparable with the available experiments.

PREVALENCE OF COMBINATORIAL CYP2C9 AND VKORC1 GENOTYPES IN PUERTO RICANS: IMPLICATIONS FOR WARFARIN MANAGEMENT IN HISPANICS

PubMed Central

Duconge, Jorge; Cadilla, Carmen L.; Windemuth, Andreas; Kocherla, Mohan; Gorowski, Krystyna; Seip, Richard L.; Bogaard, Kali; Renta, Jessica Y.; Piovanetti, Paola; D’Agostino, Darrin; Santiago-Borrero, Pedro J.; Ruaño, Gualberto

2010-01-01

Polymorphisms in the cytochrome P450 2C9 (CYP2C9) and vitamin K epoxide reductase complex subunit 1 (VKORC1) genes significantly alter the effective warfarin dose. We determined the frequencies of alleles, single carriers, and double carriers of single nucleotide polymorphisms (SNPs) in the CYP2C9 and VKORC1 genes in a Puerto Rican cohort and gauged the impact of these polymorphisms on warfarin dosage using a published algorithm. A total of 92 DNA samples were genotyped using Luminex® x-MAP technology. The polymorphism frequencies were 6.52%, 5.43% and 28.8% for CYP2C9 *2, *3 and VKORC1-1639 G>A polymorphisms, respectively. The prevalence of combinatorial genotypes was 16% for carriers of both the CYP2C9 and VKORC1 polymorphisms, 9% for carriers of CYP2C9 polymorphisms, 35% for carriers of the VKORC1 polymorphism, and the remaining 40% were non-carriers for either gene. Based on a published warfarin dosing algorithm, single, double and triple carriers of functionally deficient polymorphisms predict reductions of 1.0–1.6, 2.0–2.9, and 2.9–3.7 mg/day, respectively, in warfarin dose. Overall, 60% of the population carried at least a single polymorphism predicting deficient warfarin metabolism or responsiveness and 13% were double carriers with polymorphisms in both genes studied. Combinatorial genotyping of CYP2C9 and VKORC1 can allow for individualized dosing of warfarin among patients with gene polymorphisms, potentially reducing the risk of stroke or bleeding. PMID:20073138

Case-Control Study of Breast Cancer in India: Role of PERIOD3 Clock Gene Length Polymorphism and Chronotype

PubMed Central

Wirth, Michael D.; Burch, James B.; Hébert, James R.; Kowtal, Pradnya; Kapoor, Aparna; Steck, Susan E.; Hurley, Thomas G.; Gupta, Prakash C.; Pednekar, Mangesh S.; Youngstedt, Shawn D.; Zhang, Hongmei; Sarin, Rajiv

2014-01-01

Background This study examined a PERIOD3 (PER3) gene variable number tandem repeat polymorphism and chronotype as potential BrCA risk factors among Indian women. Methods This case-control study included sporadic, histologically confirmed BrCA cases (n=255) and controls (n=249) from India with data collection from 2010–2012. Results Women with the 4/5 or 5/5 PER3 genotype had a non-statistically significant 33% increased odds of BrCA. BrCA cases were more likely to have a morning (OR=2.43, 95% CI=1.23–4.81) or evening (OR=2.55, 95% CI=1.19–5.47) chronotype. Conclusions Findings are consistent with the possibility that extremes in chronotype may elicit circadian desynchronization, resulting in adverse health outcomes. PMID:24903750

Polymorphisms in Arsenic(+III Oxidation State) Methyltransferase (AS3MT) Predict Gene Expression of AS3MT as Well as Arsenic Metabolism

PubMed Central

Engström, Karin; Vahter, Marie; Mlakar, Simona Jurkovic; Concha, Gabriela; Nermell, Barbro; Raqib, Rubhana; Cardozo, Alejandro; Broberg, Karin

2011-01-01

Background Arsenic (As) occurs as monomethylarsonic acid (MMA) and dimethylarsinic acid (DMA) in humans, and the methylation pattern demonstrates large interindividual differences. The fraction of urinary MMA is a marker for susceptibility to As-related diseases. Objectives We evaluated the impact of polymorphisms in five methyltransferase genes on As metabolism in two populations, one in South America and one in Southeast Asia. The methyltransferase genes were arsenic(+III oxidation state) methyltransferase (AS3MT), DNA-methyltransferase 1a and 3b (DNMT1a and DNMT3b, respectively), phosphatidylethanolamine N-methyltransferase (PEMT), and betaine-homocysteine methyltransferase (BHMT). AS3MT expression was analyzed in peripheral blood. Methods Subjects were women exposed to As in drinking water in the Argentinean Andes [n = 172; median total urinary As (U-As), 200 μg/L] and in rural Bangladesh (n = 361; U-As, 100 μg/L; all in early pregnancy). Urinary As metabolites were measured by high-pressure liquid chromatography/inductively coupled plasma mass spectrometry. Polymorphisms (n = 22) were genotyped with Sequenom, and AS3MT expression was measured by quantitative real-time polymerase chain reaction using TaqMan expression assays. Results Six AS3MT polymorphisms were significantly associated with As metabolite patterns in both populations (p ≤ 0.01). The most frequent AS3MT haplotype in Bangladesh was associated with a higher percentage of MMA (%MMA), and the most frequent haplotype in Argentina was associated with a lower %MMA and a higher percentage of DMA. Four polymorphisms in the DNMT genes were associated with metabolite patterns in Bangladesh. Noncoding AS3MT polymorphisms affected gene expression of AS3MT in peripheral blood, demonstrating that one functional impact of AS3MT polymorphisms may be altered levels of gene expression. Conclusions Polymorphisms in AS3MT significantly predicted As metabolism across these two very different populations, suggesting that AS3MT may have an impact on As metabolite patterns in populations worldwide. PMID:21247820

Theory-Guided Synthesis of a Metastable Lead-Free Piezoelectric Polymorph

DOE Office of Scientific and Technical Information (OSTI.GOV)

Garten, Lauren M; Ndione, Paul F; Beaton, Daniel A

Many technologically critical materials are metastable under ambient conditions, yet the understanding of how to rationally design and guide the synthesis of these materials is limited. This work presents an integrated approach that targets a metastable lead-free piezoelectric polymorph of SrHfO3. First-principles calculations predict that the previous experimentally unrealized, metastable P4mm phase of SrHfO3 should exhibit a direct piezoelectric response (d33) of 36.9 pC N-1 (compared to d33 = 0 for the ground state). Combining computationally optimized substrate selection and synthesis conditions lead to the epitaxial stabilization of the polar P4mm phase of SrHfO3 on SrTiO3. The films are structurallymore » consistent with the theory predictions. A ferroelectric-induced large signal effective converse piezoelectric response of 5.2 pm V-1 for a 35 nm film is observed, indicating the ability to predict and target multifunctionality. This illustrates a coupled theory-experimental approach to the discovery and realization of new multifunctional polymorphs.« less

Theory-Guided Synthesis of a Metastable Lead-Free Piezoelectric Polymorph.

PubMed

Garten, Lauren M; Dwaraknath, Shyam; Walker, Julian; Mangum, John S; Ndione, Paul F; Park, Yoonsang; Beaton, Daniel A; Gopalan, Venkatraman; Gorman, Brian P; Schelhas, Laura T; Toney, Michael F; Trolier-McKinstry, Susan; Persson, Kristin A; Ginley, David S

2018-05-10

Many technologically critical materials are metastable under ambient conditions, yet the understanding of how to rationally design and guide the synthesis of these materials is limited. This work presents an integrated approach that targets a metastable lead-free piezoelectric polymorph of SrHfO 3 . First-principles calculations predict that the previous experimentally unrealized, metastable P4mm phase of SrHfO 3 should exhibit a direct piezoelectric response (d 33 ) of 36.9 pC N -1 (compared to d 33 = 0 for the ground state). Combining computationally optimized substrate selection and synthesis conditions lead to the epitaxial stabilization of the polar P4mm phase of SrHfO 3 on SrTiO 3 . The films are structurally consistent with the theory predictions. A ferroelectric-induced large signal effective converse piezoelectric response of 5.2 pm V -1 for a 35 nm film is observed, indicating the ability to predict and target multifunctionality. This illustrates a coupled theory-experimental approach to the discovery and realization of new multifunctional polymorphs. © 2018 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Myxovirus resistance, osteopontin and suppressor of cytokine signaling 3 polymorphisms predict hepatitis C virus therapy response in an admixed patient population: comparison with IL28B.

PubMed

Angelo, Ana Luiza Dias; Cavalcante, Lourianne Nascimento; Abe-Sandes, Kiyoko; Machado, Taísa Bonfim; Lemaire, Denise Carneiro; Malta, Fernanda; Pinho, João Renato; Lyra, Luiz Guilherme Costa; Lyra, Andre Castro

2013-10-01

Suppressor of cytokine signaling 3, myxovirus resistance protein and osteopontin gene polymorphisms may influence the therapeutic response in patients with chronic hepatitis C, and an association with IL28 might increase the power to predict sustained virologic response. Our aims were to evaluate the association between myxovirus resistance protein, osteopontin and suppressor of cytokine signaling 3 gene polymorphisms in combination with IL28B and to assess the therapy response in hepatitis C patients treated with pegylated-interferon plus ribavirin. Myxovirus resistance protein, osteopontin, suppressor of cytokine signaling 3 and IL28B polymorphisms were analyzed by PCR-restriction fragment length polymorphism, direct sequencing and real-time PCR. Ancestry was determined using genetic markers. We analyzed 181 individuals, including 52 who were sustained virologic responders. The protective genotype frequencies among the sustained virologic response group were as follows: the G/G suppressor of cytokine signaling 3 (rs4969170) (62.2%); T/T osteopontin (rs2853744) (60%); T/T osteopontin (rs11730582) (64.3%); and the G/T myxovirus resistance protein (rs2071430) genotype (54%). The patients who had ≥3 of the protective genotypes from the myxovirus resistance protein, the suppressor of cytokine signaling 3 and osteopontin had a greater than 90% probability of achieving a sustained response (p<0.0001). The C/C IL28B genotype was present in 58.8% of the subjects in this group. The sustained virological response rates increased to 85.7% and 91.7% by analyzing C/C IL28B with the T/T osteopontin genotype at rs11730582 and the G/G suppressor of cytokine signaling 3 genotype, respectively. Genetic ancestry analysis revealed an admixed population. Hepatitis C genotype 1 patients who were responders to interferon-based therapy had a high frequency of multiple protective polymorphisms in the myxovirus resistance protein, osteopontin and suppressor of cytokine signaling 3 genes. The combined analysis of the suppressor of cytokine signaling 3 and IL28B genotypes more effectively predicted sustained virologic response than IL28B analysis alone.

Genetic Markers of Toxicity From Capecitabine and Other Fluorouracil-Based Regimens: Investigation in the QUASAR2 Study, Systematic Review, and Meta-Analysis

PubMed Central

Rosmarin, Dan; Palles, Claire; Church, David; Domingo, Enric; Jones, Angela; Johnstone, Elaine; Wang, Haitao; Love, Sharon; Julier, Patrick; Scudder, Claire; Nicholson, George; Gonzalez-Neira, Anna; Martin, Miguel; Sargent, Daniel; Green, Erin; McLeod, Howard; Zanger, Ulrich M.; Schwab, Matthias; Braun, Michael; Seymour, Matthew; Thompson, Lindsay; Lacas, Benjamin; Boige, Valérie; Ribelles, Nuria; Afzal, Shoaib; Enghusen, Henrik; Jensen, Søren Astrup; Etienne-Grimaldi, Marie-Christine; Milano, Gérard; Wadelius, Mia; Glimelius, Bengt; Garmo, Hans; Gusella, Milena; Lecomte, Thierry; Laurent-Puig, Pierre; Martinez-Balibrea, Eva; Sharma, Rohini; Garcia-Foncillas, Jesus; Kleibl, Zdenek; Morel, Alain; Pignon, Jean-Pierre; Midgley, Rachel; Kerr, David; Tomlinson, Ian

2014-01-01

Purpose Fluourouracil (FU) is a mainstay of chemotherapy, although toxicities are common. Genetic biomarkers have been used to predict these adverse events, but their utility is uncertain. Patients and Methods We tested candidate polymorphisms identified from a systematic literature search for associations with capecitabine toxicity in 927 patients with colorectal cancer in the Quick and Simple and Reliable trial (QUASAR2). We then performed meta-analysis of QUASAR2 and 16 published studies (n = 4,855 patients) to examine the polymorphisms in various FU monotherapy and combination therapy regimens. Results Global capecitabine toxicity (grades 0/1/2 v grades 3/4/5) was associated with the rare, functional DPYD alleles 2846T>A and *2A (combined odds ratio, 5.51; P = .0013) and with the common TYMS polymorphisms 5′VNTR2R/3R and 3′UTR 6bp ins-del (combined odds ratio, 1.31; P = 9.4 × 10−6). There was weaker evidence that these polymorphisms predict toxicity from bolus and infusional FU monotherapy. No good evidence of association with toxicity was found for the remaining polymorphisms, including several currently included in predictive kits. No polymorphisms were associated with toxicity in combination regimens. Conclusion A panel of genetic biomarkers for capecitabine monotherapy toxicity would currently comprise only the four DPYD and TYMS variants above. We estimate this test could provide 26% sensitivity, 86% specificity, and 49% positive predictive value—better than most available commercial kits, but suboptimal for clinical use. The test panel might be extended to include additional, rare DPYD variants functionally equivalent to *2A and 2846A, though insufficient evidence supports its use in bolus, infusional, or combination FU. There remains a need to identify further markers of FU toxicity for all regimens. PMID:24590654

Fragment-Based Electronic Structure Approach for Computing Nuclear Magnetic Resonance Chemical Shifts in Molecular Crystals.

PubMed

Hartman, Joshua D; Beran, Gregory J O

2014-11-11

First-principles chemical shielding tensor predictions play a critical role in studying molecular crystal structures using nuclear magnetic resonance. Fragment-based electronic structure methods have dramatically improved the ability to model molecular crystal structures and energetics using high-level electronic structure methods. Here, a many-body expansion fragment approach is applied to the calculation of chemical shielding tensors in molecular crystals. First, the impact of truncating the many-body expansion at different orders and the role of electrostatic embedding are examined on a series of molecular clusters extracted from molecular crystals. Second, the ability of these techniques to assign three polymorphic forms of the drug sulfanilamide to the corresponding experimental (13)C spectra is assessed. This challenging example requires discriminating among spectra whose (13)C chemical shifts differ by only a few parts per million (ppm) across the different polymorphs. Fragment-based PBE0/6-311+G(2d,p) level chemical shielding predictions correctly assign these three polymorphs and reproduce the sulfanilamide experimental (13)C chemical shifts with 1 ppm accuracy. The results demonstrate that fragment approaches are competitive with the widely used gauge-invariant projector augmented wave (GIPAW) periodic density functional theory calculations.

NR3C1 polymorphisms in Brazilians of Caucasian, African, and Asian ancestry: glucocorticoid sensitivity and genotype association.

PubMed

Souza, Manoel Carlos L A; Martins, Clarissa S; Silva-Junior, Ivan M; Chriguer, Rosangela S; Bueno, Ana C; Antonini, Sonir R; Silva, Wilson Araújo; Zago, Marco A; Moreira, Ayrton C; Castro, Margaret de

2014-02-01

The Brazilian population has heterogeneous ethnicity. No previous study evaluated NR3C1 polymorphisms in a Brazilian healthy population. We assessed NR3C1 polymorphisms in Brazilians of Caucasian, African and Asian ancestry (n = 380). In a subgroup (n = 40), we compared the genotypes to glucocorticoid (GC) sensitivity, which was previously evaluated by plasma (PF) and salivary (SF) cortisol after dexamethasone (DEX) suppression tests, GC receptor binding affinity (K d ), and DEX-50% inhibition (IC 50 ) of concanavalin-A-stimulated mononuclear cell proliferation. p.N363S (rs6195), p.ER22/23EK (rs6189-6190), and BclI (rs41423247) allelic discrimination was performed by Real-Time PCR (Polymerase Chain Reaction). Exons 3 to 9 and exon/intron boundaries were amplified by PCR and sequenced. Genotypic frequencies (%) were: rs6195 (n = 380; AA:96.6/AG:3.14/GG:0.26), rs6189-6190 (n = 264; GG:99.6/GA:0.4), rs41423247 (n = 264; CC:57.9/CG:34.1/GG:8.0), rs6188 (n = 155; GG:69.6/GT:25.7/TT:4.7), rs258751 (n = 150; CC:88.0/CT:10.7/TT:1.3), rs6196 (n = 176; TT:77.2/TC:20.4/CC:2.4), rs67300719 (n = 137; CC:99.3/CT:0.7), and rs72542757 (n = 137; CC:99.3/CG:0.7). The rs67300719 and rs72542757 were found only in Asian descendants, in whom p.N363S and p.ER22/23EK were absent. The p.ER22/23EK was observed exclusively in Caucasian descendants. Hardy-Weinberg equilibrium was observed, except in the Asian for rs6188 and rs258751, and in the African for p.N363S. The K d , IC 50 , baseline and after DEX PF or SF did not differ between genotype groups. However, the mean DEX dose that suppressed PF or SF differed among the BclI genotypes (P = 0.03). DEX dose was higher in GG- (0.7 ± 0.2 mg) compared to GC- (0.47 ± 0.2 mg) and CC-carriers (0.47 ± 0.1 mg). The genotypic frequencies of NR3C1 polymorphisms in Brazilians are similar to worldwide populations. Additionally, the BclI polymorphism was associated with altered pituitary-adrenal axis GC sensitivity.

Isolation and characterization of new highly polymorphic DNA markers from the Huntington disease region

DOE Office of Scientific and Technical Information (OSTI.GOV)

Weber, B.; Hedrick, A.; Andrew, S.

1992-02-01

The defect causing Huntington disease (HD) has been mapped to 4p16.3, distal to the DNA marker D4S10. Subsequently, additional polymorphic markers closer to the HD gene have been isolated, which has led to the establishment of predictive testing programs for individuals at risk for HD. Approximately 17% of persons presenting to the Canadian collaborative study for predictive testing for HD have not received any modification of risk, in part because of limited informativeness of currently available DNA markers. Therefore, more highly polymorphic DNA markers are needed, which well further increase the accuracy and availability of predictive testing, specifically for familiesmore » with complex or incomplete pedigree structures. In addition, new markers are urgently needed in order to refine the breakpoints in the few known recombinant HD chromosomes, which could allow a more accurate localization of the HD gene within 4p16.3 and, therefore, accelerate the cloning of the disease gene. In this study, the authors present the identification and characterization of nine new polymorphic DNA markers, including three markers which detect highly informative multiallelic VNTR-like polymorphisms with PIC values of up to .84. These markers have been isolated from a cloned region of DNA which has been previously mapped approximately 1,000 kb from the 4p telomere.« less

Influence of Cremophor EL and genetic polymorphisms on the pharmacokinetics of paclitaxel and its metabolites using a mechanism-based model.

PubMed

Fransson, Martin N; Gréen, Henrik; Litton, Jan-Eric; Friberg, Lena E

2011-02-01

The formulation vehicle Cremophor EL has previously been shown to affect paclitaxel kinetics, but it is not known whether it also affects the kinetics of paclitaxel metabolites. This information may be important for understanding paclitaxel metabolism in vivo and in the investigation of the role of genetic polymorphisms in the metabolizing enzymes CYP2C8 and CYP3A4/CYP3A5 and the ABCB1 transporter. In this study we used the population pharmacokinetic approach to explore the influence of predicted Cremophor EL concentrations on paclitaxel (Taxol) metabolites. In addition, correlations between genetic polymorphisms and enzyme activity with clearance of paclitaxel, its two primary metabolites, 6α-hydroxypaclitaxel and p-3'-hydroxypaclitaxel, and its secondary metabolite, 6α-p-3'-dihydroxypaclitaxel were investigated. Model building was based on 1156 samples from a study with 33 women undergoing paclitaxel treatment for gynecological cancer. Total concentrations of paclitaxel were fitted to a model described previously. One-compartment models characterized unbound metabolite concentrations. Total concentrations of 6α-hydroxypaclitaxel and p-3'-hydroxypaclitaxel were strongly dependent on predicted Cremophor EL concentrations, but this association was not found for 6α-p-3'-dihydroxypaclitaxel. Clearance of 6α-hydroxypaclitaxel (fraction metabolized) was significantly correlated (p < 0.05) to the ABCB1 allele G2677T/A. Individuals carrying the polymorphisms G/A (n = 3) or G/G (n = 5) showed a 30% increase, whereas individuals with polymorphism T/T (n = 8) showed a 27% decrease relative to those with the polymorphism G/T (n = 17). The correlation of G2677T/A with 6α-hydroxypaclitaxel has not been described previously but supports other findings of the ABCB1 transporter playing a part in paclitaxel metabolism.

Cetuximab-activated natural killer (NK) and dendritic cells (DC) collaborate to trigger tumor antigen-specific T cell immunity in head and neck cancer patients

PubMed Central

Srivastava, Raghvendra M.; Lee, Steve C.; Filho, Pedro A. Andrade; Lord, Christopher A.; Jie, Hyun-bae; Davidson, H. Carter; López-Albaitero, Andrés; Gibson, Sandra P.; Gooding, William E.; Ferrone, Soldano; Ferris, Robert L.

2013-01-01

Purpose Tumor antigen (TA)-specific monoclonal antibodies (mAb) block oncogenic signaling and induce Fcγ receptor (FcγR)-mediated cytotoxicity. However, the role of CD8+ cytotoxic T lymphocyte (CTL) and FcγR in initiating innate and adaptive immune responses in mAb-treated human cancer patients is still emerging. Experimental Design FcγRIIIa codon 158 polymorphism was correlated with survival in 107 cetuximab-treated head and neck cancer (HNC) patients. Flow cytometry was performed to quantify EGFR-specific T cells in cetuximab-treated HNC patients. The effect of cetuximab on NK cell, dendritic cell (DC), and T cell activation was measured using IFN-γ release assays and flow cytometry. Results FcγR IIIa polymorphism did not predict clinical outcome in cetuximab-treated HNC patients, however elevated circulating EGFR -specific CD8+ 853-861 T cells were found in cetuximab-treated HNC patients (p<0.005). Cetuximab promoted EGFR-specific cellular immunity through the interaction of EGFR+ tumor cells and FcγRIIIa on NK cells, but not on the polymorphism per se. Cetuximab-activated NK cells induced IFN-γ dependent expression of DC maturation markers, antigen presentation machinery (APM) components such as TAP-1/2, and Th1 chemokines through NKG2D/MICA binding. Cetuximab initiated adaptive immune responses via NK-cell induced DC maturation, which enhanced cross-presentation to CTL specific for EGFR as well as another TA, MAGE-3. Conclusion Cetuximab-activated NK cells promote DC maturation and CD8+ T cell priming, leading to TA spreading and Th1 cytokine release through ‘NK-DC cross-talk.’ FcγRIIIa polymorphism did not predict clinical response to cetuximab, but was necessary for NK-DC interaction and mAb induced cross-presentation. EGFR-specific T cells in cetuximab treated HNC patients may contribute to clinical response. PMID:23444227

Weighted Genetic Risk Scores and Prediction of Weight Gain in Solid Organ Transplant Populations

PubMed Central

Saigi-Morgui, Núria; Quteineh, Lina; Bochud, Pierre-Yves; Crettol, Severine; Kutalik, Zoltán; Wojtowicz, Agnieszka; Bibert, Stéphanie; Beckmann, Sonja; Mueller, Nicolas J; Binet, Isabelle; van Delden, Christian; Steiger, Jürg; Mohacsi, Paul; Stirnimann, Guido; Soccal, Paola M.; Pascual, Manuel; Eap, Chin B

2016-01-01

Background Polygenic obesity in Solid Organ Transplant (SOT) populations is considered a risk factor for the development of metabolic abnormalities and graft survival. Few studies to date have studied the genetics of weight gain in SOT recipients. We aimed to determine whether weighted genetic risk scores (w-GRS) integrating genetic polymorphisms from GWAS studies (SNP group#1 and SNP group#2) and from Candidate Gene studies (SNP group#3) influence BMI in SOT populations and if they predict ≥10% weight gain (WG) one year after transplantation. To do so, two samples (nA = 995, nB = 156) were obtained from naturalistic studies and three w-GRS were constructed and tested for association with BMI over time. Prediction of 10% WG at one year after transplantation was assessed with models containing genetic and clinical factors. Results w-GRS were associated with BMI in sample A and B combined (BMI increased by 0.14 and 0.11 units per additional risk allele in SNP group#1 and #2, respectively, p-values<0.008). w-GRS of SNP group#3 showed an effect of 0.01 kg/m2 per additional risk allele when combining sample A and B (p-value 0.04). Models with genetic factors performed better than models without in predicting 10% WG at one year after transplantation. Conclusions This is the first study in SOT evaluating extensively the association of w-GRS with BMI and the influence of clinical and genetic factors on 10% of WG one year after transplantation, showing the importance of integrating genetic factors in the final model. Genetics of obesity among SOT recipients remains an important issue and can contribute to treatment personalization and prediction of WG after transplantation. PMID:27788139

Weighted Genetic Risk Scores and Prediction of Weight Gain in Solid Organ Transplant Populations.

PubMed

Saigi-Morgui, Núria; Quteineh, Lina; Bochud, Pierre-Yves; Crettol, Severine; Kutalik, Zoltán; Wojtowicz, Agnieszka; Bibert, Stéphanie; Beckmann, Sonja; Mueller, Nicolas J; Binet, Isabelle; van Delden, Christian; Steiger, Jürg; Mohacsi, Paul; Stirnimann, Guido; Soccal, Paola M; Pascual, Manuel; Eap, Chin B

2016-01-01

Polygenic obesity in Solid Organ Transplant (SOT) populations is considered a risk factor for the development of metabolic abnormalities and graft survival. Few studies to date have studied the genetics of weight gain in SOT recipients. We aimed to determine whether weighted genetic risk scores (w-GRS) integrating genetic polymorphisms from GWAS studies (SNP group#1 and SNP group#2) and from Candidate Gene studies (SNP group#3) influence BMI in SOT populations and if they predict ≥10% weight gain (WG) one year after transplantation. To do so, two samples (nA = 995, nB = 156) were obtained from naturalistic studies and three w-GRS were constructed and tested for association with BMI over time. Prediction of 10% WG at one year after transplantation was assessed with models containing genetic and clinical factors. w-GRS were associated with BMI in sample A and B combined (BMI increased by 0.14 and 0.11 units per additional risk allele in SNP group#1 and #2, respectively, p-values<0.008). w-GRS of SNP group#3 showed an effect of 0.01 kg/m2 per additional risk allele when combining sample A and B (p-value 0.04). Models with genetic factors performed better than models without in predicting 10% WG at one year after transplantation. This is the first study in SOT evaluating extensively the association of w-GRS with BMI and the influence of clinical and genetic factors on 10% of WG one year after transplantation, showing the importance of integrating genetic factors in the final model. Genetics of obesity among SOT recipients remains an important issue and can contribute to treatment personalization and prediction of WG after transplantation.

Association of UGT2B7 and UGT1A4 Polymorphisms with Serum Concentration of Antiepileptic Drugs in Children.

PubMed

Du, Zhongliang; Jiao, Yukun; Shi, Lianting

2016-10-31

BACKGROUND This study aimed to analyze the relationship of UGT2B7 and UGT1A4 polymorphisms with metabolism of valproic acid (VPA) and lamotrigine (LTG) in epileptic children. MATERIAL AND METHODS We administered VPA (102) and LTG (102) to 204 children with epilepsy. Blood samples were collected before the morning dose. Serum concentration of LTG was measured by high-performance liquid chromatography (HPLC). Serum VPA concentration was tested by fluorescence polarization immunoassay. UGT2B7 A268G, C802T, and G211T polymorphisms, as well as UGT1A4 L48V polymorphism, were assayed by direct automated DNA sequencing after PCR. Evaluation of efficacy was conducted using the Engel method. RESULTS The adjusted serum concentration of VPA was 4.26 μg/mL per mg/kg and LTG was 1.56 μg/mL per mg/kg. Multiple linear regression analysis revealed that VPA or LTG adjusted concentration showed a good linear relation with sex and age. UGT2B7 A268G and C802T polymorphisms were demonstrated to affect the serum concentration of VPA (F=3.147, P=0.047; F=22.754, P=0.000). UGT1A4 L48V polymorphism was not related with the serum concentration of LTG (F=5.328, P=0.006). In the efficacy analysis, we found that C802T polymorphism exerted strong effects on efficacy of VPA (χ²=9.265, P=0.010). L48V polymorphism also showed effects on efficacy of LTG (χ²=17.397, P=0.001). CONCLUSIONS UGT2B7, UGT1A4 polymorphisms play crucial roles in metabolism of VPA and LTG.

Isolation and characterization of new microsatellite markers in red tail prawn, Fenneropenaeus penicillatus, an endangered species in China.

PubMed

Yuan, Y; Shangguan, J B; Li, Z B; Ning, Y F; Huang, Y S; Li, B B; Mao, X Q

2015-11-30

Until recently, Fenneropenaeus penicillatus was considered a commercial shrimp species. However, in 2005, it was included on the Red List as an endangered species by the Chinese government. In this study, 19 new microsatellite markers in F. penicillatus were developed and tested in samples of 32 wild individuals from Nanao, China. Twelve loci were polymorphic and 7 were monomorphic. Of the 12 polymorphic loci, the number of alleles per locus ranged from 3 to 6, with an average of 4.42 alleles per locus. The polymorphism information content ranged from 0.302 to 0.670, with a mean of 0.4817. The observed and expected heterozygosities ranged from 0.2250 to 0.8889 and from 0.1111 to 0.7750, respectively. Significant deviations from Hardy-Weinberg equilibrium (HWE, adjusted P < 0.0042) after a Bonferroni correction were observed in 3 loci (NA-9, NA-57, and NA-64), whereas the other 9 loci were in HWE. These new microsatellite markers will be useful in further research on the population genetic structure of F. penicillatus.

CHI3L1 polymorphisms associate with asthma in a Taiwanese population

PubMed Central

2014-01-01

Background A genome-wide association study uncovered Chitinase 3 like 1 (CHI3L1) as a candidate gene for asthma susceptibility. CHI3L1, which encodes the YKL-40 protein, is associated with asthma in Western European and American populations and with atopy in a Korean population. However, asthma-associated polymorphisms remain unknown for a Taiwanese population. Methods We enrolled 628 adult asthmatic patients and 1:1 age-sex matched community-based controls in southern Taiwan and performed a combined effect sizes analysis to test if CHI3L1 polymorphisms were related to genetic risks for asthma in the Asian population. Ten tagSNP polymorphisms for the CHI3L1 gene were selected from the HapMap database and genotyped using a TaqMan allelic discrimination assay. Results Adjusted odds ratios of the CHI3L1 rs1538372 CC genotype (aOR = 1.97, 95% CI: 1.23–3.14) and the rs10399931 GG genotype (aOR = 1.77, 95% CI: 1.13–2.77) were significantly associated with asthma in the Taiwanese populations. Predictive values of forced expiratory volume in the first second of the forced vital capacity (12.37%, P = 0.03) and of forced vital capacity (12.10%, P = 0.036) decreased in conjunction with an increase in YKL-40 levels among CHI3L1 rs1538372 CC carriers; these values were 16.1% (P = 0.004) and 14.5% (P = 0.011), respectively, among CHI3L1 rs10399931 GG carriers. Furthermore, steroid use by asthma patients did not affect serum YKL-40 levels, but both polymorphisms had significant effects on YKL-40 levels in asthma patients who used steroids. Conclusions Our findings suggest that the CHI3L1 polymorphisms rs1538372 and rs10399931 can be used as genetic markers for predicting asthma risk in the Taiwanese population. PMID:25056157

Residue-Specific Side-Chain Polymorphisms via Particle Belief Propagation.

PubMed

Ghoraie, Laleh Soltan; Burkowski, Forbes; Li, Shuai Cheng; Zhu, Mu

2014-01-01

Protein side chains populate diverse conformational ensembles in crystals. Despite much evidence that there is widespread conformational polymorphism in protein side chains, most of the X-ray crystallography data are modeled by single conformations in the Protein Data Bank. The ability to extract or to predict these conformational polymorphisms is of crucial importance, as it facilitates deeper understanding of protein dynamics and functionality. In this paper, we describe a computational strategy capable of predicting side-chain polymorphisms. Our approach extends a particular class of algorithms for side-chain prediction by modeling the side-chain dihedral angles more appropriately as continuous rather than discrete variables. Employing a new inferential technique known as particle belief propagation, we predict residue-specific distributions that encode information about side-chain polymorphisms. Our predicted polymorphisms are in relatively close agreement with results from a state-of-the-art approach based on X-ray crystallography data, which characterizes the conformational polymorphisms of side chains using electron density information, and has successfully discovered previously unmodeled conformations.

Donor miR-196a-2 polymorphism is associated with hepatocellular carcinoma recurrence after liver transplantation in a Han Chinese population.

PubMed

Xu, Xiao; Ling, Qi; Wang, Jianguo; Xie, Haiyang; Wei, Xuyong; Lu, Di; Hu, Qichao; Zhang, Xuanyu; Wu, Liming; Zhou, Lin; Zheng, Shusen

2016-02-01

Recurrence of hepatocellular carcinoma (HCC) is one of the leading causes of death after liver transplantation (LT). We aim to evaluate the association of donor and recipient single nucleotide polymorphisms (SNPs) with the risk of HCC recurrence after LT. A total of 155 adult patients who underwent primary LT for HCC were enrolled. Ten SNPs associated with HCC susceptibility were genotyped. Patients who received donor livers with the rs11614913 homozygous CC variant presented significantly higher recurrence rates of HCC (41.7 vs. 15.3%, p = 0.009) and lower cumulative tumor-free survival (p = 0.005) than those who received TT wild-type donor livers. The donor rs11614913 genetic variant was an independent risk factor for HCC recurrence (odds ratio = 2 per each C allele, p < 0.05) and could significantly improve the predictive abilities of clinical models (Milan, UCSF and Hangzhou criteria). Donor livers homozygous for rs11614913 CC were associated with a higher miR-196a expression than TT (p = 0.002). In a lentiviral infection of mouse liver and orthotopic mouse model of HCC, the liver miR-196a overexpression group showed a significantly larger tumor size than the control group (p = 0.001). There is a close association between the tumor size and expression of miR-196a in the liver (r = 0.693, p = 0.001). In conclusion, the donor miR-196a-2 rs11614913 polymorphism is associated with HCC recurrence after LT and improves the predictive value of clinical models. The overexpression of miR-196a in the liver might provide a tumor-favorable environment for the development of HCC. © 2015 UICC.

Polymorphisms in TS, MTHFR and ERCC1 genes as predictive markers in first-line platinum and pemetrexed therapy in NSCLC patients.

PubMed

Krawczyk, Paweł; Kucharczyk, Tomasz; Kowalski, Dariusz M; Powrózek, Tomasz; Ramlau, Rodryg; Kalinka-Warzocha, Ewa; Winiarczyk, Kinga; Knetki-Wróblewska, Magdalena; Wojas-Krawczyk, Kamila; Kałakucka, Katarzyna; Dyszkiewicz, Wojciech; Krzakowski, Maciej; Milanowski, Janusz

2014-12-01

We presented retrospective analysis of up to five polymorphisms in TS, MTHFR and ERCC1 genes as molecular predictive markers for homogeneous Caucasian, non-squamous NSCLC patients treated with pemetrexed and platinum front-line chemotherapy. The following polymorphisms in DNA isolated from 115 patients were analyzed: various number of 28-bp tandem repeats in 5'-UTR region of TS gene, single nucleotide polymorphism (SNP) within the second tandem repeat of TS gene (G>C); 6-bp deletion in 3'-UTR region of the TS (1494del6); 677C>T SNP in MTHFR; 19007C>T SNP in ERCC1. Molecular examinations' results were correlated with disease control rate, progression-free survival (PFS) and overall survival. Polymorphic tandem repeat sequence (2R, 3R) in the enhancer region of TS gene and G>C SNP within the second repeat of 3R allele seem to be important for the effectiveness of platinum and pemetrexed in first-line chemotherapy. The insignificant shortening of PFS in 3R/3R homozygotes as compared to 2R/2R and 2R/3R genotypes were observed, while it was significantly shorter in patients carrying synchronous 3R allele and G nucleotide. The combined analysis of TS VNTR and MTHFR 677C>T SNP revealed shortening of PFS in synchronous carriers of 3R allele in TS and two C alleles in MTHFR. The strongest factors increased the risk of progression were poor PS, weight loss, anemia and synchronous presence of 3R allele and G nucleotide in the second repeat of 3R allele in TS. Moreover, lack of application of second-line chemotherapy, weight loss and poor performance status and above-mentioned genotype of TS gene increased risk of early mortality. The examined polymorphisms should be accounted as molecular predictor factors for pemetrexed- and platinum-based front-line chemotherapy in non-squamous NSCLC patients.

Polymorphs of LiFeSO4F as cathode materials for lithium ion batteries - a first principle computational study.

PubMed

Chung, Sai Cheong; Barpanda, Prabeer; Nishimura, Shin-Ichi; Yamada, Yuki; Yamada, Atsuo

2012-06-28

We have investigated polymorphs of LiFeSO4F, tavorite and triplite, which have been reported as cathode materials for lithium ion batteries. The predicted voltages are 3.64 and 3.90 V for tavorite and triplite, respectively, which agreed excellently with experimental data. It is found that the lithiated states (LiFeSO4F) of the polymorphs are almost degenerate in energy. The difference in voltage is mainly due to the difference in the stabilities of the delithiated states (FeSO4F). This is rationalized by the Fe(3+)-Fe(3+) repulsion in the edge sharing geometry of the triplite structure.

Patterns of gene variation in central and marginal populations of Drosophila robusta.

PubMed

Prakash, S

1973-10-01

The central and marginal populations of D. robusta differ greatly in the level of inversion polymorphism; the marginal populations are monomorphic or nearly so and the central populations are highly polymorphic. This paper presents the frequencies of alleles at forty gene loci in various populations of D. robusta, studied by electrophoresis of proteins and enzymes. Population samples were obtained from eight widely separated populations of D. robusta which included the central, the extreme marginal and the intervening populations between the center and the margins. We find that the proportion of polymorphic loci and average heterozygosity per individual is slightly higher in the marginal populations than the central populations. In D. robusta on an average, 39% of the loci are polymorphic and the average proportion of loci heterozygous per individual is 11%. A breakdown of loci in three categories, viz, hydrolytic enzymes and some other enzymes, larval proteins and glycolytic and Kreb's cycle enzymes, shows that in all populations the level of polymorphism is highest in the hydrolytic enzymes, intermediate in larval proteins and least in the glycolytic and Kreb's cycle enzymes. On the average, the proportion of loci heterozygous per individual for three groups of loci is: hydrolytic enzymes and others (.164), larval proteins (.115) and glycolytic and Kreb's cycle enzymes (.037). We also observe that in all populations the level of polymorphism on the X chromosome is far less than the expected 38%; in salivary gland cells the euchromatic length of the X chromosome is 38% of the entire genome. Lower levels of polymorphism for the X chromosome loci are explained due to low probability of balanced polymorphisms for the X-linked loci since the conditions for establishment of balanced polymorphism for X-linked loci are more restrictive than for the autosomal loci.-The polymorphic loci can be grouped according to pattern of allele frequencies in different populations as follows: (1) The allele frequencies are similar in all populations at the XDH, Pep-1 and Hex-1 loci. (2) The alleles at the Est-1, Est-2, Amy loci and the AP-4(1.0) and the LAP-1(.90) alleles show north south clinal change in frequency. (3) There is north south and east west differentiation at the Pt-5, Pt-8 and Pt-9 loci and the allele AP-4(.81). (4) Polymorphism at loci such as Fum, B.Ox, Hex-8, Pep-2 and Pep-3 are restricted to only one or two of the populations. (5) Allele frequencies at the MDH and ODH loci fluctuate between populations. (6) Allele frequencies at many polymorphic loci such as Est-1, Est-2, LAP-1, AP-4, Pt-5, Pt-8, Pt-9, Pt-16, MDH, Fum change clinally within a gene arrangement. The pattern of gene variation in D. robusta is very complex and cannot be easily explained due to migration of neutral alleles between once-isolated populations or to semi-isolation of neutral alleles. The observations of the pattern of allele variation in different populations, high levels of polymorphism in the marginal populations which have small population size and low levels of polymorphism of the X chromosome loci all support the argument in favor of balancing selection as the main mechanism for the maintenance of these polymorphisms. Environmental factors must play a role in the maintenance of a great deal of these polymorphisms, since we observe clinal allele frequency changes even within a given inversion type.

Patterns of Gene Variation in Central and Marginal Populations of DROSOPHILA ROBUSTA

PubMed Central

Prakash, Satya

1973-01-01

The central and marginal populations of D. robusta differ greatly in the level of inversion polymorphism; the marginal populations are monomorphic or nearly so and the central populations are highly polymorphic. This paper presents the frequencies of alleles at forty gene loci in various populations of D. robusta, studied by electrophoresis of proteins and enzymes. Population samples were obtained from eight widely separated populations of D. robusta which included the central, the extreme marginal and the intervening populations between the center and the margins. We find that the proportion of polymorphic loci and average heterozygosity per individual is slightly higher in the marginal populations than the central populations. In D. robusta on an average, 39% of the loci are polymorphic and the average proportion of loci heterozygous per individual is 11%. A breakdown of loci in three categories, viz, hydrolytic enzymes and some other enzymes, larval proteins and glycolytic and Kreb's cycle enzymes, shows that in all populations the level of polymorphism is highest in the hydrolytic enzymes, intermediate in larval proteins and least in the glycolytic and Kreb's cycle enzymes. On the average, the proportion of loci heterozygous per individual for three groups of loci is: hydrolytic enzymes and others (.164), larval proteins (.115) and glycolytic and Kreb's cycle enzymes (.037). We also observe that in all populations the level of polymorphism on the X chromosome is far less than the expected 38%; in salivary gland cells the euchromatic length of the X chromosome is 38% of the entire genome. Lower levels of polymorphism for the X chromosome loci are explained due to low probability of balanced polymorphisms for the X-linked loci since the conditions for establishment of balanced polymorphism for X-linked loci are more restrictive than for the autosomal loci.—The polymorphic loci can be grouped according to pattern of allele frequencies in different populations as follows: (1) The allele frequencies are similar in all populations at the XDH, Pep-1 and Hex-1 loci. (2) The alleles at the Est-1, Est-2, Amy loci and the AP-41.0 and the LAP-1.90 alleles show north south clinal change in frequency. (3) There is north south and east west differentiation at the Pt-5, Pt-8 and Pt-9 loci and the allele AP-4.81. (4) Polymorphism at loci such as Fum, B.Ox, Hex-8, Pep-2 and Pep-3 are restricted to only one or two of the populations. (5) Allele frequencies at the MDH and ODH loci fluctuate between populations. (6) Allele frequencies at many polymorphic loci such as Est-1, Est-2, LAP-1, AP-4, Pt-5, Pt-8, Pt-9, Pt-16, MDH, Fum change clinally within a gene arrangement. The pattern of gene variation in D. robusta is very complex and cannot be easily explained due to migration of neutral alleles between once-isolated populations or to semi-isolation of neutral alleles. The observations of the pattern of allele variation in different populations, high levels of polymorphism in the marginal populations which have small population size and low levels of polymorphism of the X chromosome loci all support the argument in favor of balancing selection as the main mechanism for the maintenance of these polymorphisms. Environmental factors must play a role in the maintenance of a great deal of these polymorphisms, since we observe clinal allele frequency changes even within a given inversion type. PMID:4203580

Association of genetic risk scores with body mass index in Swiss psychiatric cohorts.

PubMed

Saigi-Morgui, Núria; Vandenberghe, Frederik; Delacrétaz, Aurélie; Quteineh, Lina; Gholamrezaee, Mehdi; Aubry, Jean-Michel; von Gunten, Armin; Kutalik, Zoltán; Conus, Philippe; Eap, Chin B

2016-05-01

Weight gain is associated with psychiatric disorders and/or with psychotropic drug treatments. We analyzed in three psychiatric cohorts under psychotropic treatment the association of weighted genetic risk scores (w-GRSs) with BMI by integrating BMI-related polymorphisms from the candidate-gene approach and Genome-Wide Association Studies (GWAS). w-GRS of 32 polymorphisms associated previously with BMI in general population GWAS and 20 polymorphisms associated with antipsychotics-induced weight gain were investigated in three independent psychiatric samples. w-GRS of 32 polymorphisms were significantly associated with BMI in the psychiatric sample 1 (n=425) and were replicated in another sample (n=177). Those at the percentile 95 (p95) of the score had 2.26 and 2.99 kg/m(2) higher predicted BMI compared with individuals at the percentile 5 (p5) in sample 1 and in sample 3 (P=0.009 and 0.04, respectively). When combining all samples together (n=750), a significant difference of 1.89 kg/m(2) predicted BMI was found between p95 and p5 individuals at 12 months of treatment. Stronger associations were found among men (difference: 2.91 kg/m(2) of predicted BMI between p95 and p5, P=0.0002), whereas no association was found among women. w-GRS of 20 polymorphisms was not associated with BMI. The w-GRS of 52 polymorphisms and the clinical variables (age, sex, treatment) explained 1.99 and 3.15%, respectively, of BMI variability. The present study replicated in psychiatric cohorts previously identified BMI risk variants obtained in GWAS analyses from population-based samples. Sex-specific analysis should be considered in further analysis.

[G894T (NOS3) and G1958A (MTHFD1) gene polymorphisms and risk of ischemic heart disease in Yucatan, Mexico].

PubMed

García-González, Igrid; Solís-Cárdenas, Alberto de Jesús; Flores-Ocampo, Jorge A; Alejos-Mex, Ricardo; Herrera-Sánchez, Luis Fernando; González-Herrera, Lizbeth Josefina

2015-01-01

Cardiovascular medicine is focused on the search for genetic risk markers with predictive and/or prognostic value. Among the genetic variants of interest are G894T endothelial nitric oxide synthase and G1958A methylenetetrahydrofolate dehydrogenase1 gene polymorphisms. The aim of this study was to determine the possible association between these polymorphisms and ischemic heart disease in patients from Southern of Mexico (Yucatán). Case-control study matched by age, sex and origin was designed. We studied 98 patients with coronary disease and 101 controls. Participants were evaluated for the usual risk factors. The polymorphisms were identified using the polymerase chain reaction/restriction fragment length polymorphism analysis. Informed consent was obtained from all participants. The G894T and G1958A polymorphisms were not associated with ischemic heart disease, however, the TT genotype (G894T) was associated with the angina (OR=10.2; 95%CI, 1.51-68.8; p=0.025). The genotype GT (G894T) was the most frequent in patients with family history of coronary artery disease. Multiple logistic regression analysis identified smoking (OR=5.21; 95%CI, 2.1-12.9; p=0.000), hypertension (OR=3.54; 95%CI, 1.47-8.56; p=0.005) and obesity (OR=1.16; 95%CI, 1.1-1.27; p=0.001) as risk factors predicting the ischemic heart disease. The G894T and G1958A polymorphisms showed not association with ischemic heart disease. However, homozygosis for the 894T allele (NOS3) confers at risk to develop angina on Yucatán. Copyright © 2014 Sociedad Española de Arteriosclerosis. Published by Elsevier España. All rights reserved.

Period 3 gene polymorphism and sleep adaptation to stressful urban environments.

PubMed

Anderson, Maxwell R; Akeeb, Ameenat; Lavela, Joseph; Chen, Yuanxiu; Mellman, Thomas A

2017-02-01

This study's objective was to investigate the relationship between a variable-number tandem-repeat (VNTR) Period 3 gene (PER3) polymorphism and sleep adaptation to stressful urban environments. Seventy-five (49 female) African American participants (ages 18-35 years) living in neighbourhoods with high rates of violent crime were selected for the study based on converging criteria for good or poor sleep. Categorization of sleep quality was based on the Insomnia Severity Index (ISI), estimates of typical sleep duration and sleep efficiency. Other assessments included the Fear of Sleep Index (FOSI) and City Stress Inventory (CSI). Whole blood DNA was analysed for the 4 and 5 VNTR alleles using polymerase chain reaction (PCR) and restrictive enzyme digestion. Fifty-seven per cent of those who were homo- or heterozygous for the 4-repeat allele were poor sleepers versus 25% of those homozygous for the 5-repeat allele; χ 2  = 4.17, P = 0.041. In a logistic regression model with all the variables with significant bivariate relationships to sleep quality group, FOSI was the only significant predictor (χ 2  = 5.68, P = 0.017). FOSI scores were higher among those with the 4-repeat allele (t = 2.66, P = 0.013). The PER3 4 and 5 VNTR polymorphisms appear to influence sensitivity to the effects of stressful urban environments on sleep. While FOSI was the only variable associated independently with sleep quality category, the candidate vulnerability allele was also associated with greater 'fear of sleep'. © 2016 European Sleep Research Society.

Crystal structure of minoxidil at low temperature and polymorph prediction.

PubMed

Martín-Islán, Africa P; Martín-Ramos, Daniel; Sainz-Díaz, C Ignacio

2008-02-01

An experimental and theoretical investigation on crystal forms of the popular and ubiquitous pharmaceutical Minoxidil is presented here. A new crystallization method is presented for Minoxidil (6-(1-piperidinyl)-2,4-pyrimidinediamide 3-oxide) in ethanol-poly(ethylene glycol), yielding crystals with good quality. The crystal structure is determined at low temperature, with a final R value of 0.035, corresponding to space group P2(1) (monoclinic) with cell dimensions a = 9.357(1) A, b = 8.231(1) A, c = 12.931(2) A, and beta = 90.353(4) degrees . Theoretical calculations of the molecular structure of Minoxidil are set forward using empirical force fields and quantum-mechanical methods. A theoretical prediction for Minoxidil crystal structure shows many possible polymorphs. The predicted crystal structures are compared with X-ray experimental data obtained in our laboratory, and the experimental crystal form is found to be one of the lowest energy polymorphs.

HLA-G+3027 polymorphism is associated with tumor relapse in pediatric Hodgkin's lymphoma.

PubMed

De Re, Valli; Caggiari, Laura; Mussolin, Lara; d'Amore, Emanuele Stefano; Famengo, Barbara; De Zorzi, Mariangela; Martina, Lia; Elia, Caterina; Pillon, Marta; Santoro, Nicola; Muggeo, Paola; Buffardi, Salvatore; Bianchi, Maurizio; Sala, Alessandra; Farruggia, Piero; Vinti, Luciana; Carosella, Edgardo D; Burnelli, Roberta; Mascarin, Maurizio

2017-12-01

In this study, we tested whether polymorphisms in human leukocyte antigen G (HLA-G) were associated with event-free survival (EFS) in pediatric Hodgkin's lymphoma (HL). We evaluated the association of HLA-G 3'-UTR polymorphisms with EFS in 113 pediatric HL patients treated using the AIEOP LH-2004 protocol. Patients with the +3027-C/A genotype (rs17179101, UTR-7 haplotype) showed lower EFS than those with the +3027-C/C genotype (HR= 3.23, 95%CI: 0.99-10.54, P=0.012). Female patients and systemic B symptomatic patients with the HLA-G +3027 polymorphism showed lower EFS. Multivariate analysis showed that the +3027-A polymorphism (HR 3.17, 95%CI 1.16-8.66, P=0.025) was an independent prognostic factor. Immunohistochemical analysis showed that HL cells from patients with the +3027-C/A genotype did not express HLA-G. Moreover, HLA-G +3027 polymorphism improved EFS prediction when added to the algorithm for therapeutic group classification of pediatric HL patients. Our findings suggest HLA-G +3027 polymorphism is a prognostic marker in pediatric HL patients undergoing treatment according to LH-2004 protocol.

Attenuation of the effect of the FTO rs9939609 polymorphism on total and central body fat by physical activity in adolescents: the HELENA study.

PubMed

Ruiz, Jonatan R; Labayen, Idoia; Ortega, Francisco B; Legry, Vanessa; Moreno, Luis A; Dallongeville, Jean; Martínez-Gómez, David; Bokor, Szilvia; Manios, Yannis; Ciarapica, Donatella; Gottrand, Frederic; De Henauw, Stefaan; Molnár, Denes; Sjöström, Michael; Meirhaeghe, Aline

2010-04-01

To examine whether physical activity attenuates the effect of the FTO rs9939609 polymorphism on body fat estimates in adolescents. Cross-sectional study. Athens, Greece; Dortmund, Germany; Ghent, Belgium; Heraklion, Greece; Lille, France; Pécs, Hungary; Rome, Italy; Stockholm, Sweden; Vienna, Austria; and Zaragoza, Spain, from October 2006 to December 2007. Adolescents from the Healthy Lifestyle in Europe by Nutrition in Adolescence Cross-Sectional Study (n = 752). Physical activity. The FTO rs9939609 polymorphism was genotyped. Physical activity was assessed by accelerometry. We measured weight, height, waist circumference, and triceps and subscapular skinfolds; body mass index (BMI [calculated as weight in kilograms divided by height in meters squared]) and body fat percentage were calculated. The A allele of the FTO polymorphism was significantly associated with higher BMI (+0.42 per risk allele), higher body fat percentage (+1.03% per risk allele), and higher waist circumference (+0.85 cm per risk allele). We detected significant or borderline gene x physical activity interactions for the studied body fat estimates (for interaction, P = .02, .06, and .10 for BMI, body fat percentage, and waist circumference, respectively). Indeed, the effect of the FTO rs9939609 polymorphism on these body fat parameters was much lower in adolescents who met the daily physical activity recommendations (ie, >/=60 min/d of moderate to vigorous physical activity) compared with those who did not: +0.17 vs +0.65 per risk allele in BMI, respectively; +0.40% vs +1.70% per risk allele in body fat percentage, respectively; and +0.60 vs +1.15 cm per risk allele in waist circumference, respectively. Adolescents meeting the daily physical activity recommendations may overcome the effect of the FTO rs9939609 polymorphism on obesity-related traits.

Association of the Period3 clock gene length polymorphism with salivary cortisol secretion among police officers

PubMed Central

Wirth, Michael; Burch, James; Violanti, John; Burchfiel, Cecil; Fekedulegn, Desta; Andrew, Michael; Zhang, Hongmei; Miller, Diane B.; Youngstedt, Shawn D.; Hébert, James R.; Vena, John E.

2013-01-01

OBJECTIVE This study evaluated whether measures of waking or diurnal cortisol secretion, or self-reported psychological disturbances differed among police officers with a Period3 (PER3) clock gene length polymorphism. METHODS The cortisol awakening response was characterized via the area under the salivary cortisol curve with respect to the increase (AUCI) or total waking cortisol (AUCG). Diurnal cortisol measures included the slope of diurnal cortisol and the diurnal AUCG. Psychological disturbances were characterized using the Center for Epidemiologic Studies Depression Scale, Impact of Events Scale, and Life Events Scale. RESULTS Officers with a 4/5 or 5/5 genotype had higher awakening AUCG and greater diurnal cortisol AUCG levels compared to officers with the 4/4 genotype. Among those working more afternoon or night shifts, waking AUCI and AUCG were greater among officers with a 4/5 or 5/5 genotype compared to the 4/4 referents. CONCLUSION Cortisol secretion was modified among police officers with different PER3 VNTR clock gene variants. PMID:23524621

Genetic variants in 3′-UTRs of methylenetetrahydrofolate reductase (MTHFR) predict colorectal cancer susceptibility in Koreans

PubMed Central

Joo Jeon, Young; Woo Kim, Jong; Mi Park, Hye; Kim, Jung O; Geun Jang, Hyo; Oh, Jisu; Gyu Hwang, Seong; Won Kwon, Sung; Oh, Doyeun; Keun Kim, Nam

2015-01-01

Polymorphisms in the methylenetetrahydrofolate reductase (MTHFR) play important roles in tumor development, progression, and metastasis. Moreover, recent studies have reported that a number of 3′-UTR polymorphisms potentially bind to specific microRNAs in a variety of cancers. The aim of this study was to investigate the association of four MTHFR polymorphisms, 2572C>A [rs4846049], 4869C>G [rs1537514], 5488C>T [rs3737967], and 6685T>C [rs4846048] with colorectal cancer (CRC) in Koreans. A total of 850 participants (450 CRC patients and 400 controls) were enrolled in the study. The genotyping of MTHFR 3′-UTR polymorphisms was performed by polymerase chain reaction-restriction fragment length polymorphism analysis or TaqMan allelic discrimination assay. We found that MTHFR 2572C>A, 4869C>G, and 5488C>T genotypes were substantially associated with CRC susceptibility. Of the potentially susceptible polymorphisms, MTHFR 2572C>A was associated with increased homocysteine and decreased folate levels in the plasma based on MTHFR 677CC. Our study provides the evidences for 3′-UTR variants in MTHFR gene as potential biomarkers for use in CRC prevention. PMID:26046315

Characterization of 23 polymorphic SSR markers in Salix humboldtiana (Salicaceae) using next-generation sequencing and cross-amplification from related species1

PubMed Central

Bozzi, Jorge A.; Liepelt, Sascha; Ohneiser, Sebastian; Gallo, Leonardo A.; Marchelli, Paula; Leyer, Ilona; Ziegenhagen, Birgit; Mengel, Christina

2015-01-01

Premise of the study: We present a set of 23 polymorphic nuclear microsatellite loci, 18 of which are identified for the first time within the riparian species Salix humboldtiana (Salicaceae) using next-generation sequencing. Methods and Results To characterize the 23 loci, up to 60 individuals were sampled and genotyped at each locus. The number of alleles ranged from two to eight, with an average of 4.43 alleles per locus. The effective number of alleles ranged from 1.15 to 3.09 per locus, and allelic richness ranged from 2.00 to 7.73 alleles per locus. Conclusions The new marker set will be used for future studies of genetic diversity and differentiation as well as for unraveling spatial genetic structures in S. humboldtiana populations in northern Patagonia, Argentina. PMID:25909042

Development, characterization and cross species amplification of polymorphic microsatellite markers from expressed sequence tags of turmeric (Curcuma longa L.).

PubMed

Siju, S; Dhanya, K; Syamkumar, S; Sasikumar, B; Sheeja, T E; Bhat, A I; Parthasarathy, V A

2010-02-01

Expressed sequence tags (ESTs) from turmeric (Curcuma longa L.) were used for the screening of type and frequency of Class I (hypervariable) simple sequence repeats (SSRs). A total of 231 microsatellite repeats were detected from 12,593 EST sequences of turmeric after redundancy elimination. The average density of Class I SSRs accounts to one SSR per 17.96 kb of EST. Mononucleotides were the most abundant class of microsatellite repeat in turmeric ESTs followed by trinucleotides. A robust set of 17 polymorphic EST-SSRs were developed and used for evaluating 20 turmeric accessions. The number of alleles detected ranged from 3 to 8 per loci. The developed markers were also evaluated in 13 related species of C. longa confirming high rate (100%) of cross species transferability. The polymorphic microsatellite markers generated from this study could be used for genetic diversity analysis and resolving the taxonomic confusion prevailing in the genus.

Prediction of remission of depression with clinical variables, neuropsychological performance, and serotonergic/dopaminergic gene polymorphisms.

PubMed

Gudayol-Ferré, Esteve; Herrera-Guzmán, Ixchel; Camarena, Beatriz; Cortés-Penagos, Carlos; Herrera-Abarca, Jorge E; Martínez-Medina, Patricia; Asbun-Bojalil, Juan; Lira-Islas, Yuridia; Reyes-Ponce, Celia; Guàrdia-Olmos, Joan

2012-11-01

The aim of our work is to study the possible role of clinical variables, neuropsychological performance, and the 5HTTLPR, rs25531, and val108/58Met COMT polymorphisms on the prediction of depression remission after 12 weeks' treatment with fluoxetine. These variables have been studied as potential predictors of depression remission, but they present poor prognostic sensitivity and specificity by themselves. Seventy-two depressed patients were genotyped according to the aforementioned polymorphisms and were clinically and neuropsychologically assessed before a 12-week fluxetine treatment. Only the La allele of rs25531 polymorphism and the GG and AA forms of the val 108/158 Met polymorphism predict major depressive disorder remission after 12 weeks' treatment with fluoxetine. None of the clinical and neuropsychological variables studied predicted remission. Our results suggest that clinical and neuropsychological variables can initially predict early response to fluoxetine and mask the predictive role of genetic variables; but in remission, where clinical and neuropsychological symptoms associated with depression tend to disappear thanks to the treatment administered, the polymorphisms studied are the only variables in our model capable of predicting remission. However, placebo effects that are difficult to control require cautious interpretation of the results.

HTR2A A-1438G/T102C polymorphisms predict negative symptoms performance upon aripiprazole treatment in schizophrenic patients.

PubMed

Chen, Shih-Fen; Shen, Yu-Chih; Chen, Chia-Hsiang

2009-08-01

Aripiprazole acts as a partial agonist at dopamine D2 and D3 and serotonin 1A receptors and as an antagonist at serotonin 2A receptors (HTR2A). Since aripiprazole acts as an antagonist at HTR2A, genetic variants of HTR2A may be important in explaining variability in response to aripiprazole. This study investigated whether the efficacy of aripiprazole can be predicted by functional HTR2A A-1438G/T102C polymorphisms (rs63311/rs6313) as modified by clinical factors in Han Chinese hospitalized patients with acutely exacerbated schizophrenia. After hospitalization, the patients (n = 128) were given a 4-week course of aripiprazole. Patients were genotyped for HTR2A A-1438G/T102C polymorphisms via the restriction fragment length polymorphism method. Clinical factors such as gender, age, duration of illness, education level, diagnostic subtype, and medication dosage were noted as well. The researchers measured psychopathology biweekly, using the Positive and Negative Syndrome Scale (PANSS). A mixed model regression approach (SAS Proc MIXED) was used to analyze the effects of genetic and clinical factors on PANSS performance after aripiprazole treatment. We found that the GG/CC genotype group of HTR2A A-1438G/T102C polymorphisms predicts poor aripiprazole response specifically for negative symptoms. In addition, the clinical factors, including dosage of aripiprazole, age, duration of illness, and diagnostic subtype, were found to influence PANSS performance after aripiprazole treatment. The data suggest HTR2A A-1438G/T102C polymorphisms may predict negative symptoms performance upon aripiprazole treatment in schizophrenic patients as modified by clinical factors.

Prediction of exercise-mediated changes in metabolic markers by gene polymorphism.

PubMed

Kahara, Toshio; Takamura, Toshinari; Hayakawa, Tetsuo; Nagai, Yukihiro; Yamaguchi, Hiromi; Katsuki, Tatsuo; Katsuki, Ken-ichi; Katsuki, Michio; Kobayashi, Ken-ichi

2002-08-01

The effects of regular physical exercise on obesity-associated metabolic abnormalities vary for each individual. In this study, we investigated whether genotypes of genes associated with obesity can predict the effects of exercise on changes in metabolic markers in healthy men. Healthy Japanese men (n=106) performed the exercise program at 50% of their maximal heart rate for 20-60 min a day, 2-3 days each week for 3 months. The levels of fasting plasma glucose (FPG) and serum leptin significantly decreased after the exercise program. Polymorphisms of the beta3-adrenergic receptor (beta3AR) and uncoupling protein-1 (UCP-1) genes were analyzed with RFLP methods. In the Trp/Trp genotype of the beta3AR gene, the levels of serum leptin, FPG and fructosamine (FrAm) decreased significantly after the exercise program, but not in the Arg/Arg genotype. In the AG heterozygote and the GG homozygote of the UCP-1 gene, FPG and FrAm levels were significantly reduced, respectively. In conclusion, gene polymorphism of the beta3AR and UCP-1 was found to be associated with the exercise-mediated improvement in glucose tolerance and leptin resistance in healthy Japanese men.

The NLRP3 rs10754558 Polymorphism Is Associated with the Occurrence and Prognosis of Coronary Artery Disease in the Chinese Han Population.

PubMed

Zhou, Dong; Wang, Xinhong; Chen, Tao; Wen, Wen; Liu, Yang; Wu, Yue; Yuan, Zuyi

2016-01-01

The objective of this study is to investigate the potential association of the NLRP3 rs10754558 and CARD8 rs2043211 polymorphisms with the occurrence and prognosis of CAD. Gene polymorphisms were analyzed using the ABI PRISM-Snapshot multiplex method in 515 CAD patients and 401 control subjects. The serum level of IL-1β was investigated by ELISA assays. The clinical endpoints were evaluated during a median follow-up period of 32 months. The NLRP3 rs10754558 gene polymorphism was significantly associated with the occurrence of CAD, while the CARD8 rs2043211 gene polymorphism was not involved. Patients carrying G allele of NLRP3 rs10754558 had more severe coronary artery stenosis. Multivariable analysis revealed a significant association of the G allele with major adverse cardiac event. The serum IL-1β concentrations in patients with GG genotype were significantly increased compared with those in the patients with CC genotype. Our findings for the first time show that the NLRP3 rs10754558 polymorphism is involved in the occurrence of CAD in the Chinese Han population; and G allele can effectively predict clinical outcome of CAD. The G allele susceptibility to CAD is maybe associated with the increased level of serum IL-1β.

Association between rs2981582 polymorphism in the FGFR2 gene and the risk of breast cancer in Mexican women

PubMed Central

Murillo-Zamora, Efrén; Moreno-Macías, Hortensia; Ziv, Elad; Romieu, Isabelle; Lazcano-Ponce, Eduardo; Ángeles-Llerenas, Angélica; Pérez-Rodríguez, Edelmiro; Vidal-Millán, Silvia; Fejerman, Laura; Torres-Mejía, Gabriela

2014-01-01

Background and Aims The rs2981582 single nucleotide polymorphism in the Fibroblast Growth Factor Receptor 2 gene has been consistently associated with an increased risk of breast cancer. We evaluated the effect of rs2981582 polymorphism in the FGFR2 gene on the risk of breast cancer and its interaction with non-genetic risk factors. Methods A population based case control study was conducted in Mexico. Data from 687 cases and 907 controls were analyzed. Results The T allele of the rs2981582 polymorphism was associated with an increased risk of breast cancer (OR per allele =1.24, 95% CI 1.06 – 1.46). There was also an interaction between this polymorphism and alcohol consumption (p = 0.043); the effect of alcohol consumption on the risk of breast cancer varied according to the allelic variants of the rs2981582 polymorphism in the FGFR2 gene: OR = 3.97 (95% CI 2.10 – 7.49), OR = 2.01 (95% CI 1.23 − 3.29) and OR = 1.21 (95% CI 0.48 − 3.05) for genotypes CC, CT and TT, respectively. Conclusions This is the first study exploring the association between rs2981582 polymorphism in the FGFR2 gene and breast cancer risk in Mexican women. The interaction found may be of great public health interest, since alcohol consumption is a modifiable breast cancer risk factor. Therefore, replication of this finding is of foremost importance. PMID:24054997

Observed parenting behaviors interact with a polymorphism of the brain-derived neurotrophic factor gene to predict the emergence of oppositional defiant and callous-unemotional behaviors at age 3 years.

PubMed

Willoughby, Michael T; Mills-Koonce, Roger; Propper, Cathi B; Waschbusch, Daniel A

2013-11-01

Using the Durham Child Health and Development Study, this study (N = 171) tested whether observed parenting behaviors in infancy (6 and 12 months) and toddlerhood/preschool (24 and 36 months) interacted with a child polymorphism of the brain-derived neurotrophic factor gene to predict oppositional defiant disorder (ODD) and callous-unemotional (CU) behaviors at age 3 years. Child genotype interacted with observed harsh and intrusive (but not sensitive) parenting to predict ODD and CU behaviors. Harsh-intrusive parenting was more strongly associated with ODD and CU for children with a methionine allele of the brain-derived neurotrophic factor gene. CU behaviors were uniquely predicted by harsh-intrusive parenting in infancy, whereas ODD behaviors were predicted by harsh-intrusive parenting in both infancy and toddlerhood/preschool. The results are discussed from the perspective of the contributions of caregiving behaviors as contributing to distinct aspects of early onset disruptive behavior.

APOC3 -482C>T polymorphism, circulating apolipoprotein C-III and smoking: interrelation and roles in predicting type-2 diabetes and coronary disease.

PubMed

Onat, Altan; Erginel-Unaltuna, Nihan; Coban, Neslihan; Ciçek, Gökhan; Yüksel, Hüsniye

2011-04-01

We determined the relationship of smoking status on APOC3 -482C>T polymorphism and apolipoprotein C-III (apoC-III) concentrations and the latter two parameters' influence on risk of diabetes and coronary heart disease (CHD). Prediction of incident cases was assessed at 5.5years' follow-up in unselected 519 individuals of a general population genotyped for -482C>T polymorphism. Female sex and current smoking were significantly associated with low circulating apoC-III in subjects without (p≤0.033) than with abdominal obesity (p=0.053) or than insulin resistant -482TT homozygotes (p=0.034) who had 20-30% higher serum apoC-III. Multi-adjusted serum apoC-III was log-linearly associated with fasting triglycerides. ApoC-III levels determined the development of diabetes [RR 1.56 (95%CI 1.21; 2.01)] and CHD [RR 1.38 (1.10; 1.72) for an increment of 14%], after adjustment for confounders. APOC3 -482TT genotype is associated with high apoC-III concentrations only in the presence of abdominal obesity or insulin resistance, but not in current smokers who remain lean or insulin-sensitive. Rather than APOC3 -482C>T polymorphism, circulating apoC-III determines cardiometabolic risk. Copyright © 2011 The Canadian Society of Clinical Chemists. Published by Elsevier Inc. All rights reserved.

Identification of verotoxin type 2 variant B subunit genes in Escherichia coli by the polymerase chain reaction and restriction fragment length polymorphism analysis.

PubMed Central

Tyler, S D; Johnson, W M; Lior, H; Wang, G; Rozee, K R

1991-01-01

A set of synthetic oligonucleotide primers was designed for use in a polymerase chain reaction protocol to specifically detect the B subunit genes in vtx2ha and vtx2hb, which code for the production of the VT2 (Shiga-like toxin II) variant cytotoxins VT2v-a and VT2v-b, respectively. An additional set of primers amplified a fragment common to the B subunits of the VT2 and the VT2 variant genes. Subsequent restriction endonuclease digestion of this amplicon permitted prediction of specific VT2 and variant genotypes on the basis of predetermined restriction fragment length polymorphisms. Genotypes of 21 VT2-producing strains of Escherichia coli were determined using this polymerase chain reaction-restriction fragment length polymorphism procedure. Four strains contained B subunit target sequences only for VT2 genes, 9 strains contained sequences only for VT2v-a genes, and 3 strains contained sequences only for VT2v-b. For genes in combination, one strain contained B subunit genes for both VT2 and VT2v-a and two strains contained B subunit genes for VT2 and VT2v-b. Two strains of E. coli O91:H21 contained both VT2v-a and VT2v-b B subunit genes. The VT2 reference strain of E. coli, E32511, was found to contain the targeted sequences from both VT2 and VT2v-a genes, whereas the recombinant E. coli, pEB1, possessed only that of the VT2 gene. The specific activities of extracellular VT2 determined in HeLa cells ranged from 0.3 to 41.7 TCD50 per microgram of protein in strains carrying the VT2 gene target and from 0 to 50.0 TCD50 per microgram of protein in strains carrying only the VT2 variant target (TCD50 is the tissue culture dose by which 50% of the cells were affected), suggesting that phenotypic expression does not correlate with genotype. Images PMID:1679436

Genetic risk profiling and gene signature modeling to predict risk of complications after IPAA.

PubMed

Sehgal, Rishabh; Berg, Arthur; Polinski, Joseph I; Hegarty, John P; Lin, Zhenwu; McKenna, Kevin J; Stewart, David B; Poritz, Lisa S; Koltun, Walter A

2012-03-01

Severe pouchitis and Crohn's disease-like complications are 2 adverse postoperative complications that confound the success of the IPAA in patients with ulcerative colitis. To date, approximately 83 single nucleotide polymorphisms within 55 genes have been associated with IBD. The aim of this study was to identify single-nucleotide polymorphisms that correlate with complications after IPAA that could be utilized in a gene signature fashion to predict postoperative complications and aid in preoperative surgical decision making. One hundred forty-two IPAA patients were retrospectively classified as "asymptomatic" (n = 104, defined as no Crohn's disease-like complications or severe pouchitis for at least 2 years after IPAA) and compared with a "severe pouchitis" group (n = 12, ≥ 4 episodes pouchitis per year for 2 years including the need for long-term therapy to maintain remission) and a "Crohn's disease-like" group (n = 26, presence of fistulae, pouch inlet stricture, proximal small-bowel disease, or pouch granulomata, occurring at least 6 months after surgery). Genotyping for 83 single-nucleotide polymorphisms previously associated with Crohn's disease and/or ulcerative colitis was performed on a customized Illumina genotyping platform. The top 2 single-nucleotide polymorphisms statistically identified as being independently associated with each of Crohn's disease-like and severe pouchitis were used in a multivariate logistic regression model. These single-nucleotide polymorphisms were then used to create probability equations to predict overall chance of a positive or negative outcome for that complication. The top 2 single-nucleotide polymorphisms for Crohn's disease-like complications were in the 10q21 locus and the gene for PTGER4 (p = 0.006 and 0.007), whereas for severe pouchitis it was NOD2 and TNFSF15 (p = 0.003 and 0.011). Probability equations suggested that the risk of these 2 complications greatly increased with increasing number of risk alleles, going as high as 92% for severe pouchitis and 65% for Crohn's disease-like complications. In this IPAA patient cohort, mutations in the 10q21 locus and the PTGER4 gene were associated with Crohn's disease-like complications, whereas mutations in NOD2 and TNFSF15 correlated with severe pouchitis. Preoperative genetic analysis and use of such gene signatures hold promise for improved preoperative surgical patient selection to minimize these IPAA complications.

Genetic diversity in intraspecific hybrid populations of Eucommia ulmoides Oliver evaluated from ISSR and SRAP molecular marker analysis.

PubMed

Yu, J; Wang, Y; Ru, M; Peng, L; Liang, Z S

2015-07-03

Eucommia ulmoides Oliver, the only extant species of Eucommiaceae, is a second-category state-protected endangered plant in China. Evaluation of genetic diversity among some intraspecific hybrid populations of E. ulmoides Oliver is vital for breeding programs and further conservation of this rare species. We studied the genetic diversity of 130 accessions from 13 E. ulmoides intraspecific hybrid populations using inter-simple sequence related (ISSR) and sequence-related amplified polymorphism (SRAP) markers. Of the 100 ISSR primers and 100 SRAP primer combinations screened, eight ISSRs and eight SRAPs were used to evaluate the level of polymorphism and discriminating capacity. A total number of 65 bands were amplified using eight ISSR primers, in which 50 bands (76.9%) were polymorphic, with an average of 8.1 polymorphic fragments per primer. Alternatively, another 244 bands were observed using eight SRAP primer combinations, and 163 (66.8%) of them were polymorphic, with an average of 30.5 polymorphic fragments per primer. The unweighted pair-group method (UPGMA) analysis showed that these 13 populations could be classified into three groups by the ISSR marker and two groups by the SRAP marker. Principal coordinate analysis using SRAP was completely identical to the UPGMA-based clustering, although this was partly confirmed by the results of UPGMA cluster analysis using the ISSR marker. This study provides insights into the genetic background of E. ulmoides intraspecific hybrids. The progenies of the variations "Huazhong-3", "big fruit", "Yanci", and "smooth bark" present high genetic diversity and offer great potential for E. ulmoides breeding and conservation.

HLA-DQA1 and PLA2R1 polymorphisms and risk of idiopathic membranous nephropathy.

PubMed

Bullich, Gemma; Ballarín, José; Oliver, Artur; Ayasreh, Nadia; Silva, Irene; Santín, Sheila; Díaz-Encarnación, Montserrat M; Torra, Roser; Ars, Elisabet

2014-02-01

Single nucleotide polymorphisms (SNPs) within HLA complex class II HLA-DQ α-chain 1 (HLA-DQA1) and M-type phospholipase A2 receptor (PLA2R1) genes were identified as strong risk factors for idiopathic membranous nephropathy (IMN) development in a recent genome-wide association study. Copy number variants (CNVs) within the Fc gamma receptor III (FCGR3) locus have been associated with several autoimmune diseases, but their role in IMN has not been studied. This study aimed to validate the association of HLA-DQA1 and PLA2R1 risk alleles with IMN in a Spanish cohort, test the putative association of FCGR3A and FCGR3B CNVs with IMN, and assess the use of these genetic factors to predict the clinical outcome of the disease. A Spanish cohort of 89 IMN patients and 286 matched controls without nephropathy was recruited between October of 2009 and July of 2012. Case-control studies for SNPs within HLA-DQA1 (rs2187668) and PLA2R1 (rs4664308) genes and CNVs for FCGR3A and FCGR3B genes were performed. The contribution of these polymorphisms to predict clinical outcome and renal function decline was analyzed. This study validated the association of these HLA-DQA1 and PLA2R1 SNPs with IMN in a Spanish cohort and its increased risk when combining both risk genotypes. No significant association was found between FCGR3 CNVs and IMN. These results revealed that HLA-DQA1 and PLA2R1 genotype combination adjusted for baseline proteinuria strongly predicted response to immunosuppressive therapy. HLA-DQA1 genotype adjusted for proteinuria was also linked with renal function decline. This study confirms that HLA-DQA1 and PLA2R1 genotypes are risk factors for IMN, whereas no association was identified for FCGR3 CNVs. This study provides, for the first time, evidence of the contribution of these HLA-DQA1 and PLA2R1 polymorphisms in predicting IMN response to immunosuppressors and disease progression. Future studies are needed to validate and identify prognostic markers.

CXCR3/CCR5 pathways in metastatic melanoma patients treated with adoptive therapy and interleukin-2

PubMed Central

Bedognetti, D; Spivey, T L; Zhao, Y; Uccellini, L; Tomei, S; Dudley, M E; Ascierto, M L; De Giorgi, V; Liu, Q; Delogu, L G; Sommariva, M; Sertoli, M R; Simon, R; Wang, E; Rosenberg, S A; Marincola, F M

2013-01-01

Background: Adoptive therapy with tumour-infiltrating lymphocytes (TILs) induces durable complete responses (CR) in ∼20% of patients with metastatic melanoma. The recruitment of T cells through CXCR3/CCR5 chemokine ligands is critical for immune-mediated rejection. We postulated that polymorphisms and/or expression of CXCR3/CCR5 in TILs and the expression of their ligands in tumour influence the migration of TILs to tumours and tumour regression. Methods: Tumour-infiltrating lymphocytes from 142 metastatic melanoma patients enrolled in adoptive therapy trials were genotyped for CXCR3 rs2280964 and CCR5-Δ32 deletion, which encodes a protein not expressed on the cell surface. Expression of CXCR3/CCR5 in TILs and CXCR3/CCR5 and ligand genes in 113 available parental tumours was also assessed. Tumour-infiltrating lymphocyte data were validated by flow cytometry (N=50). Results: The full gene expression/polymorphism model, which includes CXCR3 and CCR5 expression data, CCR5-Δ32 polymorphism data and their interaction, was significantly associated with both CR and overall response (OR; P=0.0009, and P=0.007, respectively). More in detail, the predicted underexpression of both CXCR3 and CCR5 according to gene expression and polymorphism data (protein prediction model, PPM) was associated with response to therapy (odds ratio=6.16 and 2.32, for CR and OR, respectively). Flow cytometric analysis confirmed the PPM. Coordinate upregulation of CXCL9, CXCL10, CXCL11, and CCL5 in pretreatment tumour biopsies was associated with OR. Conclusion: Coordinate overexpression of CXCL9, CXCL10, CXCL11, and CCL5 in pretreatment tumours was associated with responsiveness to treatment. Conversely, CCR5-Δ32 polymorphism and CXCR3/CCR5 underexpression influence downregulation of the corresponding receptors in TILs and were associated with likelihood and degree of response. PMID:24129241

Do estrogen receptor alpha polymorphisms have any impact on the outcome in an ART program?

PubMed

Anagnostou, Elli; Malamas, Fotodotis; Mavrogianni, Despina; Dinopoulou, Vasiliki; Drakakis, Peter; Kallianidis, Konstantinos; Loutradis, Dimitris

2013-04-01

To investigate two of the most studied estrogen receptor alpha polymorphisms (PvuII and XbaI) in combination, in order to evaluate their impact on an ART program outcome. 203 normally ovulating women who underwent IVF or ICSI treatment were genotyped for PvuII and XbaI polymorphisms in ESR1 intron 1 using Real-Time PCR. The relationship between the presence of polymorphic alleles and the ovulation induction parameters and outcome was examined. Women were grouped according to the number of polymorphic alleles they carried in two groups (0-2 versus 3-4 polymorphic alleles). The presence of 3 or more polymorphic alleles was associated with significantly lower E2 levels on the day of hCG administration and a significantly lower rate of good quality embryos. There is an association between ESR1 polymorphisms and some ART parameters such as the level of E2 on the day of hCG administration and the quality of the embryos. These results underline the importance of ESR1 as a candidate gene for the prediction of ovarian response to IVF/ICSI protocols. Future research work concerning several more genes is necessary for a better evaluation of patients before entering an IVF/ICSI program.

Evaluation of the influence of alcohol dehydrogenase polymorphisms on alcohol elimination rates in African Americans.

PubMed

Marshall, Vanessa J; Ramchandani, Vijay A; Kalu, Nnenna; Kwagyan, John; Scott, Denise M; Ferguson, Clifford L; Taylor, Robert E

2014-01-01

The relationship between alcohol dehydrogenase (ADH) polymorphisms and alcohol use disorders in populations of African descent has not been clearly established. This study examined the effect of ADH1B polymorphisms on alcohol metabolism and subjective response, following intravenous (IV) alcohol administration, and the influence of gender, recent drinking history, and family history of alcoholism (FHA), in nondependent African American drinkers. The sample included eighty-seven 21- to 35-year-old, light social drinkers of African descent. Participants included 39 sib pairs, 2 sibships with 3 siblings each, and 3 individuals who were not part of a sibship. Participants received infusions via the use of the clamp method that refers to the goal of controlling breath alcohol concentration in 2 randomized sessions at 0.06 g% ethanol and 0 mg% (placebo), and a battery of subjective scales at predefined time points. Dependent measures included alcohol elimination rates (AERs), alcohol disappearance rates (ADRs), subjective measures peak scores, and area under the curve. General linear model and mixed models were performed to examine the relationship between ADH1B genotype, dependent measures, and influence of covariates. Participants with ADH1B1/1 genotypes showed higher number of drinks (p = 0.023) and drinks per drinking day (p = 0.009) compared with the persons with ADH1B1/3 genotype. AER (adjusted for body weight) was higher in ADH1B*1 homozygotes (p = 0.045) compared with ADH1B1/3 heterozygotes. ADR differed significantly between males and females (p = 0.002), regardless of body weight (p = 0.004) and lean body mass (p < 0.001) adjustments. Although a few subjective measures differed across genotype, all measures were higher in alcohol sessions compared with placebo sessions (p < 0.001). These observations were mediated by drinks per drinking day, gender, and FHA. ADH1B polymorphism had a marginal effect on alcohol pharmacokinetics following IV alcohol administration in nondependent drinkers of African descent. Session (alcohol vs. placebo) and ADH1B genotype did, however, influence subjective response to alcohol with some variation by gender, FHA, and drinks per drinking day. Copyright © 2013 by the Research Society on Alcoholism.

Association of a new FCN3 haplotype with high ficolin-3 levels in leprosy.

PubMed

Andrade, Fabiana Antunes; Beltrame, Marcia Holsbach; Bini, Valéria Bumiller; Gonçalves, Letícia Boslooper; Boldt, Angelica Beate Winter; Messias-Reason, Iara Jose de

2017-02-01

Leprosy is a chronic inflammatory disease caused by Mycobacterium leprae that mainly affects the skin and peripheral nervous system, leading to a high disability rate and social stigma. Previous studies have shown a contribution of genes encoding products of the lectin pathway of complement in the modulation of the susceptibility to leprosy; however, the ficolin-3/FCN3 gene impact on leprosy is currently unknown. The aim of the present study was to investigate if FCN3 polymorphisms (rs532781899: g.1637delC, rs28362807: g.3524_3532insTATTTGGCC and rs4494157: g.4473C>A) and ficolin-3 serum levels play a role in the susceptibility to leprosy. We genotyped up to 190 leprosy patients (being 114 (60%) lepromatous), and up to 245 controls with sequence-specific PCR. We also measured protein levels using ELISA in 61 leprosy and 73 controls. FCN3 polymorphisms were not associated with disease, but ficolin-3 levels were higher in patients with FCN3 *2B1 (CinsA) haplotype (p = 0.032). Median concentration of ficolin-3 was higher in leprosy per se (26034 ng/mL, p = 0.005) and lepromatous patients (28295 ng/mL, p = 0.016) than controls (18231 ng/mL). In addition, high ficolin-3 levels (>33362 ng/mL) were more common in leprosy per se (34.4%) and in lepromatous patients (35.5%) than controls (19.2%; p = 0.045 and p = 0.047, respectively). Our results lead us to suggest that polymorphisms in the FCN3 gene cooperate to increase ficolin-3 concentration and that it might contribute to leprosy susceptibility by favoring M. leprae infection.

Increased genomic prediction accuracy in wheat breeding through spatial adjustment of field trial data.

PubMed

Lado, Bettina; Matus, Ivan; Rodríguez, Alejandra; Inostroza, Luis; Poland, Jesse; Belzile, François; del Pozo, Alejandro; Quincke, Martín; Castro, Marina; von Zitzewitz, Jarislav

2013-12-09

In crop breeding, the interest of predicting the performance of candidate cultivars in the field has increased due to recent advances in molecular breeding technologies. However, the complexity of the wheat genome presents some challenges for applying new technologies in molecular marker identification with next-generation sequencing. We applied genotyping-by-sequencing, a recently developed method to identify single-nucleotide polymorphisms, in the genomes of 384 wheat (Triticum aestivum) genotypes that were field tested under three different water regimes in Mediterranean climatic conditions: rain-fed only, mild water stress, and fully irrigated. We identified 102,324 single-nucleotide polymorphisms in these genotypes, and the phenotypic data were used to train and test genomic selection models intended to predict yield, thousand-kernel weight, number of kernels per spike, and heading date. Phenotypic data showed marked spatial variation. Therefore, different models were tested to correct the trends observed in the field. A mixed-model using moving-means as a covariate was found to best fit the data. When we applied the genomic selection models, the accuracy of predicted traits increased with spatial adjustment. Multiple genomic selection models were tested, and a Gaussian kernel model was determined to give the highest accuracy. The best predictions between environments were obtained when data from different years were used to train the model. Our results confirm that genotyping-by-sequencing is an effective tool to obtain genome-wide information for crops with complex genomes, that these data are efficient for predicting traits, and that correction of spatial variation is a crucial ingredient to increase prediction accuracy in genomic selection models.

Influence of genetic polymorphisms of FPGS, GGH, and MTHFR on serum methotrexate levels in Chinese children with acute lymphoblastic leukemia.

PubMed

Wang, Shu-mei; Sun, Lu-lu; Zeng, Wei-xin; Wu, Wan-shui; Zhang, Guo-liang

2014-08-01

To investigate the correlation between common genetic polymorphisms of folylpolyglutamate synthase (FPGS), gamma-glutamyl hydrolase (GGH), and methylenetetrahydrofolate reductase (MTHFR) and serum levels of methotrexate (MTX) in Chinese children with acute lymphoblastic leukemia (ALL). Ninety-one children with ALL who received high-dose MTX were recruited. The polymorphisms FPGS (rs1544105 G>A), GGH (rs3758149 C>T), and MTHFR (rs1801133 C>T) were genotyped through polymerase chain reaction-restriction fragment length polymorphism analysis. Serum MTX was measured by fluorescence polarization immunoassay. The association between targeted polymorphisms and MTX concentration-to-dose (C/D) ratios was assessed, and between targeted polymorphisms and the percent of MTX above the therapeutic threshold (40 µmol/L). The minor allele frequencies of rs1544105 G (34.1%), rs3758149 T (19.2%), and rs1801133 C (48.4%) observed in our population were significantly lower than those reported for European populations (64.2, 30.8, and 69.0%, respectively). The association between the GGH rs3758149 polymorphism and MTX C/D was gender-specific; in girls, the MTX C/D at 24 h of GGH rs3758149 CC carriers (12.09 μmol/L per g/m(2)) was significantly lower than that of CT or TT carriers (16.80 μmol/L per g/m(2)). The percent of serum MTX above the therapeutic threshold in GGH rs3758149 CC carriers (18.3%) was significantly lower than that of CT and TT carriers (38.7%). The MTX C/D ratios at 24 h and the percent of MTX >40 µmol/L for the A-T-T (three variant alleles) haplotype were significantly higher than those for other haplotypes combined (P < 0.05). These data indicate that FPGS rs1544105, GGH rs3758149, and MTHFR rs1801133 polymorphisms contribute to the variability of MTX pharmacokinetics, and their genotyping may be useful to reduce toxicities associated with MTX therapy.

Comparative study of polymorphism frequencies of the CYP2D6, CYP3A5, CYP2C8 and IL-10 genes in Mexican and Spanish women with breast cancer.

PubMed

Alcazar-González, Gregorio Antonio; Calderón-Garcidueñas, Ana Laura; Garza-Rodríguez, María Lourdes; Rubio-Hernández, Gabriela; Escorza-Treviño, Sergio; Olano-Martin, Estibaliz; Cerda-Flores, Ricardo Martín; Castruita-Avila, Ana Lilia; González-Guerrero, Juan Francisco; le Brun, Stéphane; Simon-Buela, Laureano; Barrera-Saldaña, Hugo Alberto

2013-10-01

Pharmacogenetic studies in breast cancer (BC) may predict the efficacy of tamoxifen and the toxicity of paclitaxel and capecitabine. We determined the frequency of polymorphisms in the CYP2D6 gene associated with activation of tamoxifen, and those of the genes CYP2C8, CYP3A5 and DPYD associated with toxicity of paclitaxel and capecitabine. We also included a IL-10 gene polymorphism associated with advanced tumor stage at diagnosis. Genomic DNAs from 241 BC patients from northeast Mexico were genotyped using DNA microarray technology. For tamoxifen processing, CYP2D6 genotyping predicted that 90.8% of patients were normal metabolizers, 4.2% ultrarapid, 2.1% intermediate and 2.9% poor metabolizers. For paclitaxel and the CYP2C8 gene, 75.3% were normal, 23.4% intermediate and 1.3% poor metabolizers. Regarding the DPYD gene, only one patient was a poor metabolizer. For the IL-10 gene, 47.1% were poor metabolizers. These results contribute valuable information towards personalizing BC chemotherapy in Mexican women.

Effect of CYP3A4 genetic polymorphisms on the genotoxicity of 4,4'-methylene-bis(2-chloroaniline)-exposed workers.

PubMed

Wang, Chung-Ching; Chen, Wei-Liang; Hsiung, Chia-Ni; Chiang, Sheng-Ta; Wang, Ying-Chuan; Loh, Ching-Hui; Lin, I-Shen; Chen, Hong-I; Liou, Saou-Hsing

2017-01-01

We investigated the relationship between 4,4'-methylene-bis(2-chloroaniline) (MBOCA) exposure and micronucleus (MN) frequency, and how this association was affected by genetic polymorphism of the cytochrome P450 enzyme (CYP3A4). We divided the study population into an exposed group (n=44 with total urine MBOCA ≥20 μg/g creatinine) and a control group (n=47 with total urine MBOCA <20 μg/g creatinine). Lymphocyte MN frequency (MNF) and micronucleated cell (MNC) frequency were measured by the cytokinesis-block MN assay method. MNF reported as the number of micronuclei in binucleated cells per 1000 cells, and MNC reported as the number of binucleated cells with the presence of MN per 1000 cells. CYP3A4 alleles were measured by PCR-based restriction fragment length polymorphism (PCR-RFLP). The mean MNF (6.11 vs 4.46 MN/1000 cells, p<0.001) and MNC (5.75 vs 4.15 MN/1000 cells, p<0.001) in the exposed workers was significantly higher than that in the controls. The CYP3A4 polymorphism A/A+A/G influenced the difference in the mean MNF (5.97 vs 4.38 MN/1000 cells, p<0.001) and MNC (5.60 vs 4.15 MN/1000 cells, p<0.001) between the MBOCA-exposed and control groups. After adjusting risk factors, the MNF level in the MBOCA-exposed workers was 0.520 MN cells/1000 cells (p<0.001) higher than the control group among the CYP3A4 A/A+A/G genotype. Similarly, the MNC level in the MBOCA-exposed workers was 0.593 MN/1000 cells (p<0.001) higher than the control group among the CYP3A4 A/A+A/G genotype. However, the difference in adjusted MNF and MNC between the exposed and control groups was not significant for the CYP3A4 polymorphism with the G/G genotype. We recommend that lymphocytes MNF and MNC are good indicators to evaluate MBOCA genotoxicity. Individuals with the CYP3A4 polymorphism A/A and A/G genotypes appear to be more susceptible to MBOCA genotoxicity. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/.

Polymorphism of TS 3'-UTR predicts survival of Chinese advanced gastric cancer patients receiving first-line capecitabine plus paclitaxel.

PubMed

Gao, J; He, Q; Hua, D; Mao, Y; Li, Y; Shen, L

2013-08-01

Capecitabine-containing chemotherapy was widely used in clinic medication. We investigated the association of the thymidylate synthase (TS), methylenetetrahydrofolate reductase (MTHFR), and dihydropyrimidine dehydrogenase (DPD) polymorphisms with the clinical outcome of Chinese advanced gastric cancer patients receiving first-line capecitabine plus paclitaxel. Blood samples were collected prior to treatment from 125 patients with advanced gastric cancer and the TS (two or three repeats of a 28 bp sequence in 5'-untranslated region and 6 bp insertion or deletion in 3'-untranslated region), MTHFR (C677T) and DPD (IVS14+1G > A) polymorphisms were determined using PCR amplification and Sanger sequencing. The median age of 125 patients was 58 years (range, 23-76) with female 42 and male 83, and the response rate, median progression-free survival and overall survival (OS) were 43.2 %, 5.2 and 11.0 months. The median OS in patients with TS ins6/ins6 genotype (6.8 months) was significantly shorter than those in patients with ins6/del6 (11.0 months, P = 0.016) and del6/del6 (11.5 months, P = 0.039) genotypes. Cox multivariate analysis also showed that TS ins6/ins6 genotype was the independent poor OS predictor (P = 0.001, HR = 3.182). No significant associations were found between the polymorphisms of TS 5'-UTR/MTHFR and clinical outcome, and no IVS14+1G > A polymorphism of DPD was found in this study. We first reported that TS 3'-UTR ins6/ins6 genotype could predict the poor survival of advanced gastric cancer patients treated with capecitabine plus paclitaxel, which would be further verified in a large multicenter study.

The Effect of ACE I/D Polymorphisms Alone and With Concomitant Risk Factors on Coronary Artery Disease.

PubMed

Amara, Ahmed; Mrad, Meriem; Sayeh, Aicha; Lahideb, Dhaker; Layouni, Samy; Haggui, Abdeddayem; Fekih-Mrissa, Najiba; Haouala, Habib; Nsiri, Brahim

2018-01-01

Coronary artery disease (CAD), also known as atherosclerotic heart disease, is a leading cause of mortality and morbidity throughout the world. The role of insertion/deletion (I/D) polymorphisms of the angiotensin-converting enzyme (ACE) gene in the etiology of CAD remains to be more completely clarified. The aim of this study was to determine the role of the ACE I/D polymorphism in patients with CAD and to study the association together with traditional risk factors in assessing the risk of CAD. Our study population included 145 Tunisian patients with symptomatic CAD and a control group of 300 people matched for age and sex. All participants in the study were genotyped for the ACE I/D polymorphisms obtained by polymerase chain reaction amplification on genomic DNA. Our analysis showed that the ACE D allele frequency ( P < 10 -3 ; odds ratio [OR] = 5.2; 95% confidence interval [CI] = 3.6-7.6) and DD genotype ( P < 10 -3 ; OR = 6.8; 95% CI = 4.4-10) are significantly more prevalent among patients with CAD than in controls and may be predisposing to CAD. We further found that the risk of CAD is greatly potentiated by several concomitant risk factors (smoking, diabetes, hypertension, dyslipidemia, and a family history of CAD). The ACE D allele may be predictive in individuals who may be at risk of developing CAD. Further investigations of these polymorphisms and their possible synergisms with traditional risk factors for CAD could help to ascertain better predictability for CAD susceptibility.

[The value of 5-HTT gene polymorphism for the assessment and prediction of male adolescence violence].

PubMed

Yu, Yue; Liu, Xiang; Yang, Zhen-xing; Qiu, Chang-jian; Ma, Xiao-hong

2012-08-01

To establish an adolescent violence crime prediction model, and to assess the value of serotonin transporter (5-HTT) gene polymorphism for the assessment and prediction of violent crime. Investigative tools were used to analyze the difference in personality dimensions, social support, coping styles, aggressiveness, impulsivity, and family condition scale between 223 adolescents with violence behavior and 148 adolescents without violence behavior. The distribution of 5-HTT gene polymorphisms (5-HTTLPR and 5-HTTVNTR) was compared between the two groups. The role of 5-HTT gene polymorphism on adolescent personality, impulsion and aggression scale also was also analyzed. Stepwise logistic regression was used to establish a predictive model for adolescent violent crime. Significant difference was found between the violence group and the control group on multiple dimensions of psychology and environment scales. However, no statistical difference was found with regard to the 5-HTT genotypes and alleles between adolescents with violent behaviors and normal controls. The rate of prediction accuracy was not significantly improved when 5-HTT gene polymorphism was taken into the model. The violent crime of adolescents was closely related with social and environmental factors. No association was found between 5-HTT polymorphisms and adolescent violence criminal behavior.

A comparative genomics strategy for targeted discovery of single-nucleotide polymorphisms and conserved-noncoding sequences in orphan crops.

PubMed

Feltus, F A; Singh, H P; Lohithaswa, H C; Schulze, S R; Silva, T D; Paterson, A H

2006-04-01

Completed genome sequences provide templates for the design of genome analysis tools in orphan species lacking sequence information. To demonstrate this principle, we designed 384 PCR primer pairs to conserved exonic regions flanking introns, using Sorghum/Pennisetum expressed sequence tag alignments to the Oryza genome. Conserved-intron scanning primers (CISPs) amplified single-copy loci at 37% to 80% success rates in taxa that sample much of the approximately 50-million years of Poaceae divergence. While the conserved nature of exons fostered cross-taxon amplification, the lesser evolutionary constraints on introns enhanced single-nucleotide polymorphism detection. For example, in eight rice (Oryza sativa) genotypes, polymorphism averaged 12.1 per kb in introns but only 3.6 per kb in exons. Curiously, among 124 CISPs evaluated across Oryza, Sorghum, Pennisetum, Cynodon, Eragrostis, Zea, Triticum, and Hordeum, 23 (18.5%) seemed to be subject to rigid intron size constraints that were independent of per-nucleotide DNA sequence variation. Furthermore, we identified 487 conserved-noncoding sequence motifs in 129 CISP loci. A large CISP set (6,062 primer pairs, amplifying introns from 1,676 genes) designed using an automated pipeline showed generally higher abundance in recombinogenic than in nonrecombinogenic regions of the rice genome, thus providing relatively even distribution along genetic maps. CISPs are an effective means to explore poorly characterized genomes for both DNA polymorphism and noncoding sequence conservation on a genome-wide or candidate gene basis, and also provide anchor points for comparative genomics across a diverse range of species.

A Comparative Genomics Strategy for Targeted Discovery of Single-Nucleotide Polymorphisms and Conserved-Noncoding Sequences in Orphan Crops1[W

PubMed Central

Feltus, F.A.; Singh, H.P.; Lohithaswa, H.C.; Schulze, S.R.; Silva, T.D.; Paterson, A.H.

2006-01-01

Completed genome sequences provide templates for the design of genome analysis tools in orphan species lacking sequence information. To demonstrate this principle, we designed 384 PCR primer pairs to conserved exonic regions flanking introns, using Sorghum/Pennisetum expressed sequence tag alignments to the Oryza genome. Conserved-intron scanning primers (CISPs) amplified single-copy loci at 37% to 80% success rates in taxa that sample much of the approximately 50-million years of Poaceae divergence. While the conserved nature of exons fostered cross-taxon amplification, the lesser evolutionary constraints on introns enhanced single-nucleotide polymorphism detection. For example, in eight rice (Oryza sativa) genotypes, polymorphism averaged 12.1 per kb in introns but only 3.6 per kb in exons. Curiously, among 124 CISPs evaluated across Oryza, Sorghum, Pennisetum, Cynodon, Eragrostis, Zea, Triticum, and Hordeum, 23 (18.5%) seemed to be subject to rigid intron size constraints that were independent of per-nucleotide DNA sequence variation. Furthermore, we identified 487 conserved-noncoding sequence motifs in 129 CISP loci. A large CISP set (6,062 primer pairs, amplifying introns from 1,676 genes) designed using an automated pipeline showed generally higher abundance in recombinogenic than in nonrecombinogenic regions of the rice genome, thus providing relatively even distribution along genetic maps. CISPs are an effective means to explore poorly characterized genomes for both DNA polymorphism and noncoding sequence conservation on a genome-wide or candidate gene basis, and also provide anchor points for comparative genomics across a diverse range of species. PMID:16607031

A NOS3 polymorphism determines endothelial response to folate in children with type 1 diabetes or obesity.

PubMed

Wiltshire, Esko J; Peña, Alexia S; MacKenzie, Karen; Bose-Sundernathan, Tulika; Gent, Roger; Couper, Jennifer J

2015-02-01

To determine the effect of polymorphisms in NOS3 and folate pathway enzymes on vascular function and folate status and endothelial response to folate in children with diabetes or obesity. A total of 244 subjects (age 13.8 ± 2.8 years, 125 males) were studied for NOS3 and/or folate pathway polymorphisms using polymerase chain reaction/restriction fragment length polymorphism, including at baseline: 139 with type 1 diabetes; 58 with obesity; and 47 controls. The effect of NOS3 genotype on endothelial response to folate (5 mg) was assessed in 85 subjects with diabetes and 28 obese subjects who received active treatment during intervention trials. Vascular function (flow-mediated dilatation [FMD] and glyceryl trinitrate-mediated dilatation), clinical, and biochemical measurements were assessed at baseline and 8 weeks in folate intervention studies. Folate pathway enzyme and NOS3 polymorphisms did not significantly affect baseline vascular function. The polymorphism in intron 4 of endothelial nitric oxide synthase altered endothelial response to folate significantly: in subjects with diabetes FMD improved by 6.4 ± 5% (insertion carriers) vs 2.3 ± 6.6% (deletion carriers), P = .01; in obese subjects FMD improved by 1.8 ± 5.4% (insertion carriers) and deteriorated by -3.2 ± 7.2% (deletion carriers), P = .05. More subjects carrying the insertion normalized FMD after folate supplementation (insertion 64% vs deletion 28%, χ(2) = 10.14, P = .001). A NOS3 polymorphism predicts endothelial response to folate in children with diabetes or obesity, with implications for vascular risk and folate intervention studies. Copyright © 2015 Elsevier Inc. All rights reserved.

APOA5 -1131T>C and APOC3 -455T>C polymorphisms are associated with an increased risk of coronary heart disease.

PubMed

Sun, Y; Zhou, R B; Chen, D M

2015-12-28

The aim of this study was to investigate correlations between apolipoprotein A-V (APOA5) -1131T>C and apolipoprotein C-III (APOC3) -455T>C polymorphisms and coronary heart disease (CHD). PubMed, Ovid, Cochrane Library, Embase, China National Knowledge Infrastructure, and Wanfang databases were searched using combinations of keywords relating to these polymorphisms and CHD. Studies retrieved from database searches were screened using our stringent inclusion and exclusion criteria, and Comprehensive Meta-Analysis Version 2.0 software was used for statistical analyses. In total, 115 studies were initially retrieved and after further selection, 11 were included in the meta-analysis. These 11 articles comprised 4840 patients with CHD in the case group and 4913 healthy participants in the control group. Meta-analysis revealed that APOA5 -1131T>C and APOC3 -455T>C polymorphisms increased CHD risk. In addition, subgroup analysis by ethnicity showed that while the -1131T>C polymorphism elevated the risk of CHD in the Caucasian population under both allelic and dominant models, this increased risk was observed only under a dominant model in the Asian population. The results of our meta-analysis point to a strong link between both APOA5 -1131T>C and APOC3 -455T>C polymorphisms and an increased risk of CHD. Thus, these polymorphisms constitute important predictive indicators of CHD susceptibility.

Warfarin pharmacogenetics: a single VKORC1 polymorphism is predictive of dose across 3 racial groups.

PubMed

Limdi, Nita A; Wadelius, Mia; Cavallari, Larisa; Eriksson, Niclas; Crawford, Dana C; Lee, Ming-Ta M; Chen, Chien-Hsiun; Motsinger-Reif, Alison; Sagreiya, Hersh; Liu, Nianjun; Wu, Alan H B; Gage, Brian F; Jorgensen, Andrea; Pirmohamed, Munir; Shin, Jae-Gook; Suarez-Kurtz, Guilherme; Kimmel, Stephen E; Johnson, Julie A; Klein, Teri E; Wagner, Michael J

2010-05-06

Warfarin-dosing algorithms incorporating CYP2C9 and VKORC1 -1639G>A improve dose prediction compared with algorithms based solely on clinical and demographic factors. However, these algorithms better capture dose variability among whites than Asians or blacks. Herein, we evaluate whether other VKORC1 polymorphisms and haplotypes explain additional variation in warfarin dose beyond that explained by VKORC1 -1639G>A among Asians (n = 1103), blacks (n = 670), and whites (n = 3113). Participants were recruited from 11 countries as part of the International Warfarin Pharmacogenetics Consortium effort. Evaluation of the effects of individual VKORC1 single nucleotide polymorphisms (SNPs) and haplotypes on warfarin dose used both univariate and multi variable linear regression. VKORC1 -1639G>A and 1173C>T individually explained the greatest variance in dose in all 3 racial groups. Incorporation of additional VKORC1 SNPs or haplotypes did not further improve dose prediction. VKORC1 explained greater variability in dose among whites than blacks and Asians. Differences in the percentage of variance in dose explained by VKORC1 across race were largely accounted for by the frequency of the -1639A (or 1173T) allele. Thus, clinicians should recognize that, although at a population level, the contribution of VKORC1 toward dose requirements is higher in whites than in nonwhites; genotype predicts similar dose requirements across racial groups.

NADH Dehydrogenase Subunit-2 237 Leu/Met Polymorphism Modulates the Effects of Coffee Consumption on the Risk of Hypertension in Middle-Aged Japanese Men

PubMed Central

Kokaze, Akatsuki; Ishikawa, Mamoru; Matsunaga, Naomi; Karita, Kanae; Yoshida, Masao; Ohtsu, Tadahiro; Shirasawa, Takako; Sekii, Hideaki; Ito, Taku; Kawamoto, Teruyoshi; Takashima, Yutaka

2009-01-01

Background Habitual coffee consumption has been reported to lower blood pressure in the Japanese population. The NADH dehydrogenase subunit-2 237 leucine/methionine (ND2-237 Leu/Met) polymorphism is associated with longevity and modifies the effects of alcohol consumption on blood pressure in the Japanese population. The objective of this study was to determine whether this polymorphism also modifies the effects of coffee consumption on blood pressure or the risk of hypertension in middle-aged Japanese men. Methods A total of 398 men (mean age ± standard deviation, 53.8 ± 7.8 years) were selected from among individuals visiting the hospital for regular medical check-ups. Hypertension was defined as a systolic blood pressure ≥140 mm Hg, diastolic blood pressure ≥90 mm Hg, or antihypertensive drug treatment. Polymerase chain reaction-restriction fragment length polymorphism using the restriction enzyme AluI was performed to determine ND2-237 Leu/Met genotype. Results In subjects with ND2-237Leu, coffee consumption was significantly and negatively associated with diastolic blood pressure (P = 0.007). The odds ratio (OR) for hypertension was significantly lower in subjects with ND2-237Leu who consumed 2 or 3 cups of coffee per day than in those who consumed less than 1 cup of coffee per day (OR, 0.517; 95% confidence interval [CI], 0.276 to 0.968; P = 0.039). After adjustment, the OR remained significant (OR = 0.399; 95% CI, 0.184 to 0.869; P = 0.020). Moreover, after adjustment, the OR was significantly lower in subjects with ND2-237Leu who consumed more than 4 cups of coffee per day than in those who consumed less than 1 cup of coffee per day (OR, 0.246; 95% CI, 0.062 to 0.975; P = 0.046). However, the association between ND2-237Met genotype and hypertension did not depend on coffee consumption. Conclusions The present results suggest that the ND2-237 Leu/Met polymorphism modulates the effects of coffee consumption on hypertension risk in middle-aged Japanese men. PMID:19667492

Meta-analysis of the association between the Trp64Arg polymorphism of the beta-3 adrenergic receptor and susceptibility to gestational diabetes mellitus.

PubMed

Guan, Lianyue; Cui, Xiaofeng; Zhou, Hui

2018-02-01

The study aimed to explore the associations between Trp64Arg polymorphism of Beta-3 Adrenergic receptor (ADRB3) and susceptibility to gestational diabetes mellitus (GDM). Relevant studies till December 2013 were identified through searching electronic databases. A meta-analysis was conducted on associations between Trp64Arg polymorphism in ADRB3 and susceptibility to GDM. We found no association between Trp64Arg polymorphism in ADRB3 and susceptibility to GDM in overall population (Arg vs. Trp: OR = 1.20, 95%CI = 0.99-1.47, p = .16; Trp/Arg + Arg/Arg vs. Trp/Trp: OR = 1.22, 95%CI = 0.99-1.50, p = .11). In subgroup analysis on European Caucasian population, Trp64Arg in ADRB3 was associated with susceptibility to GDM. Trp64Arg polymorphism in ADRB3 had certain association with susceptibility to GDM in the European Caucasian population. Impact statement What is already known on this subject: Gestational diabetes mellitus (GDM) is recognised as carbohydrate intolerance of varied severity that begins or is first recognised during pregnancy. A missense mutation in the codon 64 of the Beta-3 adrenergic receptor (ADRB3), Trp64Arg, leads to the substitution of tryptophan by arginine in the first intracellular loop of the ADRB3 receptor. Trp64Arg Polymorphism has also been reportedly associated with increased body weight, type 2 diabetes mellitus, insulin resistance and obesity. However, other investigators have found that the Trp64Arg polymorphism of ADRB3 has no effect on insulin resistance, obesity or type 2 diabetes mellitus. What the results of the study add: Our present meta-analysis demonstrated that Trp64Arg polymorphism in ADRB3 was associated with susceptibility to GDM in the European Caucasian population. Trp64Arg polymorphism in ADRB3 may be able to predict the occurrence of GDM and used for the diagnosis of it in clinic. What the implications are of these findings for clinical practice and future research: The findings in this study may provide a basis for the further study on Trp64Arg polymorphism in future research.

Role of Key TYMS Polymorphisms on Methotrexate Therapeutic Outcome in Portuguese Rheumatoid Arthritis Patients

PubMed Central

Lima, Aurea; Seabra, Vítor; Bernardes, Miguel; Azevedo, Rita; Sousa, Hugo; Medeiros, Rui

2014-01-01

Background Therapeutic outcome of rheumatoid arthritis (RA) patients treated with methotrexate (MTX) can be modulated by thymidylate synthase (TS) levels, which may be altered by genetic polymorphisms in TS gene (TYMS). This study aims to elucidate the influence of TYMS polymorphisms in MTX therapeutic outcome (regarding both clinical response and toxicity) in Portuguese RA patients. Methods Clinicopathological data from 233 Caucasian RA patients treated with MTX were collected, outcomes were defined and patients were genotyped for the following TYMS polymorphisms: 1) 28 base pairs (bp) variable number tandem repeat (rs34743033); 2) single nucleotide polymorphism C>G (rs2853542); and 3) 6 bp sequence deletion (1494del6, rs34489327). Chi-square and binary logistic regression analyses were performed, using genotype and haplotype-based approaches. Results Considering TYMS genotypes, 3R3R (p = 0.005, OR = 2.34), 3RC3RG (p = 0.016, OR = 3.52) and 6bp− carriers (p = 0.011, OR = 1.96) were associated with non-response to MTX. Multivariate analysis confirmed the increased risk for non-response to MTX in 6bp− carriers (p = 0.016, OR = 2.74). Data demonstrated that TYMS polymorphisms were in linkage disequilibrium (p<0.00001). Haplotype multivariate analysis revealed that haplotypes harboring both 3R and 6bp− alleles were associated with non-response to MTX. Regarding MTX-related toxicity, no statistically significant differences were observed in relation to TYMS genotypes and haplotypes. Conclusion Our study reveals that TYMS polymorphisms could be important to help predicting clinical response to MTX in RA patients. Despite the potential of these findings, translation into clinical practice needs larger studies to confirm these evidences. PMID:25279663

Polymorphisms of Mannose-binding Lectin and Toll-like Receptors 2, 3, 4, 7 and 8 and the Risk of Respiratory Infections and Acute Otitis Media in Children.

PubMed

Toivonen, Laura; Vuononvirta, Juho; Mertsola, Jussi; Waris, Matti; He, Qiushui; Peltola, Ville

2017-05-01

Mannose-binding lectin (MBL) and toll-like receptors (TLRs) are important components of the innate immune system. We assessed the susceptibility of children with genetic variants in these factors to respiratory infections, rhinovirus infections and acute otitis media. In a prospective cohort study, blood samples from 381 Finnish children were analyzed for polymorphisms in MBL2 at codons 52, 54 and 57, TLR2 Arg753Gln, TLR3 Leu412Phe, TLR4 Asp299Gly, TLR7 Gln11Leu and TLR8 Leu651Leu. Children were followed up for respiratory infections until 24 months of age with daily diaries. Polymerase chain reaction and antigen tests were used for detection of respiratory viruses from nasal swabs. Children with MBL variant genotype had a mean of 59 days with symptoms of respiratory infection per year, compared with 49 days in those with wild-type (P = 0.01). TLR8 polymorphisms were associated with an increased risk and TLR7 polymorphisms with a decreased risk of recurrent rhinovirus infections (P = 0.02 for both). TLR2 polymorphisms were associated with recurrent acute otitis media (P = 0.02). MBL polymorphisms were associated with an increased and TLR7 polymorphisms with a decreased risk of rhinovirus-associated acute otitis media (P = 0.03 and P = 0.006, respectively). Genetic polymorphisms in MBL and TLRs promote susceptibility to or protection against respiratory infections. In addition to environmental factors, genetic variations may explain why some children are more prone to respiratory infections.

The TP53 gene polymorphisms and survival of sporadic breast cancer patients.

PubMed

Bišof, V; Salihović, M Peričić; Narančić, N Smolej; Skarić-Jurić, T; Jakić-Razumović, J; Janićijević, B; Rudan, P

2012-06-01

The TP53 gene polymorphisms, Arg72Pro and PIN3 (+16 bp), can have prognostic and predictive value in different cancers including breast cancer. The aim of the present study is to investigate a potential association between different genotypes of these polymorphisms and clinicopathological variables with survival of breast cancer patients in Croatian population. Ninety-four women with sporadic breast cancer were retrospectively analyzed. Median follow-up period was 67.9 months. The effects of basic clinical and histopathological characteristics of tumor on survival were tested by Cox's proportional hazards regression analysis. The TNM stage was associated with overall survival by Kaplan-Meier analysis, univariate, and multivariate Cox's proportional hazards regression analysis, while grade was associated with survival by Kaplan-Meier analysis and univariate Cox's proportional hazards regression analysis. Different genotypes of the Arg72Pro and PIN3 (+16 bp) polymorphisms had no significant impact on survival in breast cancer patients. However, in subgroup of patients treated with chemotherapy without anthracycline, the A2A2 genotype of the PIN3 (+16 bp) polymorphism was associated with poorer overall survival than other genotypes by Kaplan-Meier analysis (P = 0.048). The TP53 polymorphisms, Arg72Pro and PIN3 (+16 bp), had no impact on survival in unselected sporadic breast cancer patients in Croatian population. However, the results support the role of the A2A2 genotype of the PIN3 (+16 bp) polymorphism as a marker for identification of patients that may benefit from anthracycline-containing chemotherapy.

How and how much does RAD-seq bias genetic diversity estimates?

PubMed

Cariou, Marie; Duret, Laurent; Charlat, Sylvain

2016-11-08

RAD-seq is a powerful tool, increasingly used in population genomics. However, earlier studies have raised red flags regarding possible biases associated with this technique. In particular, polymorphism on restriction sites results in preferential sampling of closely related haplotypes, so that RAD data tends to underestimate genetic diversity. Here we (1) clarify the theoretical basis of this bias, highlighting the potential confounding effects of population structure and selection, (2) confront predictions to real data from in silico digestion of full genomes and (3) provide a proof of concept toward an ABC-based correction of the RAD-seq bias. Under a neutral and panmictic model, we confirm the previously established relationship between the true polymorphism and its RAD-based estimation, showing a more pronounced bias when polymorphism is high. Using more elaborate models, we show that selection, resulting in heterogeneous levels of polymorphism along the genome, exacerbates the bias and leads to a more pronounced underestimation. On the contrary, spatial genetic structure tends to reduce the bias. We confront the neutral and panmictic model to "ideal" empirical data (in silico RAD-sequencing) using full genomes from natural populations of the fruit fly Drosophila melanogaster and the fungus Shizophyllum commune, harbouring respectively moderate and high genetic diversity. In D. melanogaster, predictions fit the model, but the small difference between the true and RAD polymorphism makes this comparison insensitive to deviations from the model. In the highly polymorphic fungus, the model captures a large part of the bias but makes inaccurate predictions. Accordingly, ABC corrections based on this model improve the estimations, albeit with some imprecisions. The RAD-seq underestimation of genetic diversity associated with polymorphism in restriction sites becomes more pronounced when polymorphism is high. In practice, this means that in many systems where polymorphism does not exceed 2 %, the bias is of minor importance in the face of other sources of uncertainty, such as heterogeneous bases composition or technical artefacts. The neutral panmictic model provides a practical mean to correct the bias through ABC, albeit with some imprecisions. More elaborate ABC methods might integrate additional parameters, such as population structure and selection, but their opposite effects could hinder accurate corrections.

The Making of a CYP3A Biomarker Panel for Guiding Drug Therapy

PubMed Central

Wang, Danxin; Sadee, Wolfgang

2012-01-01

CYP3A ranks among the most abundant cytochrome P450 enzymes in the liver, playing a dominant role in metabolic elimination of clinically used drugs. A main member in CYP3A family, CYP3A4 expression and activity vary considerably among individuals, attributable to genetic and non-genetic factors, affecting drug dosage and efficacy. However, the extent of genetic influence has remained unclear. This review assesses current knowledge on the genetic factors influencing CYP3A4 activity. Coding region CYP3A4 polymorphisms are rare and account for only a small portion of inter-person variability in CYP3A metabolism. Except for the promoter allele CYP3A4*1B with ambiguous effect on expression, common CYP3A4 regulatory polymorphisms were thought to be lacking. Recent studies have identified a relatively common regulatory polymorphism, designated CYP3A4*22 with robust effects on hepatic CYP3A4 expression. Combining CYP3A4*22 with CYP3A5 alleles *1, *3 and *7 has promise as a biomarker predicting overall CYP3A activity. Also contributing to variable expression, the role of polymorphisms in transcription factors and microRNAs is discussed. PMID:24466438

Psychological Distress Following Marital Separation Interacts with a Polymorphism in the Serotonin Transporter Gene to Predict Cardiac Vagal Control in the Laboratory

PubMed Central

Hasselmo, Karen; Sbarra, David A.; O'Connor, Mary-Frances; Moreno, Francisco A.

2015-01-01

Marital separation is linked to negative mental and physical health; however, the strength of this link may vary across people. This study examined changes in respiratory sinus arrhythmia (RSA), used to assess cardiac vagal control, in recently separated adults (N = 79; M time since separation = 3.5 months). When reflecting over the separation, self-reported psychological distress following the separation interacted with a polymorphism in the serotonin transporter gene (5-HTTLPR) and a relevant single nucleotide polymorphism (SNP), rs25531, to predict RSA. Among people reporting emotional difficulties after the separation, those who were homozygous for the short allele had lower RSA levels while reflecting on their relationship than other genotypes. The findings, although limited by the relatively small sample size, are discussed in terms of how higher-sensitivity genotypes may interact with psychological responses to stress to alter physiology. PMID:25630596

The 5-HTTLPR and BDNF polymorphisms moderate the association between uncinate fasciculus connectivity and antidepressants treatment response in major depression.

PubMed

Tatham, Erica L; Hall, Geoff B C; Clark, Darren; Foster, Jane; Ramasubbu, Rajamannar

2017-03-01

Symptom improvement in depression due to antidepressant treatment is highly variable and clinically unpredictable. Linking neuronal connectivity and genetic risk factors in predicting antidepressant response has clinical implications. Our investigation assessed whether indices of white matter integrity, serotonin transporter-linked polymorphism (5-HTTLPR) and brain-derived neurotrophic factor (BDNF) val66met polymorphism predicted magnitude of depression symptom change following antidepressant treatment. Fractional anisotropy (FA) was used as an indicator of white matter integrity and was assessed in the uncinate fasciculus and superior longitudinal fasciculus using tract-based spatial statistics (TBSS) and probabilistic tractography. Forty-six medication-free patients with major depressive disorder participated in a diffusion tensor imaging scan prior to completing an 8-week treatment regime with citalopram or quetiapine XR. Indexed improvements in Hamilton Depression Rating Scale score from baseline to 8-week endpoint were used as an indicator of depression improvement. Carriers of the BDNF met allele exhibited lower FA values in the left uncinate fasciculus relative to val/val individuals [F(1, 40) = 7.314, p = 0.009]. Probabilistic tractography identified that higher FA in the left uncinate fasciculus predicted percent change in depression severity, with BDNF moderating this association [F(3, 30) = 3.923, p = 0.018]. An interaction between FA in the right uncinate fasciculus and 5-HTTLPR also predicted percent change in depression severity [F(5, 25) = 5.315, p = 0.002]. Uncorrected TBSS results revealed significantly higher FA in hippocampal portions of the cingulum bundle in responders compared to non-responders (p = 0.016). The predictive value of prefrontal and amygdala/hippocampal WM connectivity on antidepressant treatment response may be influenced by 5-HTTLPR and BDNF polymorphisms in MDD.

Oxytocin efficacy is modulated by dosage and oxytocin receptor genotype in young adults with high-functioning autism: a 24-week randomized clinical trial

PubMed Central

Kosaka, H; Okamoto, Y; Munesue, T; Yamasue, H; Inohara, K; Fujioka, T; Anme, T; Orisaka, M; Ishitobi, M; Jung, M; Fujisawa, T X; Tanaka, S; Arai, S; Asano, M; Saito, D N; Sadato, N; Tomoda, A; Omori, M; Sato, M; Okazawa, H; Higashida, H; Wada, Y

2016-01-01

Recent studies have suggested that long-term oxytocin administration can alleviate the symptoms of autism spectrum disorder (ASD); however, factors influencing its efficacy are still unclear. We conducted a single-center phase 2, pilot, randomized, double-blind, placebo-controlled, parallel-group, clinical trial in young adults with high-functioning ASD, to determine whether oxytocin dosage and genetic background of the oxytocin receptor affects oxytocin efficacy. This trial consisted of double-blind (12 weeks), open-label (12 weeks) and follow-up phases (8 weeks). To examine dose dependency, 60 participants were randomly assigned to high-dose (32 IU per day) or low-dose intranasal oxytocin (16 IU per day), or placebo groups during the double-blind phase. Next, we measured single-nucleotide polymorphisms (SNPs) in the oxytocin receptor gene (OXTR). In the intention-to-treat population, no outcomes were improved after oxytocin administration. However, in male participants, Clinical Global Impression-Improvement (CGI-I) scores in the high-dose group, but not the low-dose group, were significantly higher than in the placebo group. Furthermore, we examined whether oxytocin efficacy, reflected in the CGI-I scores, is influenced by estimated daily dosage and OXTR polymorphisms in male participants. We found that >21 IU per day oxytocin was more effective than ⩽21 IU per day, and that a SNP in OXTR (rs6791619) predicted CGI-I scores for ⩽21 IU per day oxytocin treatment. No severe adverse events occurred. These results suggest that efficacy of long-term oxytocin administration in young men with high-functioning ASD depends on the oxytocin dosage and genetic background of the oxytocin receptor, which contributes to the effectiveness of oxytocin treatment of ASD. PMID:27552585

Oxytocin efficacy is modulated by dosage and oxytocin receptor genotype in young adults with high-functioning autism: a 24-week randomized clinical trial.

PubMed

Kosaka, H; Okamoto, Y; Munesue, T; Yamasue, H; Inohara, K; Fujioka, T; Anme, T; Orisaka, M; Ishitobi, M; Jung, M; Fujisawa, T X; Tanaka, S; Arai, S; Asano, M; Saito, D N; Sadato, N; Tomoda, A; Omori, M; Sato, M; Okazawa, H; Higashida, H; Wada, Y

2016-08-23

Recent studies have suggested that long-term oxytocin administration can alleviate the symptoms of autism spectrum disorder (ASD); however, factors influencing its efficacy are still unclear. We conducted a single-center phase 2, pilot, randomized, double-blind, placebo-controlled, parallel-group, clinical trial in young adults with high-functioning ASD, to determine whether oxytocin dosage and genetic background of the oxytocin receptor affects oxytocin efficacy. This trial consisted of double-blind (12 weeks), open-label (12 weeks) and follow-up phases (8 weeks). To examine dose dependency, 60 participants were randomly assigned to high-dose (32 IU per day) or low-dose intranasal oxytocin (16 IU per day), or placebo groups during the double-blind phase. Next, we measured single-nucleotide polymorphisms (SNPs) in the oxytocin receptor gene (OXTR). In the intention-to-treat population, no outcomes were improved after oxytocin administration. However, in male participants, Clinical Global Impression-Improvement (CGI-I) scores in the high-dose group, but not the low-dose group, were significantly higher than in the placebo group. Furthermore, we examined whether oxytocin efficacy, reflected in the CGI-I scores, is influenced by estimated daily dosage and OXTR polymorphisms in male participants. We found that >21 IU per day oxytocin was more effective than ⩽21 IU per day, and that a SNP in OXTR (rs6791619) predicted CGI-I scores for ⩽21 IU per day oxytocin treatment. No severe adverse events occurred. These results suggest that efficacy of long-term oxytocin administration in young men with high-functioning ASD depends on the oxytocin dosage and genetic background of the oxytocin receptor, which contributes to the effectiveness of oxytocin treatment of ASD.

Time-on-task decrement in vigilance is modulated by inter-individual vulnerability to homeostatic sleep pressure manipulation

PubMed Central

Maire, Micheline; Reichert, Carolin F.; Gabel, Virginie; Viola, Antoine U.; Krebs, Julia; Strobel, Werner; Landolt, Hans-Peter; Bachmann, Valérie; Cajochen, Christian; Schmidt, Christina

2014-01-01

Under sleep loss, vigilance is reduced and attentional failures emerge progressively. It becomes difficult to maintain stable performance over time, leading to growing performance variability (i.e., state instability) in an individual and among subjects. Task duration plays a major role in the maintenance of stable vigilance levels, such that the longer the task, the more likely state instability will be observed. Vulnerability to sleep-loss-dependent performance decrements is highly individual and is also modulated by a polymorphism in the human clock gene PERIOD3 (PER3). By combining two different protocols, we manipulated sleep-wake history by once extending wakefulness for 40 h (high sleep pressure condition) and once by imposing a short sleep-wake cycle by alternating 160 min of wakefulness and 80 min naps (low sleep pressure condition) in a within-subject design. We observed that homozygous carriers of the long repeat allele of PER3 (PER35/5) experienced a greater time-on-task dependent performance decrement (i.e., a steeper increase in the number of lapses) in the Psychomotor Vigilance Task compared to the carriers of the short repeat allele (PER34/4). These genotype-dependent effects disappeared under low sleep pressure conditions, and neither motivation, nor perceived effort accounted for these differences. Our data thus suggest that greater sleep-loss related attentional vulnerability based on the PER3 polymorphism is mirrored by a greater state instability under extended wakefulness in the short compared to the long allele carriers. Our results undermine the importance of time-on-task related aspects when investigating inter-individual differences in sleep loss-induced behavioral vulnerability. PMID:24639634

Molecular Cloning and Characterization of the Human ErbB4 Gene: Identification of Novel Splice Isoforms in the Developing and Adult Brain

PubMed Central

Tan, Wei; Dean, Michael; Law, Amanda J.

2010-01-01

ErbB4 is a growth factor receptor tyrosine kinase essential for neurodevelopment. Genetic variation in ErbB4 is associated with schizophrenia and risk-associated polymorphisms predict overexpression of ErbB4 CYT-1 isoforms in the brain in the disorder. The molecular mechanism of association is unclear because the polymorphisms flank exon 3 of the gene and reside 700 kb distal to the CYT-1 defining exon. We hypothesized that the polymorphisms are indirectly associated with ErbB4 CYT-1 via splicing of exon 3 on the CYT-1 background. We report via cloning and sequencing of adult and fetal human brain cDNA libraries the identification of novel splice isoforms of ErbB4, whereby exon 3 is skipped (del.3). ErbB4 del.3 transcripts exist as CYT-2 isoforms and are predicted to produce truncated proteins. Furthermore, our data refine the structure of the human ErbB4 gene, clarify that juxtamembrane (JM) splice variants of ErbB4, JM-a and JM-b respectively, are characterized by the replacement of a 75 nucleotide (nt) sequence with a 45-nt insertion, and demonstrate that there are four alternative exons in the gene. Our analyses reveal that novel splice variants of ErbB4 exist in the developing and adult human brain and, given the failure to identify ErbB4 del.3 CYT-1 transcripts, suggest that the association of risk polymorphisms in the ErbB4 gene with CYT-1 transcript levels is not mediated via an exon 3 splicing event. PMID:20886074

ACTN3 R577X Polymorphism and Neuromuscular Response to Resistance Training

PubMed Central

Gentil, Paulo; Pereira, Rinaldo W.; Leite, Tailce K.M.; Bottaro, Martim

2011-01-01

The R577X polymorphism at the ACTN3 gene has been associated with muscle strength, hypertrophy and athletic status. The X allele, which is associated with the absence of ACTN3 protein is supposed to impair performance of high force/velocity muscle contractions. The purpose of the present study was to investigate the association of the R577X polymorphism with the muscle response to resistance training in young men. One hundred forty one men performed two resistance training sessions per week for 11 weeks. Participants were tested for 1RM bench press, knee extensors peak torque, and knee extensors muscle thickness at baseline and after the training period. Genotyping was conducted using de DdeI restriction enzyme. Genotype distribution was 34.4% for RR, 47% for RX and 18.6% for the XX genotype. According to the results, the R577X polymorphism at the ACTN3 gene is not associated with baseline muscle strength or with the muscle strength response to resistance training. However, only carriers of the R allele showed increases in muscle thickness in response to training. Key points ACTN3 Genotype distribution in the present study was similar to others populations (34.4% for RR, 47% for RX, and 18.6% for the XX). The R577X polymorphism at the ACTN3 gene is not associated with baseline muscle strength or with the muscle strength response to resistance training. It appears that the R allele carriers respond better to muscle thickness gains in response to training. PMID:24149888

ACTN3 R577X Polymorphism and Neuromuscular Response to Resistance Training.

PubMed

Gentil, Paulo; Pereira, Rinaldo W; Leite, Tailce K M; Bottaro, Martim

2011-01-01

The R577X polymorphism at the ACTN3 gene has been associated with muscle strength, hypertrophy and athletic status. The X allele, which is associated with the absence of ACTN3 protein is supposed to impair performance of high force/velocity muscle contractions. The purpose of the present study was to investigate the association of the R577X polymorphism with the muscle response to resistance training in young men. One hundred forty one men performed two resistance training sessions per week for 11 weeks. Participants were tested for 1RM bench press, knee extensors peak torque, and knee extensors muscle thickness at baseline and after the training period. Genotyping was conducted using de DdeI restriction enzyme. Genotype distribution was 34.4% for RR, 47% for RX and 18.6% for the XX genotype. According to the results, the R577X polymorphism at the ACTN3 gene is not associated with baseline muscle strength or with the muscle strength response to resistance training. However, only carriers of the R allele showed increases in muscle thickness in response to training. Key pointsACTN3 Genotype distribution in the present study was similar to others populations (34.4% for RR, 47% for RX, and 18.6% for the XX).The R577X polymorphism at the ACTN3 gene is not associated with baseline muscle strength or with the muscle strength response to resistance training.It appears that the R allele carriers respond better to muscle thickness gains in response to training.

Human induced pluripotent stem cell line with cytochrome P450 enzyme polymorphism (CYP2C19*2/CYP3A5*3C) generated from lymphoblastoid cells.

PubMed

Lee, Jaehun; Woo, Dong-Hun; Park, Han-Jin; Park, Kijung; Ko, Duck Sung; Kim, Jong-Hoon

2018-03-01

Cytochrome P450 (CYP) comprises a superfamily of monooxygenase responsible for the metabolism of xenobiotics and approximately 75% of drugs in use today. Thus, genetic polymorphisms in CYP genes contribute to interindividual differences in hepatic metabolism of drugs, affecting on individual drug efficacy and may cause adverse effects. Here, we generated a human induced pluripotent stem cell (hiPSC) line with pharmacologically important traits (CYP2C19*2/CYP3A5*3C), which are highly polymorphic in Asian from lymphoblastoid cells. This hiPSC line could be a valuable source for predicting individual drug responses in the drug screening process that uses hiPSC-derived somatic cells, including hepatocytes. Copyright © 2018 The Authors. Published by Elsevier B.V. All rights reserved.

A model of ecological and evolutionary consequences of color polymorphism.

PubMed

Forsman, Anders; Ahnesjö, Jonas; Caesar, Sofia; Karlsson, Magnus

2008-01-01

We summarize direct and indirect effects on fitness components of animal color pattern and present a synthesis of theories concerning the ecological and evolutionary dynamics of chromatic multiple niche polymorphisms. Previous endeavors have aimed primarily at identifying conditions that promote the evolution and maintenance of polymorphisms. We consider in a conceptual model also the reciprocal influence of color polymorphism on population processes and propose that polymorphism entails selective advantages that may promote the ecological success of polymorphic species. The model begins with an evolutionary branching event from mono- to polymorphic condition that, under the influence of correlational selection, is predicted to promote the evolution of physical integration of coloration and other traits (cf. multi-trait coevolution and complex phenotypes). We propose that the coexistence within a population of alternative ecomorphs with coadapted gene complexes promotes utilization of diverse environmental resources, population stability and persistence, colonization success, and range expansions, and enhances the evolutionary potential and speciation. Conversely, we predict polymorphic populations to be less vulnerable to environmental change and at lower risk of range contractions and extinctions compared with monomorphic populations. We offer brief suggestions as to how these falsifiable predictions may be tested.

The germline BIM deletion polymorphism is not associated with the treatment efficacy of sorafenib in patients with advanced hepatocellular carcinoma.

PubMed

Shao, Yu-Yun; Chang, Yung-Lin; Huang, Chung-Yi; Hsu, Chih-Hung; Cheng, Ann-Lii

2013-01-01

A germline BIM deletion polymorphism has been proposed to predict a poor treatment efficacy of certain kinase inhibitors. The current study aimed to explore whether the BIM deletion polymorphism predicts the treatment efficacy of sorafenib for advanced hepatocellular carcinoma (HCC). All patients who were enrolled in clinical trials to receive sorafenib-containing regimens as first-line therapy for advanced HCC and consented to providing peripheral blood samples were included. Polymerase chain reaction followed by gel electrophoresis was used to detect the germline BIM deletion polymorphism. A total of 89 patients were enrolled; 69 (77%) patients had chronic hepatitis B infection, and 18 (20%) had chronic hepatitis C infection. The heterozygous BIM deletion polymorphism was identified in 9 (10%) patients. Patients with and without the BIM deletion polymorphism had similar response rates (11 vs. 6%) and disease control rates (56 vs. 61%). The time to progression, progression-free survival, and overall survival were similar between patients with and without the BIM deletion polymorphism. After adjusting for basic clinicopathologic variables and treatment regimens, the BIM polymorphism still could not predict treatment outcomes. The BIM deletion polymorphism was not associated with the treatment efficacy of sorafenib for advanced HCC. © 2013 S. Karger AG, Basel.

[Associations between chronotype, road accidents and polymorphisms in genes linked with biological clock and dopaminergic system].

PubMed

Taranov, A O; Puchkova, A N; Slominsky, P A; Tupitsyna, T V; Dementiyenko, V V; Dorokhov, V B

2017-01-01

Public transport driving is a highly demanding activity requiring high skills and responsibility. Shift work, problems with regular sleep schedule negatively impact psychomotor reactions, cognitive functions and ability to react appropriately to the changing environment. For professional drivers all these factors may lead to the increased risk of a road accident. Individual differences in chronotype, cognitive and emotional control are partially genetically determined. Our study aimed to investigate the possible associations between chronotype parameters, traffic accident history and single nucleotide polymorphisms (SNPs) in a number of genes: RORA (rs1159814), CLOCK (rs12649507), PER3 (rs2640909), NPSR1 (rs324981), NPAS2 (rs4851377), DRD3 (rs6280), SLC6A3 (rs6347), DBH (rs1611125). We have studied 303 professional bus drivers working on rolling shifts in the Moscow region who had a recorded history of road accidents. The studied group was genotyped on selected SNPs and has filled out two chronotype questionnaires: MCTQ and shortened SWPAQ (Putilov A.A, 2014). A mixed chronotype with high levels of morning and evening alertness prevailed in the group. A prominent social jetlag caused by shift work was found. For SNP in PER3 gene there was an association with morning activation. SNP in CLOCK gene was associated with social jetlag and the risk to cause a crash. Minor alleles of SNPs in NPSR1and SLC6A3 correlated with later chronotype and increased risk of a road accident. We suppose that these polymorphisms may be amongst the genetic factors connecting chronotype and road accident risk.

Isolation and characterization of polymorphic microsatellite markers for blue fox (Alopex lagopus).

PubMed

Li, Y M; Guo, P C; Lu, J Y; Bai, C Y; Zhao, Z H; Yan, S Q

2016-06-03

The blue fox, belonging to the family Canidae, is a coat color variant of the native arctic fox (Alopex lagopus). To date, microsatellite loci in blue fox are typically amplified using canine simple sequence repeat primers. In the present study, we constructed an (AC)n enrichment library, and isolated and identified 17 polymorphic microsatellite markers for blue fox. The number of alleles per locus is from two to seven based on 24 examined individuals. The expected and observed heterozygosities were in the range of 0.3112 to 0.8236 and 0.2917 to 0.8750, respectively. The polymorphic information content per locus ranged from 0.2583 to 0.8022. These polymorphic markers can be useful for future population genetic studies of both farmed blue foxes and wild arctic foxes.

Factors affecting high-density lipoprotein cholesterol in HIV-infected patients on nevirapine-based antiretroviral therapy

PubMed Central

Padmapriyadarsini, C.; Ramesh, K.; Sekar, L.; Ramachandran, Geetha; Reddy, Devaraj; Narendran, G.; Sekar, S.; Chandrasekar, C.; Anbarasu, D.; Wanke, Christine; Swaminathan, Soumya

2017-01-01

Background & objectives: Cardiovascular disease (CVD) risk with low high-density lipoprotein cholesterol (HDL-C) and high triglycerides is common in the general population in India. As nevirapine (NVP)-based antiretroviral therapy (ART) tends to increase HDL-C, gene polymorphisms associated with HDL-C metabolism in HIV-infected adults on stable NVP-based ART were studied. Methods: A cross-sectional study was conducted between January 2013 and July 2014 among adults receiving NVP-based ART for 12-15 months. Blood lipids were estimated and gene polymorphisms in apolipoprotein C3 (APOC3), cholesteryl ester transfer protein (CETP) and lipoprotein lipase (LPL) genes were analyzed by real-time polymerase chain reaction. Framingham's 10-yr CVD risk score was estimated. Logistic regression was done to show factors related to low HDL-C levels. Results: Of the 300 patients included (mean age: 38.6±8.7 yr; mean CD4 count 449±210 cell/μl), total cholesterol (TC) >200 mg/dl was observed in 116 (39%) patients. Thirty nine per cent males and 47 per cent females had HDL-C levels below normal while 32 per cent males and 37 per cent females had TC/HDL ratio of 4.5 and 4.0, respectively. Body mass index [adjusted odds ratio (aOR)=1.70, 95% confidence interval (CI) 1.01-2.84, P=0.04] and viral load (aOR=3.39, 95% CI: 1.52-7.52, P=0.003) were negatively associated with serum HDL-C levels. The 10-yr risk score of developing CVD was 11-20 per cent in 3 per cent patients. Allelic variants of APOC3 showed a trend towards low HDL-C. Interpretation & conclusions: High-risk lipid profiles for atherosclerosis and cardiovascular disease were common among HIV-infected individuals, even after 12 months of NVP-based ART. Targeted interventions to address these factors should be recommended in the national ART programmes. PMID:28948955

Genetic polymorphisms in varied environments.

PubMed

Powell, J R

1971-12-03

Thirteen experimenital populationis of Drosophila willistoni were maintained in cages, in some of which the environments were relatively constant and in others varied. After 45 weeks, the populations were assayed by gel electrophoresis for polymorphisms at 22 protein loci. The average heterozygosity per individual and the average unmber of alleles per locus were higher in populations maintained in heterogeneous environments than in populations in more constant enviroments.

Autophagy-related polymorphisms predict hypertension in patients with metastatic colorectal cancer treated with FOLFIRI and bevacizumab: Results from TRIBE and FIRE-3 trials.

PubMed

Berger, Martin D; Yamauchi, Shinichi; Cao, Shu; Hanna, Diana L; Sunakawa, Yu; Schirripa, Marta; Matsusaka, Satoshi; Yang, Dongyun; Groshen, Susan; Zhang, Wu; Ning, Yan; Okazaki, Satoshi; Miyamoto, Yuji; Suenaga, Mitsukuni; Lonardi, Sara; Cremolini, Chiara; Falcone, Alfredo; Heinemann, Volker; Loupakis, Fotios; Stintzing, Sebastian; Lenz, Heinz-Josef

2017-05-01

The most frequent bevacizumab-related side-effects are hypertension, proteinuria, bleeding and thromboembolism. To date, there is no biomarker that predicts anti-VEGF-associated toxicity. As autophagy inhibits angiogenesis, we hypothesised that single-nucleotide polymorphisms (SNPs) within autophagy-related genes may predict bevacizumab-mediated toxicity in patients with metastatic colorectal cancer (mCRC). Patients with mCRC treated with first-line FOLFIRI and bevacizumab in two phase III randomised trials, namely the TRIBE trial (n = 219, discovery cohort) and the FIRE-3 trial (n = 234, validation cohort) were included in this study. Patients receiving treatment with FOLFIRI and cetuximab (FIRE-3, n = 204) served as a negative control. 12 SNPs in eight autophagy-related genes (ATG3/5/8/13, beclin 1, FIP200, unc-51-like kinase 1, UVRAG) were analysed by PCR-based direct sequencing. The FIP200 rs1129660 variant showed significant associations with hypertension in the TRIBE cohort. Patients harbouring any G allele of the FIP200 rs1129660 SNP showed a significantly lower rate of grade 2-3 hypertension compared with the A/A genotype (3% versus 15%, odds ratio [OR] 0.17; 95% confidence interval [CI], 0.02-0.73; P = 0.009). Similarly, G allele carriers of the FIP200 rs1129660 SNP were less likely to develop grade 2-3 hypertension than patients with an A/A genotype in the FIRE-3 validation cohort (9% versus 20%, OR 0.43; 95% CI, 0.14-1.11; P = 0.077), whereas this association could not be observed in the control cohort (12% versus 9%, OR 1.40; 95% CI, 0.45-4.04; P = 0.60). This is the first report demonstrating that polymorphisms in the autophagy-related FIP200 gene may predict hypertension in patients with mCRC treated with FOLFIRI and bevacizumab. Copyright © 2017 Elsevier Ltd. All rights reserved.

[The influence of hormonal replacement therapy on bone density in postmenopausal women depending on polymorphism of vitamin D receptor (VDR) and estrogen receptor (ER) genes].

PubMed

Brodowska, Agnieszka

2003-01-01

Osteoporosis is still an important health problem in modern societies. The densitometric criterion for the diagnosis of this condition established by WHO in 1994 is bone mass density (BMD) lower than 2.5 standard deviation (SD) from the mean value for young healthy individuals of the same sex. Between 60 and 90% of bone density (quantity of bone tissue in the human skeleton) at the time when growth is terminated is genetically determined. For this reason, genes predisposing to osteoporosis and mechanisms of their activity remain the object of investigations. Among them are genes coding for vitamin D receptor (VDR), estrogen receptor (ER), type I collagen, TGF-beta and IL-6. Diminishing bone density past the age of thirty is a physiologic process. Bone loss averages 0.3-0.6% per year. Acceleration of this process to 1.2-6% per year in postmenopausal women has been attributed to constantly decreasing estrogen concentration. Hence, the gold standard in osteoporosis prevention and treatment includes estrogen-progestagen therapy enriched with vitamin D analogues, calcium-rich diet and regular physical exercises. Treatment of osteoporosis can be long and expensive. The condition may lead to disability. Osteoporotic fractures and their complications may be fatal. For these reasons, the chief priority in osteoporosis is prevention. Unfortunately, current diagnostic methods (for detection of osteoporosis and monitoring of treatment) remain unsatisfactory. Molecular techniques offer a promising approach to diagnosis and monitoring of therapy. Additionally, the risk of osteoporosis in 1st degree relatives can be assessed and early prevention can be started. The present study addressed the following questions: 1. Are there differences in spine BMD in untreated women with postmenopausal osteoporosis depending on polymorphism of VDR and ER genes? 2. Does efficacy of treatment (increase in spine BMD) in women with postmenopausal osteoporosis depend on polymorphism of VDR and ER genes? 3. What estrogen concentration is necessary to protect bone tissue depending on the polymorphism of VDR and ER genes? The study group included 44 postmenopausal women aged 44-75 years with primary osteoporosis on cyclic HRT (hormonal replacement therapy). Two hormonal preparations were administered: Systen 50 (Jansen Cilag) transdermal system twice per week between day 1 and 21 of the cycle; Provera (Upjohn) 5 mg tablets daily between day 16 and 27 of the cycle. This therapy was supplemented with vitamin D analogue (Alphacalcidolum, Glaxo-Poznan) orally at 0.25 microg per day, calcium-enriched (1200 mg daily) diet and regular physical exercise. Patients were qualified to the study on the basis of a questionnaire. Women with secondary osteoporosis were excluded. TSH, FT3, and FT4 concentrations, as well as fasting glucose were measured. 24 h glycemia was established in women with elevated glucose levels. Polymorphism of the ER gene was studied with Xba I and Pvu II restrictases. Polymorphism of the VDR gene was studied with Bsm I restrictase. Age and BMI were recorded. Spine BMD was determined with DEXA (Dual Energy X-ray Absorptiometry (Lunar instrument) before treatment and after 12 months of HRT. Serum estradiol concentrations were measured before treatment and after 2 months of HTR. The following conclusions were drawn: 1. There is no connection between VDR and ER gene polymorphism and degree of osteoporosis before treatment. 2. XX, PP and Bb markers or X, P, B alleles are associated with a significant decrease in therapeutic efficacy. Nevertheless, satisfactory results were achieved in each woman with primary osteoporosis. 3. Estradiol concentration in serum before and during HRT does not depend on the polymorphism of VDR and ER genes.

Why don't we find more polymorphs?

PubMed

Price, Sarah L

2013-08-01

Crystal structure prediction (CSP) studies are not limited to being a search for the most thermodynamically stable crystal structure, but play a valuable role in understanding polymorphism, as shown by interdisciplinary studies where the crystal energy landscape has been explored experimentally and computationally. CSP usually produces more thermodynamically plausible crystal structures than known polymorphs. This article illustrates some reasons why: because (i) of approximations in the calculations, particularly the neglect of thermal effects (see §1.1); (ii) of the molecular rearrangement during nucleation and growth (see §1.2); (iii) the solid-state structures observed show dynamic or static disorder, stacking faults, other defects or are not crystalline and so represent more than one calculated structure (see §1.3); (iv) the structures are metastable relative to other molecular compositions (see §1.4); (v) the right crystallization experiment has not yet been performed (see §1.5) or (vi) cannot be performed (see §1.6) and the possibility (vii) that the polymorphs are not detected or structurally characterized (see §1.7). Thus, we can only aspire to a general predictive theory for polymorphism, as this appears to require a quantitative understanding of the kinetic factors involved in all possible multi-component crystallizations. For a specific molecule, analysis of the crystal energy landscape shows the potential complexity of its crystallization behaviour.

A priori calculations of the free energy of formation from solution of polymorphic self-assembled monolayers.

PubMed

Reimers, Jeffrey R; Panduwinata, Dwi; Visser, Johan; Chin, Yiing; Tang, Chunguang; Goerigk, Lars; Ford, Michael J; Sintic, Maxine; Sum, Tze-Jing; Coenen, Michiel J J; Hendriksen, Bas L M; Elemans, Johannes A A W; Hush, Noel S; Crossley, Maxwell J

2015-11-10

Modern quantum chemical electronic structure methods typically applied to localized chemical bonding are developed to predict atomic structures and free energies for meso-tetraalkylporphyrin self-assembled monolayer (SAM) polymorph formation from organic solution on highly ordered pyrolytic graphite surfaces. Large polymorph-dependent dispersion-induced substrate-molecule interactions (e.g., -100 kcal mol(-1) to -150 kcal mol(-1) for tetratrisdecylporphyrin) are found to drive SAM formation, opposed nearly completely by large polymorph-dependent dispersion-induced solvent interactions (70-110 kcal mol(-1)) and entropy effects (25-40 kcal mol(-1) at 298 K) favoring dissolution. Dielectric continuum models of the solvent are used, facilitating consideration of many possible SAM polymorphs, along with quantum mechanical/molecular mechanical and dispersion-corrected density functional theory calculations. These predict and interpret newly measured and existing high-resolution scanning tunnelling microscopy images of SAM structure, rationalizing polymorph formation conditions. A wide range of molecular condensed matter properties at room temperature now appear suitable for prediction and analysis using electronic structure calculations.

HLA-DQA1 and PLA2R1 Polymorphisms and Risk of Idiopathic Membranous Nephropathy

PubMed Central

Bullich, Gemma; Ballarín, José; Oliver, Artur; Ayasreh, Nadia; Silva, Irene; Santín, Sheila; Díaz-Encarnación, Montserrat M.; Torra, Roser

2014-01-01

Summary Background and objectives Single nucleotide polymorphisms (SNPs) within HLA complex class II HLA-DQ α-chain 1 (HLA-DQA1) and M-type phospholipase A2 receptor (PLA2R1) genes were identified as strong risk factors for idiopathic membranous nephropathy (IMN) development in a recent genome-wide association study. Copy number variants (CNVs) within the Fc gamma receptor III (FCGR3) locus have been associated with several autoimmune diseases, but their role in IMN has not been studied. This study aimed to validate the association of HLA-DQA1 and PLA2R1 risk alleles with IMN in a Spanish cohort, test the putative association of FCGR3A and FCGR3B CNVs with IMN, and assess the use of these genetic factors to predict the clinical outcome of the disease. Design, settings, participants, & measurements A Spanish cohort of 89 IMN patients and 286 matched controls without nephropathy was recruited between October of 2009 and July of 2012. Case-control studies for SNPs within HLA-DQA1 (rs2187668) and PLA2R1 (rs4664308) genes and CNVs for FCGR3A and FCGR3B genes were performed. The contribution of these polymorphisms to predict clinical outcome and renal function decline was analyzed. Results This study validated the association of these HLA-DQA1 and PLA2R1 SNPs with IMN in a Spanish cohort and its increased risk when combining both risk genotypes. No significant association was found between FCGR3 CNVs and IMN. These results revealed that HLA-DQA1 and PLA2R1 genotype combination adjusted for baseline proteinuria strongly predicted response to immunosuppressive therapy. HLA-DQA1 genotype adjusted for proteinuria was also linked with renal function decline. Conclusion This study confirms that HLA-DQA1 and PLA2R1 genotypes are risk factors for IMN, whereas no association was identified for FCGR3 CNVs. This study provides, for the first time, evidence of the contribution of these HLA-DQA1 and PLA2R1 polymorphisms in predicting IMN response to immunosuppressors and disease progression. Future studies are needed to validate and identify prognostic markers. PMID:24262501

Increased Genomic Prediction Accuracy in Wheat Breeding Through Spatial Adjustment of Field Trial Data

PubMed Central

Lado, Bettina; Matus, Ivan; Rodríguez, Alejandra; Inostroza, Luis; Poland, Jesse; Belzile, François; del Pozo, Alejandro; Quincke, Martín; Castro, Marina; von Zitzewitz, Jarislav

2013-01-01

In crop breeding, the interest of predicting the performance of candidate cultivars in the field has increased due to recent advances in molecular breeding technologies. However, the complexity of the wheat genome presents some challenges for applying new technologies in molecular marker identification with next-generation sequencing. We applied genotyping-by-sequencing, a recently developed method to identify single-nucleotide polymorphisms, in the genomes of 384 wheat (Triticum aestivum) genotypes that were field tested under three different water regimes in Mediterranean climatic conditions: rain-fed only, mild water stress, and fully irrigated. We identified 102,324 single-nucleotide polymorphisms in these genotypes, and the phenotypic data were used to train and test genomic selection models intended to predict yield, thousand-kernel weight, number of kernels per spike, and heading date. Phenotypic data showed marked spatial variation. Therefore, different models were tested to correct the trends observed in the field. A mixed-model using moving-means as a covariate was found to best fit the data. When we applied the genomic selection models, the accuracy of predicted traits increased with spatial adjustment. Multiple genomic selection models were tested, and a Gaussian kernel model was determined to give the highest accuracy. The best predictions between environments were obtained when data from different years were used to train the model. Our results confirm that genotyping-by-sequencing is an effective tool to obtain genome-wide information for crops with complex genomes, that these data are efficient for predicting traits, and that correction of spatial variation is a crucial ingredient to increase prediction accuracy in genomic selection models. PMID:24082033

The role of ITPA and ribavirin transporter genes polymorphisms in prediction of ribavirin-induced anaemia in chronic hepatitis C Egyptian patients.

PubMed

El Desoky, Ehab S; Abdelhafez, Alaa T; Cusato, Jessica; Kamel, Sherif I; Hussein, Abeer Mr; De Nicolo, Amedeo; Di Perri, Giovanni; D'Avolio, Antonio

2017-09-01

Few data are available concerning the roles of polymorphisms of inosine triphosphatase (ITPA) gene and ribavirin (RBV) transporter genes in the prediction of RBV-induced anaemia among Egyptians with chronic hepatitis C (CHC). Genotyping of three ITPA gene variants and two variants of RBV transporter genes has been performed in 123 patients under pegylated interferon-α/ribavirin treatment. The baseline haemoglobin and ITPA rs1127354 CA/AA have been found as predictors of anaemia at 4, 8 and 12 weeks of RBV therapy. In addition, ITPA rs7270101 AC/CC and age predicted anaemia after 12 weeks of therapy. In conclusion, the ITPA variant rs1127354C>A significantly predict RBV-induced anaemia during the first 3 months of treatment and it is recommended to be assessed before RBV administration. © 2017 John Wiley & Sons Australia, Ltd.

Combined crystal structure prediction and high-pressure crystallization in rational pharmaceutical polymorph screening

PubMed Central

Neumann, M. A.; van de Streek, J.; Fabbiani, F. P. A.; Hidber, P.; Grassmann, O.

2015-01-01

Organic molecules, such as pharmaceuticals, agro-chemicals and pigments, frequently form several crystal polymorphs with different physicochemical properties. Finding polymorphs has long been a purely experimental game of trial-and-error. Here we utilize in silico polymorph screening in combination with rationally planned crystallization experiments to study the polymorphism of the pharmaceutical compound Dalcetrapib, with 10 torsional degrees of freedom one of the most flexible molecules ever studied computationally. The experimental crystal polymorphs are found at the bottom of the calculated lattice energy landscape, and two predicted structures are identified as candidates for a missing, thermodynamically more stable polymorph. Pressure-dependent stability calculations suggested high pressure as a means to bring these polymorphs into existence. Subsequently, one of them could indeed be crystallized in the 0.02 to 0.50 GPa pressure range and was found to be metastable at ambient pressure, effectively derisking the appearance of a more stable polymorph during late-stage development of Dalcetrapib. PMID:26198974

Study of single nucleotide polymorphisms of FBW7 and its substrate genes revealed a predictive factor for paclitaxel plus cisplatin chemotherapy in Chinese patients with advanced esophageal squamous cell carcinoma.

PubMed

Liu, Ying; Xu, Shu Ning; Chen, Yong Shun; Wu, Xiao Yuan; Qiao, Lei; Li, Ke; Yuan, Long

2016-07-12

Paclitaxel plays a major role in the treatment of advanced esophageal squamous cell carcinoma. However, there is no biomarker that could be used to predict the clinical response of paclitaxel. This work was conducted to investigate the association of genetic polymorphisms in FBW7 and its substrate genes and the clinical response of paclitaxel. Patients with advanced esophageal squamous cell carcinoma were treated with paclitaxel 175 mg/m2 over 3 hours day 1 and cisplatin 75 mg/m2 day 1, every 3 weeks. The genotypes of 11 FBW7 and its substrate gene polymorphisms were determined by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) method. Statistical analysis revealed that patients with mTOR rs1057079 AG (ORadjusted: 4.59; 95% CI: 1.78-11.86) genotype had significant correlation with the clinical response of paclitaxel when compared with AA genotype after adjustment for sex, age, and chemotherapy cycle. The median progression-free survival (PFS) of patients with advanced ESCC who received paclitaxel plus cisplatin (TP) as first-line treatment is 14.3 months (95% CI: 9.0-19.60 months). The median PFS (mPFS) of AG genotypes and AA genotypes in mTOR rs1057079 were 17.31 months (95% CI: 15.9-18.67 months) and 9.8 months (95% CI: 8.58-11.02 months) (p=0.019), respectively.

Isolation and characterization of 21 polymorphic microsatellite loci in the Japanese dace (Tribolodon hakonensis)

USGS Publications Warehouse

Koizumi, Noriyuki; Quinn, Thomas W.; Park, Myeongsoo; Fike, Jennifer A.; Nishida, Kazuya; Takemura, Takeshi; Watabe, Keiji; Mori, Atsushi

2011-01-01

Twenty one polymorphic microsatellite loci for the Japanese dace (Tribolodon hakonensis) were isolated and characterized. The number of observed alleles per locus in 32 individuals ranged from 3 to 30. The observed and expected heterozygosities ranged from 0.125 to 0.969 and from 0.175 to 0.973, respectively. All loci conformed to Hardy–Weinberg equilibrium, no linkage disequilibrium was observed between pairs of loci and no loci showed evidence of null alleles. These microsatellite loci will be useful for investigating the intraspecific genetic variation and population structure of this species.

PATTERNS OF ALLOZYME DIVERSITY IN THE THREATENED PLANT ERIGERON PARISHII (ASTERACEAE). (R826102)

EPA Science Inventory

Thirty-one occurrences of Erigeron parishii, a narrowly endemic plant threatened by mining, were sampled for allozyme diversity. This taxon held considerable genetic variation at the [4 allozyme loci surveyed. Species (e.g., alleles per locus [A] = 4.3 and proportion of polymorph...

Incorporating Single-nucleotide Polymorphisms Into the Lyman Model to Improve Prediction of Radiation Pneumonitis

DOE Office of Scientific and Technical Information (OSTI.GOV)

Tucker, Susan L., E-mail: sltucker@mdanderson.org; Li Minghuan; Xu Ting

2013-01-01

Purpose: To determine whether single-nucleotide polymorphisms (SNPs) in genes associated with DNA repair, cell cycle, transforming growth factor-{beta}, tumor necrosis factor and receptor, folic acid metabolism, and angiogenesis can significantly improve the fit of the Lyman-Kutcher-Burman (LKB) normal-tissue complication probability (NTCP) model of radiation pneumonitis (RP) risk among patients with non-small cell lung cancer (NSCLC). Methods and Materials: Sixteen SNPs from 10 different genes (XRCC1, XRCC3, APEX1, MDM2, TGF{beta}, TNF{alpha}, TNFR, MTHFR, MTRR, and VEGF) were genotyped in 141 NSCLC patients treated with definitive radiation therapy, with or without chemotherapy. The LKB model was used to estimate the risk ofmore » severe (grade {>=}3) RP as a function of mean lung dose (MLD), with SNPs and patient smoking status incorporated into the model as dose-modifying factors. Multivariate analyses were performed by adding significant factors to the MLD model in a forward stepwise procedure, with significance assessed using the likelihood-ratio test. Bootstrap analyses were used to assess the reproducibility of results under variations in the data. Results: Five SNPs were selected for inclusion in the multivariate NTCP model based on MLD alone. SNPs associated with an increased risk of severe RP were in genes for TGF{beta}, VEGF, TNF{alpha}, XRCC1 and APEX1. With smoking status included in the multivariate model, the SNPs significantly associated with increased risk of RP were in genes for TGF{beta}, VEGF, and XRCC3. Bootstrap analyses selected a median of 4 SNPs per model fit, with the 6 genes listed above selected most often. Conclusions: This study provides evidence that SNPs can significantly improve the predictive ability of the Lyman MLD model. With a small number of SNPs, it was possible to distinguish cohorts with >50% risk vs <10% risk of RP when they were exposed to high MLDs.« less

Screening toll-like receptor markers to predict latent tuberculosis infection and subsequent tuberculosis disease in a Chinese population.

PubMed

Wu, Linlin; Hu, Yi; Li, Dange; Jiang, Weili; Xu, Biao

2015-04-01

We investigated whether polymorphisms in the toll-like receptor genes or gene-gene interactions are associated with susceptibility to latent tuberculosis infection (LTBI) or subsequent pulmonary tuberculosis (PTB) in a Chinese population. Two matched case-control studies were undertaken. Previously reported polymorphisms in the toll-like receptors (TLRs) were compared between 422 healthy controls (HC) and 205 LTBI patients and between 205 LTBI patients and 109 PTB patients, to assess whether these polymorphisms and their interactions are associated with LTBI or PTB. A PCR-based restriction fragment length polymorphism analysis was used to detect genetic polymorphisms in the TLR genes. Nonparametric multifactor dimensionality reduction (MDR) was used to analyze the effects of interactions between complex disease genes and other genes or environmental factors. Sixteen markers in TLR1, TLR2, TLR4, TLR6, TLR8, TLR9, and TIRAP were detected. In TLR2, the frequencies of the CC genotype (OR = 2.262; 95% CI: 1.433-3.570) and C allele (OR = 1.566; 95% CI: 1.223-1.900) in single-nucleotide polymorphism (SNP) rs3804100 were significantly higher in the LTBI group than in the HC group, whereas the GA genotype of SNP rs5743708 was associated with PTB (OR = 6.087; 95% CI: 1.687-21.968). The frequencies of the GG genotype of SNP rs7873784 in TLR4 (OR = 2.136; 95% CI: 1.312-3.478) and the CC genotype of rs3764879 in TLR8 (OR = 1.982; 95% CI: 1.292-3.042) were also significantly higher in the PTB group than in the HC group. The TC genotype frequency of SNP rs5743836 in TLR9 was significantly higher in the LTBI group than in the HC group (OR = 1.664; 95% CI: 1.201-2.306). An MDR analysis of gene-gene and gene-environment interactions identified three SNPs (rs10759932, rs7873784, and rs10759931) that predicted LTBI with 84% accuracy (p = 0.0004) and three SNPs (rs3804100, rs1898830, and rs10759931) that predicted PTB with 80% accuracy (p = 0.0001). Our results suggest that genetic variation in TLR2, 4, 8 and 9, implicating TLR-related pathways affecting the innate immunity response, modulate LTBI and PTB susceptibility in Chinese.

Nucleation of metastable aragonite CaCO3 in seawater.

PubMed

Sun, Wenhao; Jayaraman, Saivenkataraman; Chen, Wei; Persson, Kristin A; Ceder, Gerbrand

2015-03-17

Predicting the conditions in which a compound adopts a metastable structure when it crystallizes out of solution is an unsolved and fundamental problem in materials synthesis, and one which, if understood and harnessed, could enable the rational design of synthesis pathways toward or away from metastable structures. Crystallization of metastable phases is particularly accessible via low-temperature solution-based routes, such as chimie douce and hydrothermal synthesis, but although the chemistry of the solution plays a crucial role in governing which polymorph forms, how it does so is poorly understood. Here, we demonstrate an ab initio technique to quantify thermodynamic parameters of surfaces and bulks in equilibrium with an aqueous environment, enabling the calculation of nucleation barriers of competing polymorphs as a function of solution chemistry, thereby predicting the solution conditions governing polymorph selection. We apply this approach to resolve the long-standing "calcite-aragonite problem"--the observation that calcium carbonate precipitates as the metastable aragonite polymorph in marine environments, rather than the stable phase calcite--which is of tremendous relevance to biomineralization, carbon sequestration, paleogeochemistry, and the vulnerability of marine life to ocean acidification. We identify a direct relationship between the calcite surface energy and solution Mg:Ca [corrected] ion concentrations, showing that the calcite nucleation barrier surpasses that of metastable aragonite in solutions with Mg:Ca ratios consistent with modern seawater, allowing aragonite to dominate the kinetics of nucleation. Our ability to quantify how solution parameters distinguish between polymorphs marks an important step toward the ab initio prediction of materials synthesis pathways in solution.

Nucleation of metastable aragonite CaCO 3 in seawater

DOE PAGES

Sun, Wenhao; Jayaraman, Saivenkataraman; Chen, Wei; ...

2015-03-04

Predicting the conditions in which a compound adopts a metastable structure when it crystallizes out of solution is an unsolved and fundamental problem in materials synthesis, and one which, if understood and harnessed, could enable the rational design of synthesis pathways toward or away from metastable structures. Crystallization of metastable phases is particularly accessible via low-temperature solution-based routes, such as chimie douce and hydrothermal synthesis, but although the chemistry of the solution plays a crucial role in governing which polymorph forms, how it does so is poorly understood. Here, we demonstrate an ab initio technique to quantify thermodynamic parameters ofmore » surfaces and bulks in equilibrium with an aqueous environment, enabling the calculation of nucleation barriers of competing polymorphs as a function of solution chemistry, thereby predicting the solution conditions governing polymorph selection. We apply this approach to resolve the long-standing “calcite–aragonite problem”––the observation that calcium carbonate precipitates as the metastable aragonite polymorph in marine environments, rather than the stable phase calcite––which is of tremendous relevance to biomineralization, carbon sequestration, paleogeochemistry, and the vulnerability of marine life to ocean acidification. We identify a direct relationship between the calcite surface energy and solution Mg–Ca ion concentrations, showing that the calcite nucleation barrier surpasses that of metastable aragonite in solutions with Mg:Ca ratios consistent with modern seawater, allowing aragonite to dominate the kinetics of nucleation. The ability to quantify how solution parameters distinguish between polymorphs marks an important step toward the ab initio prediction of materials synthesis pathways in solution.« less

ABCB1 polymorphism as prognostic factor in breast cancer patients treated with docetaxel and doxorubicin neoadjuvant chemotherapy

PubMed Central

Kim, Hee-Jun; Im, Seock-Ah; Keam, Bhumsuk; Ham, Hye Seon; Lee, Kyung Hun; Kim, Tae Yong; Kim, Yu Jung; Oh, Do-Youn; Kim, Jee Hyun; Han, Wonshik; Jang, In-Jin; Kim, Tae-You; Park, In Ae; Noh, Dong Young

2015-01-01

Expression of the adenosine triphosphate-binding cassette B1 (ABCB1) transporter and P-glycoprotein are associated with resistance to anticancer drugs. The purpose of this study was to investigate the role of single nucleotide polymorphism in the ABCB1 and CYP3A genes in breast cancer patients who were treated with neoadjuvant chemotherapy. Stage II/III breast cancer patients were treated with three cycles of neoadjuvant, after which the patients received curative surgery and adjuvant chemotherapy. The polymorphisms of ABCB1 and CYP3A were genotyped. The correlation of polymorphism of ABCB1, CYP3A, and clinical outcomes was analyzed. Among the 216 patients, ABCB1 3435TT genotype had a longer overall survival (OS). than CC/CT. Multivariate analyses demonstrated that good PS, invasive ductal carcinoma, non-triple negative phenotype and initial operable stage were significantly associated with a lower death risk. ABCB1 3435TT genotype had a higher AUC than CC/CT for docetaxel. These higher AUCs in the C3435TT was associated with increased toxicities of neutropenia and diarrhea. This study showed that the genetic polymorphism of ABCB1 C3435T might be associated with a longer OS. Our results also suggest that the prediction of docetaxel toxicity might be possible for C3435T polymorphism. This study results provides valuable information on individualized therapy according to genotypes. PMID:25410489

Polymorphous computing fabric

DOEpatents

Wolinski, Christophe Czeslaw [Los Alamos, NM; Gokhale, Maya B [Los Alamos, NM; McCabe, Kevin Peter [Los Alamos, NM

2011-01-18

Fabric-based computing systems and methods are disclosed. A fabric-based computing system can include a polymorphous computing fabric that can be customized on a per application basis and a host processor in communication with said polymorphous computing fabric. The polymorphous computing fabric includes a cellular architecture that can be highly parameterized to enable a customized synthesis of fabric instances for a variety of enhanced application performances thereof. A global memory concept can also be included that provides the host processor random access to all variables and instructions associated with the polymorphous computing fabric.

CXCL12 chemokine genotypes as predictive biomarkers of ovarian cancer outcome.

PubMed

Coelho, Ana; Pereira, Deolinda; Nogal, Ana; Pinto, Daniela; Catarino, Raquel; Araújo, António; Medeiros, Rui

2009-01-01

Ovarian cancer is an aggressive disease with high mortality. The CXCL12 chemokine has been associated with the development of this neoplasia. The aim of this study was to evaluate the genetic influence of the CXCL12-3'A polymorphism as a prognostic/predictive factor in ovarian cancer patients treated with platinum/paclitaxel chemotherapy. The mean survival rates for early stages (I/II) of the disease were statistically different according to patient genotype (96 months for GG and 57 months for A carrier genotypes; p=0.017). The mean progression-free interval was statistically lower in patients with early stages (I/II) of the tumour carrying the A allele (55 months) than in those carrying the GG genotype (91 months; P=0.009). The CXCL12-3'A polymorphism leads to a poorer response to chemotherapy with cisplatin/paclitaxel, and diminishes the mean survival rate and the progression-free interval in patients with ovarian cancer. CXCL12-3'A may therefore serve as an important predictive biomarker for the determination of outcome in ovarian cancer.

Comparison of macro and micro Raman measurement for reliable quantitative analysis of pharmaceutical polymorphs.

PubMed

Paiva, Eduardo M; da Silva, Vitor H; Poppi, Ronei J; Pereira, Claudete F; Rohwedder, Jarbas J R

2018-05-12

This work reports on the use of micro- and macro-Raman measurements for quantification of mebendazole (MBZ) polymorphs A, B, and C in mixtures. Three Raman spectrophotometers were studied with a laser spot size of 3, 80 and 100 μm and spectral resolutions of 3.9, 9 and 4 cm -1 , respectively. The samples studied were ternary mixtures varying the MBZ polymorphs A and C from 0 to 100% and polymorph B from 0 to 30%. Partial Least Squares (PLS) regression models were developed using the pre-processing spectra (2nd derivative) of the ternary mixtures. The best performance was obtained when the macro-Raman configuration was applied, obtaining RMSEP values of 1.68%, 1.24% and 2.03% w/w for polymorphs A, B, and C, respectively. In general, micro-Raman presented worst results for MBZ polymorphs prediction because the spectra obtained with this configuration does not represent the bulk proportion of mixtures, which have different particle morphologies and sizes. In addition, the influence of these particle features on micro-Raman measurements was also studied. Finally, the results demonstrated that reliable analytical quantifying of MBZ polymorphs can be reached using a laser with wider area illuminated, thus enabling acquisition of more reproductive and representative spectra of the mixtures. Copyright © 2018 Elsevier B.V. All rights reserved.

[The polymorphism of catechol-O-methyltransferase (COMT) and hemochromatosis (HFE) genes in the radiocontaminated regions residents with different chromosome aberration frequency].

PubMed

Ivanova, T I; Kondrashova, T V; Krikunova, L I; Smirnova, I A; Shentereva, N I; Sychenkova, N I; Rykova, E V; Zharikova, I A; Khorokhorina, V A; Riabchenko, N I; Zamulaeva, I A

2010-01-01

The association between polymorphisms in genes COMT, HFE that takes part in oxidative stress regulation, and chromosome aberration frequency in lymphocytes was assessed in 278 female residents of radiation polluted regions of Central Russia: Bryansk (322 kBk/m2) and Tula Districts (137Cs - 171 kBk/m2). The C187G, G845A genotyping of HFE and G1947A (H/L) of COMT was done by means of polymerase chain reaction-restriction fragment length polymorphism. Studied population was divided into 3 subgroups by level of chromosome aberrations per cell (0-2, 3-4, >5). There was shown statistically significant difference in distribution of COMTand HFE genotypes between the groups. The high frequency of chromosome aberrations (> or = 5%) was associated with homozygotes of the high activity COMT G/G and HFE CC. Heterozygotes for G1947A COMT and C187G HFE reveal negative association with the high frequency of chromosome aberrations and correspond to "resistance factors".

A molecular dynamics study of ambient and high pressure phases of silica: structure and enthalpy variation with molar volume.

PubMed

Rajappa, Chitra; Sringeri, S Bhuvaneshwari; Subramanian, Yashonath; Gopalakrishnan, J

2014-06-28

Extensive molecular dynamics studies of 13 different silica polymorphs are reported in the isothermal-isobaric ensemble with the Parrinello-Rahman variable shape simulation cell. The van Beest-Kramer-van Santen (BKS) potential is shown to predict lattice parameters for most phases within 2%-3% accuracy, as well as the relative stabilities of different polymorphs in agreement with experiment. Enthalpies of high-density polymorphs - CaCl2-type, α-PbO2-type, and pyrite-type - for which no experimental data are available as yet, are predicted here. Further, the calculated enthalpies exhibit two distinct regimes as a function of molar volume-for low and medium-density polymorphs, it is almost independent of volume, while for high-pressure phases a steep dependence is seen. A detailed analysis indicates that the increased short-range contributions to enthalpy in the high-density phases arise not only from an increased coordination number of silicon but also shorter Si-O bond lengths. Our results indicate that amorphous phases of silica exhibit better optimization of short-range interactions than crystalline phases at the same density while the magnitude of Coulombic contributions is lower in the amorphous phase.

IFNL4 and IFNL3 Associated Polymorphisms Strongly Influence the Spontaneous IFN-Alpha Receptor-1 Expression in HCV-Infected Patients

PubMed Central

Bordi, Licia; Caglioti, Claudia; Garbuglia, Anna Rosa; Lapa, Daniele; Castilletti, Concetta; Taibi, Chiara; Capobianchi, Maria Rosaria; Lalle, Eleonora

2015-01-01

Single-nucleotide polymorphism in IFNL3 gene (rs12979860) predicts spontaneous and therapy-induced HCV clearance. In a previous study from our group PBMC from patients with favourable rs12979860 genotype showed higher levels of IFNAR-1 mRNA. Recently, a dinucleotide polymorphism, ss469415590 (TT or ΔG), has been discovered in the region upstream IFNL3 gene, which is in high linkage disequilibrium with rs12979860. ss469415590[ΔG] is a frameshift variant that creates a novel gene, designed IFNL4, encoding the interferon-lambda 4 protein (IFNL4). The aim of the present study was to extend the analysis of IFNAR-1 mRNA levels to the ss469415590 variants. Our results highlight that the difference of IFNAR-1 mRNA levels between favourable and unfavourable genotype combinations, at both rs12979860 and ss469415590 loci, is stronger than that observed for single polymorphisms at each locus. These findings suggest may represent the biological basis for the observed association between IFNL3 CC and IFNL4 TT/TT genotypes and favourable outcome of either natural HCV infection (clearance vs chronic evolution) or IFN-based therapy. PMID:25675103

A priori calculations of the free energy of formation from solution of polymorphic self-assembled monolayers

PubMed Central

Reimers, Jeffrey R.; Panduwinata, Dwi; Visser, Johan; Chin, Yiing; Tang, Chunguang; Goerigk, Lars; Ford, Michael J.; Sintic, Maxine; Sum, Tze-Jing; Coenen, Michiel J. J.; Hendriksen, Bas L. M.; Elemans, Johannes A. A. W.; Hush, Noel S.; Crossley, Maxwell J.

2015-01-01

Modern quantum chemical electronic structure methods typically applied to localized chemical bonding are developed to predict atomic structures and free energies for meso-tetraalkylporphyrin self-assembled monolayer (SAM) polymorph formation from organic solution on highly ordered pyrolytic graphite surfaces. Large polymorph-dependent dispersion-induced substrate−molecule interactions (e.g., −100 kcal mol−1 to −150 kcal mol−1 for tetratrisdecylporphyrin) are found to drive SAM formation, opposed nearly completely by large polymorph-dependent dispersion-induced solvent interactions (70–110 kcal mol−1) and entropy effects (25–40 kcal mol−1 at 298 K) favoring dissolution. Dielectric continuum models of the solvent are used, facilitating consideration of many possible SAM polymorphs, along with quantum mechanical/molecular mechanical and dispersion-corrected density functional theory calculations. These predict and interpret newly measured and existing high-resolution scanning tunnelling microscopy images of SAM structure, rationalizing polymorph formation conditions. A wide range of molecular condensed matter properties at room temperature now appear suitable for prediction and analysis using electronic structure calculations. PMID:26512115

X-Ray Cross-Complementing Group 1 and Thymidylate Synthase Polymorphisms Might Predict Response to Chemoradiotherapy in Rectal Cancer Patients

DOE Office of Scientific and Technical Information (OSTI.GOV)

Lamas, Maria J., E-mail: mlamasd@yahoo.es; Duran, Goretti; Gomez, Antonio

2012-01-01

Purpose: 5-Fluorouracil-based chemoradiotherapy before total mesorectal excision is currently the standard treatment of Stage II and III rectal cancer patients. We used known predictive pharmacogenetic biomarkers to identify the responders to preoperative chemoradiotherapy in our series. Methods and Materials: A total of 93 Stage II-III rectal cancer patients were genotyped using peripheral blood samples. The genes analyzed were X-ray cross-complementing group 1 (XRCC1), ERCC1, MTHFR, EGFR, DPYD, and TYMS. The patients were treated with 225 mg/m{sup 2}/d continuous infusion of 5-fluorouracil concomitantly with radiotherapy (50.4 Gy) followed by total mesorectal excision. The outcomes were measured by tumor regression grade (TRG)more » as a major response (TRG 1 and TRG 2) or as a poor response (TRG3, TRG4, and TRG5). Results: The major histopathologic response rate was 47.3%. XRCC1 G/G carriers had a greater probability of response than G/A carriers (odds ratio, 4.18; 95% confidence interval, 1.62-10.74, p = .003) Patients with polymorphisms associated with high expression of thymidylate synthase (2R/3G, 3C/3G, and 3G/3G) showed a greater pathologic response rate compared with carriers of low expression (odds ratio, 2.65; 95% confidence interval, 1.10-6.39, p = .02) No significant differences were seen in the response according to EGFR, ERCC1, MTHFR{sub C}677 and MTHFR{sub A}1298 expression. Conclusions: XRCC1 G/G and thymidylate synthase (2R/3G, 3C/3G, and 3G/3G) are independent factors of a major response. Germline thymidylate synthase and XRCC1 polymorphisms might be useful as predictive markers of rectal tumor response to neoadjuvant chemoradiotherapy with 5-fluorouracil.« less

Prevalence and Mental Health Correlates of Sleep Disruption Among Military Members Serving in a Combat Zone

DTIC Science & Technology

2014-07-01

likely yielded higher operational tempo, greater security concerns, more hazardous environ­ mental exposures, exaggerated daily operational stressors,43...Burmeister M: PER3 polymorphism and insomnia severity in alcohol dependence. Sleep 2012; 35(4): 571-7. 10. Pigeon WR. Pinquart M, Conner K: Meta

Comparative study on the use of specific and heterologous microsatellite primers in the stingless bees Melipona rufiventris and M. mondury (Hymenoptera, Apidae)

PubMed Central

2010-01-01

Due to their high degree of polymorphism, microsatellites are considered useful tools for studying population genetics. Nevertheless, studies of genetic diversity in stingless bees by means of these primers have revealed a low level of polymorphism, possibly the consequence of the heterologous primers used, since in most cases these were not specifically designed for the species under consideration. Herein we compared the number of polymorphic loci and alleles per locus, as well as observed heterozygosity in Melipona rufiventris and M. mondury populations, using specific and heterologous primers. The use of specific primers placed in evidence the greater frequency of polymorphic loci and alleles per locus, besides an expressive increase in observed heterozygosity in M. rufiventris and M. mondury, thereby reinforcing the idea that populational studies should be undertaken by preferably using species-specific microsatellite primers. PMID:21637499

Comparative study on the use of specific and heterologous microsatellite primers in the stingless bees Melipona rufiventris and M. mondury (Hymenoptera, Apidae).

PubMed

Lopes, Denilce Meneses; de Oliveira Campos, Lúcio Antônio; Salomão, Tânia Maria Fernandes; Tavares, Mara Garcia

2010-04-01

Due to their high degree of polymorphism, microsatellites are considered useful tools for studying population genetics. Nevertheless, studies of genetic diversity in stingless bees by means of these primers have revealed a low level of polymorphism, possibly the consequence of the heterologous primers used, since in most cases these were not specifically designed for the species under consideration. Herein we compared the number of polymorphic loci and alleles per locus, as well as observed heterozygosity in Melipona rufiventris and M. mondury populations, using specific and heterologous primers. The use of specific primers placed in evidence the greater frequency of polymorphic loci and alleles per locus, besides an expressive increase in observed heterozygosity in M. rufiventris and M. mondury, thereby reinforcing the idea that populational studies should be undertaken by preferably using species-specific microsatellite primers.

Development of novel polymorphic microsatellite markers for the silver fox (Vulpes vulpes).

PubMed

Yan, S Q; Bai, C Y; Qi, S M; Li, Y M; Li, W J; Sun, J H

2015-06-01

The silver fox (Vulpes vulpes), a coat color variant of the red fox, is one of the most important fur-bearing animals. To date, development of microsatellite loci for the silver fox has been limited and mainly based on cross-amplification by using canine SSR primers. In this study, 28 polymorphic microsatellite markers were isolated and identified for silver fox through the construction and screening of an (AC)n-enriched library. The number of alleles per locus ranged from 2 to 8 based on 48 individuals tested. The expected and observed hetero- zygosity and polymorphism information content per locus ranged from 0.2544 to 0.859, 0.2083 to 0.7917, and 0.2181 to 0.821, respectively. The polymorphic markers presented in this study may be useful for future analysis of the genetic diversity and population structure of farmed silver fox and wild red fox.

Psychological distress following marital separation interacts with a polymorphism in the serotonin transporter gene to predict cardiac vagal control in the laboratory.

PubMed

Hasselmo, Karen; Sbarra, David A; O'Connor, Mary-Frances; Moreno, Francisco A

2015-06-01

Marital separation is linked to negative mental and physical health; however, the strength of this link may vary across people. This study examined changes in respiratory sinus arrhythmia (RSA), used to assess cardiac vagal control, in recently separated adults (N = 79; M time since separation = 3.5 months). When reflecting on the separation, self-reported psychological distress following the separation interacted with a polymorphism in the serotonin transporter gene (5-HTTLPR) and a relevant single nucleotide polymorphism (SNP), rs25531, to predict RSA. Among people reporting emotional difficulties after the separation, those who were homozygous for the short allele had lower RSA levels while reflecting on their relationship than other genotypes. The findings, although limited by the relatively small sample size, are discussed in terms of how higher-sensitivity genotypes may interact with psychological responses to stress to alter physiology. © 2015 Society for Psychophysiological Research.

Transferability of microsatellite markers of Capsicum annuum L. to C. frutescens L. and C. chinense Jacq.

PubMed

Carvalho, S I C; Ragassi, C F; Oliveira, I B; Amaral, Z P S; Reifschneider, F J B; Faleiro, F G; Buso, G S C

2015-07-17

In order to support further genetic, diversity, and phylogeny studies of Capsicum species, the transferability of a Capsicum annuum L. simple sequence repeat (SSR) microsatellite set was analyzed for C. frutescens L. ("malagueta" and "tabasco" peppers) and C. chinense Jacq. (smell peppers, among other types). A total of 185 SSR primers were evaluated in 12 accessions from 115 C. frutescens L. and 480 C. chinense Jacq, representing different types within each species. Transferability to C. frutescens L. and C. chinense Jacq. occurred for 116 primers (62.7%). Nineteen (16.37%) were polymorphic in C. frutescens L. and 36 (31.03%) in C. chinense Jacq., 17 of which were coincident and could be used to analyze samples obtained for the 2 species. Among these primers, CA49 showed a different amplitude range of alleles between the 2 species (130-132 base pairs for C. frutescens L. and 120-128 base pairs for C. chinense Jacq.), and could differentiate the species. A total of 55 alleles were identified among the 19 polymorphic SSR loci among accessions of C. frutescens L., with the number of alleles per locus ranging from 2 to 5, a mean of 2.89, and the polymorphic information content ranging from 0.30 to 0.65. The number of alleles identified in C. chinense Jacq. was 119, ranging from 2 to 5 alleles per locus, an average of 3.30, and polymorphic information content from 0.19 to 0.68. The C. annuum L. SSR primers were most often transfer-able and polymorphic for C. frutescens L. and C. chinense Jacq., and we present a set of SSR for each species.

CYP1A1, CYP3A5 and CYP3A7 polymorphisms and testicular cancer susceptibility.

PubMed

Kristiansen, W; Haugen, T B; Witczak, O; Andersen, J M; Fosså, S D; Aschim, E L

2011-02-01

Testicular cancer (TC) incidence is increasing worldwide, but the aetiology remains largely unknown. An unbalanced level of oestrogens and androgens in utero is hypothesized to influence TC risk. Polymorphisms in genes encoding cytochrome P450 (CYP) enzymes involved in metabolism of reproductive hormones, such as CYP1A1, CYP3A5 and CYP3A7, may contribute to variability of an individual's susceptibility to TC. The aim of this case-control study was to investigate possible associations between different CYP genotypes and TC, as well as histological type of TC. The study comprised 652 TC cases and 199 controls of Norwegian Caucasian origin. Genotyping of the CYP1A1*2A (MspI), CYP1A1*2C (I462V), CYP1A1*4 (T461N), CYP3A5*3C (A6986G) and CYP3A7*2 (T409R) polymorphisms was performed using TaqMan allelic discrimination or sequencing. The CYP1A1*2A allele was associated with 44% reduced risk of TC with each polymorphic allele [odds ratio (OR) = 0.56, 95% confidence interval (CI) = 0.40-0.78, p(trend) = 0.001], whereas the CYP1A1*2C allele was associated with 56% reduced risk of TC with each polymorphic allele (OR = 0.44, 95% CI = 0.25-0.75, p(trend) = 0.003). The decreased risk per allele was significant for seminomas (OR = 0.46, 95% CI, 0.31-0.70, p(trend) < 0.001 and OR = 0.31, 95% CI = 0.14-0.66, p(trend) = 0.002, respectively), but only borderline significant for non-seminomas (OR = 0.65, 95% CI = 0.45-0.95, p(trend) = 0.027 and OR = 0.55, 95% CI = 0.30-1.01, p(trend) = 0.052, respectively). There were no statistically significant differences in the distribution of the CYP3A5*3C and CYP3A7*2 polymorphic alleles between TC cases and controls. This study suggests that polymorphisms in the CYP1A1 gene may contribute to variability of individual susceptibility to TC. © 2010 The Authors. International Journal of Andrology © 2010 European Academy of Andrology.

SNPs in DNA repair or oxidative stress genes and late subcutaneous fibrosis in patients following single shot partial breast irradiation

PubMed Central

2012-01-01

Background The aim of this study was to evaluate the potential association between single nucleotide polymorphisms related response to radiotherapy injury, such as genes related to DNA repair or enzymes involved in anti-oxidative activities. The paper aims to identify marker genes able to predict an increased risk of late toxicity studying our group of patients who underwent a Single Shot 3D-CRT PBI (SSPBI) after BCS (breast conserving surgery). Methods A total of 57 breast cancer patients who underwent SSPBI were genotyped for SNPs (single nucleotide polymorphisms) in XRCC1, XRCC3, GST and RAD51 by Pyrosequencing technology. Univariate analysis (ORs and 95% CI) was performed to correlate SNPs with the risk of developing ≥ G2 fibrosis or fat necrosis. Results A higher significant risk of developing ≥ G2 fibrosis or fat necrosis in patients with: polymorphic variant GSTP1 (Ile105Val) (OR = 2.9; 95%CI, 0.88-10.14, p = 0.047). Conclusions The presence of some SNPs involved in DNA repair or response to oxidative stress seem to be able to predict late toxicity. Trial Registration ClinicalTrials.gov: NCT01316328 PMID:22272830

Association of eNOS and ACE gene polymorphisms and plasma nitric oxide with risk of non-small cell lung cancer in South India.

PubMed

Peddireddy, Vidyullatha; Badabagni, Siva Prasad; Gundimeda, Sandhya Devi; Mundluru, Hema Prasad

2018-01-01

The role of ACE and eNOS gene polymorphisms and their association with various cancers were reported. However, their role in the lung cancer is unclear. In this study, we analyzed eNOS and ACE gene polymorphisms and the risk of non-small cell lung cancer (NSCLC) in South Indian population. For the eNOS gene, the homozygous "AA" genotypic frequency was significantly associated with NSCLC with an overall risk of 3.6-fold (P = 0.006, odds ratio = 3.58, 95% confidence interval = 1.66, 7.723). The heterozygous "I/D" genotypic frequency of ACE gene was significantly higher in NSCLC patients when compared to the controls with a 2.29-fold risk for NSCLC. Multiple regression analyses indicated that gender, smoking status, and polymorphisms in eNOS and ACE genes as the strongest predicting factors for an increased susceptibility to NSCLC. We report for the first time that polymorphisms in the eNOS "A/A" (homozygous mutant) and ACE "I/D" genotypes might contribute to the increased risk of NSCLC in the South Indian population. © 2016 John Wiley & Sons Ltd.

Identification of single nucleotide polymorphism in ginger using expressed sequence tags

PubMed Central

Chandrasekar, Arumugam; Riju, Aikkal; Sithara, Kandiyl; Anoop, Sahadevan; Eapen, Santhosh J

2009-01-01

Ginger (Zingiber officinale Rosc) (Family: Zingiberaceae) is a herbaceous perennial, the rhizomes of which are used as a spice. Ginger is a plant which is well known for its medicinal applications. Recently EST-derived SNPs are a free by-product of the currently expanding EST (Expressed Sequence Tag) databases. The development of high-throughput methods for the detection of SNPs (Single Nucleotide Polymorphism) and small indels (insertion/deletion) has led to a revolution in their use as molecular markers. Available (38139) Ginger EST sequences were mined from dbEST of NCBI. CAP3 program was used to assemble EST sequences into contigs. Candidate SNPs and Indel polymorphisms were detected using the perl script AutoSNP version 1.0 which has used 31905 ESTs for detecting SNPs and Indel sites. We found 64026 SNP sites and 7034 indel polymorphisms with frequency of 0.84 SNPs / 100 bp. Among the three tissues from which the EST libraries had been generated, Rhizomes had high frequency of 1.08 SNPs/indels per 100 bp whereas the leaves had lowest frequency of 0.63 per 100 bp and root is showing relative frequency 0.82/100bp. Transitions and transversion ratio is 0.90. In overall detected SNP, transversion is high when compare to transition. These detected SNPs can be used as markers for genetic studies. Availability The results of the present study hosted in our webserver www.spices.res.in/spicesnip PMID:20198184

Epigenetic responses to drought stress in rice (Oryza sativa L.).

PubMed

Gayacharan; Joel, A John

2013-07-01

Cytosine methylation polymorphism plays a key role in gene regulation, mainly in expression of genes in crop plants. The differential expression of cytosine methylation over drought stress response was analyzed in rice using drought susceptible but agronomically superior lines IR 20 and CO 43, and drought tolerant genotypes PL and PMK 3 and their F1 hybrids. The parents and hybrids were subjected to two moisture regimes viz., one under drought condition and another under control condition. The cytosine methylation polymorphism in genomic DNA was quantified under both the conditions at the reproductive stage of the plant using the Methylation Sensitive Amplified Polymorphism (MSAP) technique devised by Xiong et al. (261:439-446, 1999). The results depicted that under drought condition, hyper-methylation was predominant in the drought susceptible genotypes while drought tolerant genotypes presented hypo-methylation behavior. While imposing drought, spikelet sterility per cent was positively correlated to percentage of methylation whereas, panicle length, number of seed per panicle, panicle weight, 100 seed weight, and yield/plant were negatively correlated indicating the role of epigenetic regulation in yield attributing traits in response to drought. Thus, methylation can be considered as an important epigenetic regulatory mechanism in rice plants to adapt drought situation. From this study, we speculate that the hyper- methylation may be an indicator of drought susceptibility and the hypo-methylation for drought tolerance and this methylation polymorphism can be effectively used in drought screening program.

γ-Herringbone Polymorph of 6,13-Bis(trimethylsilylethynyl)pentacene: A Potential Material for Enhanced Hole Mobility.

PubMed

Bhat, Vinayak; Gopan, Gopika; Nair, Nanditha G; Hariharan, Mahesh

2018-04-06

The introduction of the trialkylsilylethynyl group to the acene core is known to predominantly transform the herringbone structure of pentacene to a slip-stacked packing. However, herein, the occurrence of an unforeseen polymorph of 6,13-bis(trimethylsilylethynyl)pentacene (TMS-pentacene), with an atypical γ-herringbone packing arrangement, is reported. Intermolecular noncovalent interactions in the γ-herringbone polymorph are determined from Hirshfeld surface and quantum theory of atoms-in-molecules (QTAIM) analyses. Furthermore, a comparative truncated symmetry-adapted perturbation theory (SAPT(0)) energy decomposition analysis discloses the role of exchange repulsions that govern molecular packing in the γ-herringbone polymorph. Moreover, the computationally predicted electronic coupling and anisotropic mobility reveal the possibility of enhanced hole transport (μ h =3.7 cm 2  V -1  s -1 ) in the γ-herringbone polymorph, in contrast to the reported polymorph with a hole mobility of μ h =0.1 cm 2  V -1  s -1 . © 2018 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.

Microsatellite markers for Leucobryum boninense (Leucobryaceae), endemic to the Bonin Islands, Japan.

PubMed

Oguri, Emiko; Yamaguchi, Tomio; Kajita, Tadashi; Murakami, Noriaki

2013-05-01

Microsatellite primers were developed for Leucobryum boninense, endemic to the Bonin Islands, Japan, to investigate its level of genetic diversity and population genetic structure. • Using next-generation sequencing, 21 primer sets were developed, among which nine loci were polymorphic in the populations of the Bonin Islands. Among these polymorphic loci, the number of alleles per locus ranged from two to 10 (mean = 3.444) and the expected heterozygosity ranged from 0.066 to 0.801 (mean = 0.338). • These results indicate the utility of the nine microsatellite markers that we developed for population genetic studies of L. boninense.

The individual and combined influence of ACE and ACTN3 genotypes on muscle phenotypes before and after strength training.

PubMed

Erskine, R M; Williams, A G; Jones, D A; Stewart, C E; Degens, H

2014-08-01

Alternative measures of muscle size, strength, and power to those used in previous studies could help resolve the controversy surrounding associations between polymorphisms of the angiotensin-I converting enzyme (ACE) and α-actinin-3 (ACTN3) genes and skeletal muscle phenotypes, and the responses to resistance training (RT). To this end, we measured quadriceps femoris muscle volume (Vm), physiological cross-sectional area (PCSA), maximum isometric force (Ft), specific force (Ft per unit PCSA), maximum isoinertial strength (1-RM), and maximum power (Wmax ; n = 40) before and after 9-week knee extension RT in 51 previously untrained young men, who were genotyped for the ACE I/D and ACTN3 R577X polymorphisms. ACTN3 R-allele carriers had greater Vm, 1-RM, and Wmax than XX homozygotes at baseline (all P < 0.05), but responses to RT were independent of ACTN3 genotype (all P > 0.05). Muscle phenotypes were independent of ACE genotype before (all P > 0.05) and after RT (all P > 0.01). However, people with the "optimal" ACE+ACTN3 genotype combination had greater baseline 1-RM and Wmax compared to those with the "suboptimal" profile (both P < 0.0125). We show for the first time that the ACTN3 R577X polymorphism is associated with human Vm and (independently and in combination with the ACE I/D polymorphism) influences 1-RM and Wmax. © 2013 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

TCF7L2 polymorphism associates with new-onset diabetes after transplantation.

PubMed

Ghisdal, Lidia; Baron, Christophe; Le Meur, Yannick; Lionet, Arnaud; Halimi, Jean-Michel; Rerolle, Jean-Philippe; Glowacki, François; Lebranchu, Yvon; Drouet, Mireille; Noël, Christian; El Housni, Hakim; Cochaux, Pascale; Wissing, Karl Martin; Abramowicz, Daniel; Abramowicz, Marc

2009-11-01

New-onset diabetes after transplantation (NODAT) is a serious and frequent complication in transplant recipients. Whether NODAT shares the same susceptibility genes as type 2 diabetes is unknown. In this multicenter study, we genotyped 1076 white patients without diabetes at transplantation for 11 polymorphisms that associate with type 2 diabetes. We defined NODAT as a fasting plasma glucose > or =126 mg/dl on at least two occasions or de novo hypoglycemic therapy. We compared clinical and genetic factors between patients who developed NODAT within 6 mo of transplantation (n = 118; incidence 11%) and patients without diabetes (n = 958). In multivariate analysis, NODAT significantly associated with the following characteristics: TCF7L2 polymorphism (odds ratio [OR] 1.60 per each T allele; P = 0.002), age (OR 1.03 per year; P < 0.001), body mass index at transplantation (OR 1.09 per unit; P < 0.001), tacrolimus use (OR 2.26; P < 0.001), and the occurrence of a corticoid-treated acute rejection episode (OR 2.78; P < 0.001). In summary, our data show that the TCF7L2 rs7903146 polymorphism, a known risk factor for type 2 diabetes in the general population, also associates with NODAT.

ACTN3 genotype does not influence muscle power.

PubMed

Hanson, E D; Ludlow, A T; Sheaff, A K; Park, J; Roth, S M

2010-11-01

The R577X polymorphism within the ACTN3 gene has been associated with elite athletic performance, strength, power, fat free mass, and adaptations to strength training, though inconsistencies exist in the literature. The specific muscle power phenotypes most influenced by the polymorphism are uncertain. The purpose of this study was to examine the association between ACTN3 R577X genotype and muscle power phenotypes. Recreationally active young men and women (N=57) were selected to complete 2 muscle performance assessments, an isokinetic fatigue protocol at testing speeds of 180°  s (-1) and 250°  s (-1) and a 30 s Wingate test. Isokinetic torque and Wingate power significantly decreased over the duration of each test, but no differences in the rate of decline were observed among ACTN3 genotype groups. Similarly, no significant genotype differences were observed for isokinetic peak torque, Wingate absolute or relative peak power, or fatigue index. These results indicate that in recreationally active individuals the ACTN3 R577X polymorphism is not associated with muscle performance phenotypes, supporting recent findings that R577X may only be important for predicting performance in elite athletes. Our data also indicate that using this polymorphism for genetic screening in the lay population is scientifically questionable.

Prediction of response to chemoradiation in rectal cancer by a gene polymorphism in the epidermal growth factor receptor promoter region

DOE Office of Scientific and Technical Information (OSTI.GOV)

Spindler, Karen-Lise Garm; Nielsen, Jens Nederby; Lindebjerg, Jan

2006-10-01

Purpose: Epidermal growth factor receptor (EGFR) has been associated with radioresistance in solid tumors. Recently a polymorphism in the Sp1 recognition site of the EGFR promoter region was identified. The present study investigated the predictive value of this polymorphism for the outcome of chemoradiation in locally advanced rectal cancer. Methods and Materials: The study included 77 patients with locally advanced T3 rectal tumors. Treatment consisted of preoperative radiation therapy at a total tumor dose of 65 Gy and concomitant chemotherapy with Uftoral. Blood samples from 63 patients were evaluated for Sp1 -216 G/T polymorphism by polymerase chain reaction analysis. Forty-eightmore » primary tumor biopsies were available for EGFR immunostaining. Patients underwent surgery 8 weeks after treatment. Pathologic response evaluation was performed according to the tumor regression grade (TRG) system. Results: Forty-nine percent had major response (TRG1-2) and 51% moderate response (TRG 3-4) to chemoradiation. The rates of major response were 34% (10/29) in GG homozygote patients compared with 65% (22/34) in patients with T containing variants (p = 0.023). Fifty-eight percent of biopsies were positive for EGFR expression (28/48). The major response rates with regard to EGFR immunostaining were not significantly different. EGFR-positive tumors were found in 83% of the GG homozygote patients compared with 38% of patients with TT or GT variants (p = 0.008). Conclusions: There was a significant correlation between EGFR Sp1 -216 G/T polymorphism and treatment response to chemoradiation in locally advanced rectal cancer. Further investigations of a second set of patient and other treatment schedules are warranted.« less

LPA gene: interaction between the apolipoprotein(a) size ('kringle IV' repeat) polymorphism and a pentanucleotide repeat polymorphism influences Lp(a) lipoprotein level.

PubMed

Røsby, O; Berg, K

2000-01-01

In order to search for factors influencing the Lp(a) lipoprotein level, we have examined the apolipoprotein(a) (apo(a)) size polymorphism as well as a pentanucleotide (TTTTA) repeat polymorphism in the 5' control region of the LPA gene. Lp(a) lipoprotein levels were compared between individuals with different genotypes as defined by pulsed field gel electrophoresis of DNA plugs, and PCR of DNA samples followed by polyacrylamide gel electrophoresis. DNA plugs and DNA were prepared from blood samples collected from blood donors. Twenty-seven different K IV repeat alleles were observed in the 71 women and 92 men from which apo(a) size polymorphism results were obtained. Alleles encoding 26-32 Kringle IV repeats were the most frequent. Alleles encoding seven to 11 TTTTA repeats were detected in the 84 women and 122 men included in the pentanucleotide polymorphism study, and homozygosity for eight TTTTA repeats was the most common genotype. The eight TTTTA repeat allele occurred with almost any apo(a) allele. An inverse relationship between number of K IV repeats and Lp(a) concentration was confirmed. The contributions of the apo(a) size polymorphism and the pentanucleotide repeat polymorphism to the interindividual variance of Lp(a) lipoprotein concentrations were 9.7 and 3.5%, respectively (type IV sum of squares). Nineteen per cent of the variance in Lp(a) lipoprotein level appeared to be the result of the multiplication product (interaction) between the apo(a) size polymorphism and the pentanucleotide repeat polymorphism. The contribution of the apo(a) size polymorphism alone to the variation in Lp(a) lipoprotein level was lower than previously reported. However, the multiplicative interaction effect between the K IV repeat polymorphism and the pentanucleotide repeat polymorphism may be an important factor explaining the variation in Lp(a) lipoprotein levels among the populations.

Genetic polymorphisms in lung disease: bandwagon or breakthrough?

PubMed Central

Iannuzzi, Michael C; Maliarik, Mary; Rybicki, Benjamin

2002-01-01

The study of genetic polymorphisms has touched every aspect of pulmonary and critical care medicine. We review recent progress made using genetic polymorphisms to define pathophysiology, to identify persons at risk for pulmonary disease and to predict treatment response. Several pitfalls are commonly encountered in studying genetic polymorphisms, and this article points out criteria that should be applied to design high-quality genetic polymorphism studies. PMID:11980584

Quantitative assessment of hematopoietic chimerism by quantitative real-time polymerase chain reaction of sequence polymorphism systems after hematopoietic stem cell transplantation.

PubMed

Qin, Xiao-ying; Li, Guo-xuan; Qin, Ya-zhen; Wang, Yu; Wang, Feng-rong; Liu, Dai-hong; Xu, Lan-ping; Chen, Huan; Han, Wei; Wang, Jing-zhi; Zhang, Xiao-hui; Li, Jin-lan; Li, Ling-di; Liu, Kai-yan; Huang, Xiao-jun

2011-08-01

Analysis of changes in recipient and donor hematopoietic cell origin is extremely useful to monitor the effect of hematopoietic stem cell transplantation (HSCT) and sequential adoptive immunotherapy by donor lymphocyte infusions. We developed a sensitive, reliable and rapid real-time PCR method based on sequence polymorphism systems to quantitatively assess the hematopoietic chimerism after HSCT. A panel of 29 selected sequence polymorphism (SP) markers was screened by real-time PCR in 101 HSCT patients with leukemia and other hematological diseases. The chimerism kinetics of bone marrow samples of 8 HSCT patients in remission and relapse situations were followed longitudinally. Recipient genotype discrimination was possible in 97.0% (98 of 101) with a mean number of 2.5 (1-7) informative markers per recipient/donor pair. Using serial dilutions of plasmids containing specific SP markers, the linear correlation (r) of 0.99, the slope between -3.2 and -3.7 and the sensitivity of 0.1% were proved reproducible. By this method, it was possible to very accurately detect autologous signals in the range from 0.1% to 30%. The accuracy of the method in the very important range of autologous signals below 5% was extraordinarily high (standard deviation <1.85%), which might significantly improve detection accuracy of changes in autologous signals early in the post-transplantation course of follow-up. The main advantage of the real-time PCR method over short tandem repeat PCR chimerism assays is the absence of PCR competition and plateau biases, with demonstrated greater sensitivity and linearity. Finally, we prospectively analyzed bone marrow samples of 8 patients who received allografts and presented the chimerism kinetics of remission and relapse situations that illustrated the sensitivity level and the promising clinical application of this method. This SP-based real-time PCR assay provides a rapid, sensitive, and accurate quantitative assessment of mixed chimerism that can be useful in predicting graft rejection and early relapse.

Genetic variants in adiponectin and blood pressure responses to dietary sodium or potassium interventions: a family-based association study

PubMed Central

Chu, C; Wang, Y; Ren, K-y; Yan, D-y; Guo, T-s; Zheng, W-l; Yuan, Z-y; Mu, J-j

2016-01-01

Previous studies have shown that genetic factors might have an important role in blood pressure (BP) responses to dietary salt or potassium intake. The aim of this study was to assess the association of common genetic variants of the adiponectin gene with BP responses to controlled dietary sodium or potassium interventions. Subjects (n=334) from 124 families in rural areas of Northern China were recruited. After a 3-day baseline observation, participants sequentially maintained a 7-day low-sodium diet (NaCl, 3 g per day; or sodium, 51.3 mmol per day), followed by a 7-day high-sodium diet (NaCl, 18 g per day; or sodium, 307.8 mmol per day) and a 7-day high-sodium plus potassium supplementation intervention (KCl, 4.5 g per day; or potassium, 60 mmol per day). A total of seven single nucleotide polymorphisms (SNPs) in the adiponectin gene were selected as the study sites. After adjustment for multiple testing, the adiponectin SNP rs16861205 was significantly associated with the diastolic BP (DBP) response to low-salt intervention, and the DBP and mean arterial pressure (MAP) responses to high-salt intervention (P=0.028, 0.023 and 0.027, respectively). SNP rs822394 was associated with the DBP and MAP responses to low-salt intervention and the DBP response to high-salt intervention (P=0.023, 0.030 and 0.033 respectively). Meanwhile, significant association also existed between SNP rs16861194 and the systolic BP response to potassium supplementation intervention (P=0.026). In addition, SNP rs822394 was significantly associated with basal DBP after adjustment for multiple testing (P=0.033). Our study indicated that the genetic polymorphisms in the adiponectin gene are significantly associated with BP responses to dietary sodium and potassium intake. PMID:27011258

Genetic variants in adiponectin and blood pressure responses to dietary sodium or potassium interventions: a family-based association study.

PubMed

Chu, C; Wang, Y; Ren, K-Y; Yan, D-Y; Guo, T-S; Zheng, W-L; Yuan, Z-Y; Mu, J-J

2016-09-01

Previous studies have shown that genetic factors might have an important role in blood pressure (BP) responses to dietary salt or potassium intake. The aim of this study was to assess the association of common genetic variants of the adiponectin gene with BP responses to controlled dietary sodium or potassium interventions. Subjects (n=334) from 124 families in rural areas of Northern China were recruited. After a 3-day baseline observation, participants sequentially maintained a 7-day low-sodium diet (NaCl, 3 g per day; or sodium, 51.3 mmol per day), followed by a 7-day high-sodium diet (NaCl, 18 g per day; or sodium, 307.8 mmol per day) and a 7-day high-sodium plus potassium supplementation intervention (KCl, 4.5 g per day; or potassium, 60 mmol per day). A total of seven single nucleotide polymorphisms (SNPs) in the adiponectin gene were selected as the study sites. After adjustment for multiple testing, the adiponectin SNP rs16861205 was significantly associated with the diastolic BP (DBP) response to low-salt intervention, and the DBP and mean arterial pressure (MAP) responses to high-salt intervention (P=0.028, 0.023 and 0.027, respectively). SNP rs822394 was associated with the DBP and MAP responses to low-salt intervention and the DBP response to high-salt intervention (P=0.023, 0.030 and 0.033 respectively). Meanwhile, significant association also existed between SNP rs16861194 and the systolic BP response to potassium supplementation intervention (P=0.026). In addition, SNP rs822394 was significantly associated with basal DBP after adjustment for multiple testing (P=0.033). Our study indicated that the genetic polymorphisms in the adiponectin gene are significantly associated with BP responses to dietary sodium and potassium intake.

Predicting survival using clinical risk scores and non-HLA immunogenetics.

PubMed

Balavarca, Y; Pearce, K; Norden, J; Collin, M; Jackson, G; Holler, E; Dressel, R; Kolb, H-J; Greinix, H; Socie, G; Toubert, A; Rocha, V; Gluckman, E; Hromadnikova, I; Sedlacek, P; Wolff, D; Holtick, U; Dickinson, A; Bickeböller, H

2015-11-01

Previous studies of non-histocompatibility leukocyte antigen (HLA) gene single-nucleotide polymorphisms (SNPs) on subgroups of patients undergoing allogeneic haematopoietic stem cell transplantation (HSCT) revealed an association with transplant outcome. This study further evaluated the association of non-HLA polymorphisms with overall survival in a cohort of 762 HSCT patients using data on 26 polymorphisms in 16 non-HLA genes. When viewed in addition to an already established clinical risk score (EBMT-score), three polymorphisms: rs8177374 in the gene for MyD88-adapter-like (MAL; P=0.026), rs9340799 in the oestrogen receptor gene (ESR; P=0.003) and rs1800795 in interleukin-6 (IL-6; P=0.007) were found to be associated with reduced overall survival, whereas the haplo-genotype (ACC/ACC) in IL-10 was protective (P=0.02). The addition of these non-HLA polymorphisms in a Cox regression model alongside the EBMT-score improved discrimination between risk groups and increased the level of prediction compared with the EBMT-score alone (gain in prediction capability for EBMT-genetic-score 10.8%). Results also demonstrated how changes in clinical practice through time have altered the effects of non-HLA analysis. The study illustrates the significance of non-HLA genotyping prior to HSCT and the importance of further investigation into non-HLA gene polymorphisms in risk prediction.

Prenatal maternal depression and child serotonin transporter linked polymorphic region (5-HTTLPR) and dopamine receptor D4 (DRD4) genotype predict negative emotionality from 3 to 36 months.

PubMed

Green, Cathryn Gordon; Babineau, Vanessa; Jolicoeur-Martineau, Alexia; Bouvette-Turcot, Andrée-Anne; Minde, Klaus; Sassi, Roberto; St-André, Martin; Carrey, Normand; Atkinson, Leslie; Kennedy, James L; Steiner, Meir; Lydon, John; Gaudreau, Helene; Burack, Jacob A; Levitan, Robert; Meaney, Michael J; Wazana, Ashley

2017-08-01

Prenatal maternal depression and a multilocus genetic profile of two susceptibility genes implicated in the stress response were examined in an interaction model predicting negative emotionality in the first 3 years. In 179 mother-infant dyads from the Maternal Adversity, Vulnerability, and Neurodevelopment cohort, prenatal depression (Center for Epidemiologic Studies Depressions Scale) was assessed at 24 to 36 weeks. The multilocus genetic profile score consisted of the number of susceptibility alleles from the serotonin transporter linked polymorphic region gene (5-HTTLPR): no long-rs25531(A) (LA: short/short, short/long-rs25531(G) [LG], or LG/LG] vs. any LA) and the dopamine receptor D4 gene (six to eight repeats vs. two to five repeats). Negative emotionality was extracted from the Infant Behaviour Questionnaire-Revised at 3 and 6 months and the Early Child Behavior Questionnaire at 18 and 36 months. Mixed and confirmatory regression analyses indicated that prenatal depression and the multilocus genetic profile interacted to predict negative emotionality from 3 to 36 months. The results were characterized by a differential susceptibility model at 3 and 6 months and by a diathesis-stress model at 36 months.

Association of matrix metalloproteinase-3 gene 5A/6A polymorphism with the recurrence of ischemic stroke: A prospective observational study.

PubMed

Huang, Xiaoya; Ye, Qiang; Zhang, Zheng; Huang, Xiangdong; Zhu, Zhenguo; Chen, Yanyan; Li, Jia; Chen, Siyan; Xia, Niange; Mao, Xinlei; Han, Liya; Ye, Zusen

2017-11-01

Studies have demonstrated that matrix metalloproteinase-3 (MMP-3) is involved in the development and progression of atherosclerosis. However, there is no information available on the association of MMP-3 5A/6A polymorphism with recurrent ischemic stroke (IS) in different IS subtypes. We investigated the potential associations between MMP-3 serum level and -1171 5A/6A polymorphism and the recurrence of IS in a Chinese population. Consecutive acute first-ever IS patients were enrolled between August 2008 and October 2013. The genotypes of MMP-3 5A/6A polymorphism were determined using polymerase chain reaction-restriction fragment length polymorphism. IS recurrence was monitored after the index event and multivariate Cox proportional hazards model was constructed to identify factors related to future IS recurrence. A total of 1282 eligible patients were enrolled. During a 2-year follow-up period, 157 (12.25%) patients had recurrent events. MMP-3 level was significantly higher in patients with 5A/6A or 5A/5A genotype (22.72±7.29ng/ul) than in patients with 6A/6A genotype (20.48±7.58ng/ul), P<0.001. No interaction between MMP-3 5A/6A polymorphism and the risk of recurrence in total IS patients was found. The variant 5A/6A+5A/5A genotype and the 5A allele were significantly associated with a high risk of recurrence for large-artery atherosclerosis (LAA) (multivariate-adjusted, P=0.002, 0.001, respectively), but not for small-artery occlusion and cardioembolism. Our finding showed that MMP-3 5A/6A may be a useful biomarker for predicting recurrence for LAA stroke patients and 5A allele carrier may bear a higher risk of recurrence among patients with the subtype of LAA. Copyright © 2017. Published by Elsevier B.V.

Genetic predictors of long-term response to growth hormone (GH) therapy in children with GH deficiency and Turner syndrome: the influence of a SOCS2 polymorphism.

PubMed

Braz, Adriana F; Costalonga, Everlayny F; Trarbach, Ericka B; Scalco, Renata C; Malaquias, Alexsandra C; Guerra-Junior, Gil; Antonini, Sonir R R; Mendonca, Berenice B; Arnhold, Ivo J P; Jorge, Alexander A L

2014-09-01

There is great interindividual variability in the response to GH therapy. Ascertaining genetic factors can improve the accuracy of growth response predictions. Suppressor of cytokine signaling (SOCS)-2 is an intracellular negative regulator of GH receptor (GHR) signaling. The objective of the study was to assess the influence of a SOCS2 polymorphism (rs3782415) and its interactive effect with GHR exon 3 and -202 A/C IGFBP3 (rs2854744) polymorphisms on adult height of patients treated with recombinant human GH (rhGH). Genotypes were correlated with adult height data of 65 Turner syndrome (TS) and 47 GH deficiency (GHD) patients treated with rhGH, by multiple linear regressions. Generalized multifactor dimensionality reduction was used to evaluate gene-gene interactions. Baseline clinical data were indistinguishable among patients with different genotypes. Adult height SD scores of patients with at least one SOCS2 single-nucleotide polymorphism rs3782415-C were 0.7 higher than those homozygous for the T allele (P < .001). SOCS2 (P = .003), GHR-exon 3 (P= .016) and -202 A/C IGFBP3 (P = .013) polymorphisms, together with clinical factors accounted for 58% of the variability in adult height and 82% of the total height SD score gain. Patients harboring any two negative genotypes in these three different loci (homozygosity for SOCS2 T allele; the GHR exon 3 full-length allele and/or the -202C-IGFBP3 allele) were more likely to achieve an adult height at the lower quartile (odds ratio of 13.3; 95% confidence interval of 3.2-54.2, P = .0001). The SOCS2 polymorphism (rs3782415) has an influence on the adult height of children with TS and GHD after long-term rhGH therapy. Polymorphisms located in GHR, IGFBP3, and SOCS2 loci have an influence on the growth outcomes of TS and GHD patients treated with rhGH. The use of these genetic markers could identify among rhGH-treated patients those who are genetically predisposed to have less favorable outcomes.

CD44 Gene Polymorphisms in Breast Cancer Risk and Prognosis: A Study in North Indian Population

PubMed Central

Tulsyan, Sonam; Agarwal, Gaurav; Lal, Punita; Agrawal, Sushma; Mittal, Rama Devi; Mittal, Balraj

2013-01-01

Background Cell surface biomarker CD44 plays an important role in breast cancer cell growth, differentiation, invasion, angiogenesis and tumour metastasis. Therefore, we aimed to investigate the role of CD44 gene polymorphisms in breast cancer risk and prognosis in North Indian population. Materials & Methods A total of 258 breast cancer patients and 241 healthy controls were included in the case-control study for risk prediction. According to RECIST, 114 patients who received neo-adjuvant chemotherapy were recruited for the evaluation of breast cancer prognosis. We examined the association of tagging SNP (rs353639) of Hapmap Gujrati Indians in Houston (GIH population) in CD44 gene along with a significant reported SNP (rs13347) in Chinese population by genotyping using Taqman allelic discrimination assays. Statistical analysis was done using SPSS software, version 17. In-silico analysis for prediction of functional effects was done using F-SNP and FAST-SNP. Results No significant association of both the genetic variants of the CD44 gene polymorphisms was found with breast cancer risk. On performing univariate analysis with clinicopathological characteristics and treatment response, we found significant association of genotype (CT+TT) of rs13347 polymorphism with earlier age of onset (P = 0.029, OR = 0.037). However, significance was lost in multivariate analysis. For rs353639 polymorphism, significant association was seen with clinical tumour size, both at the genotypic (AC+CC) (P = 0.039, OR = 3.02) as well as the allelic (C) (P = 0.042, OR = 2.87) levels. On performing multivariate analysis, increased significance of variant genotype (P = 0.017, OR = 4.29) and allele (P = 0.025, OR = 3.34) of rs353639 was found with clinical tumour size. In-silico analysis using F-SNP, showed altered transcriptional regulation for rs353639 polymorphism. Conclusions These findings suggest that CD44 rs353639 genetic variants may have significant effect in breast cancer prognosis. However, both the polymorphisms- rs13347 and rs353639 had no effect on breast cancer susceptibility. PMID:23940692

Genetic differences in human circadian clock genes among worldwide populations.

PubMed

Ciarleglio, Christopher M; Ryckman, Kelli K; Servick, Stein V; Hida, Akiko; Robbins, Sam; Wells, Nancy; Hicks, Jennifer; Larson, Sydney A; Wiedermann, Joshua P; Carver, Krista; Hamilton, Nalo; Kidd, Kenneth K; Kidd, Judith R; Smith, Jeffrey R; Friedlaender, Jonathan; McMahon, Douglas G; Williams, Scott M; Summar, Marshall L; Johnson, Carl Hirschie

2008-08-01

The daily biological clock regulates the timing of sleep and physiological processes that are of fundamental importance to human health, performance, and well-being. Environmental parameters of relevance to biological clocks include (1) daily fluctuations in light intensity and temperature, and (2) seasonal changes in photoperiod (day length) and temperature; these parameters vary dramatically as a function of latitude and locale. In wide-ranging species other than humans, natural selection has genetically optimized adaptiveness along latitudinal clines. Is there evidence for selection of clock gene alleles along latitudinal/photoperiod clines in humans? A number of polymorphisms in the human clock genes Per2, Per3, Clock, and AANAT have been reported as alleles that could be subject to selection. In addition, this investigation discovered several novel polymorphisms in the human Arntl and Arntl2 genes that may have functional impact upon the expression of these clock transcriptional factors. The frequency distribution of these clock gene polymorphisms is reported for diverse populations of African Americans, European Americans, Ghanaians, Han Chinese, and Papua New Guineans (including 5 subpopulations within Papua New Guinea). There are significant differences in the frequency distribution of clock gene alleles among these populations. Population genetic analyses indicate that these differences are likely to arise from genetic drift rather than from natural selection.

Polymorphism of the p53 tumor suppressor gene is associated with susceptibility to uterine leiomyoma.

PubMed

Denschlag, Dominik; Bettendorf, Herta; Watermann, Dirk; Keck, Christoph; Tempfer, Clemens; Pietrowski, Detlef

2005-07-01

To evaluate the association between the presence of uterine leiomyoma and two single nuclear polymorphisms of the p53 tumor suppressor and the angiopoietin-2 (ANGPT2) genes. Prospective case control study. Academic research institution. One hundred thirty-two women with clinically and surgically diagnosed uterine leiomyomas and 280 controls. Peripheral venous puncture. Genotyping was performed by polymerase chain reaction-based amplification of the Arg and Pro variants at codon 72 of the p53 gene and by restriction fragment length polymorphism analysis of the G/G and G/A alleles in exon 4 of the ANGPT2 gene. Comparing women with uterine leiomyomas and controls, no statistically significant difference with respect to allele frequency and genotype distribution were ascertained for the ANGPT2 polymorphism (P=.2 and P=.5, respectively). However, for the p53 tumor suppressor gene polymorphism, statistically significant differences in terms of a higher Pro allele frequency and a higher prevalence of the Pro/Pro genotype among women with uterine leiomyoma (32.0% vs. 16.0%, respectively, and 21.3% vs. 4.7%, respectively) were ascertained (P=.001, OR 1.74; 95% CI 1.24-2.45, P=.001; OR 3.84, 95% CI 1.81-8.14; respectively). Carriage of the p53 polymorphism at codon 72 predicts the susceptibility to leiomyoma in a Caucasian population and may contribute to the pathogenesis of uterine leiomyoma.

Predicting stroke through genetic risk functions: The CHARGE risk score project

PubMed Central

Ibrahim-Verbaas, Carla A; Fornage, Myriam; Bis, Joshua C; Choi, Seung Hoan; Psaty, Bruce M; Meigs, James B; Rao, Madhu; Nalls, Mike; Fontes, Joao D; O’Donnell, Christopher J.; Kathiresan, Sekar; Ehret, Georg B.; Fox, Caroline S; Malik, Rainer; Dichgans, Martin; Schmidt, Helena; Lahti, Jari; Heckbert, Susan R; Lumley, Thomas; Rice, Kenneth; Rotter, Jerome I; Taylor, Kent D; Folsom, Aaron R; Boerwinkle, Eric; Rosamond, Wayne D; Shahar, Eyal; Gottesman, Rebecca F.; Koudstaal, Peter J; Amin, Najaf; Wieberdink, Renske G.; Dehghan, Abbas; Hofman, Albert; Uitterlinden, André G; DeStefano, Anita L.; Debette, Stephanie; Xue, Luting; Beiser, Alexa; Wolf, Philip A.; DeCarli, Charles; Ikram, M. Arfan; Seshadri, Sudha; Mosley, Thomas H; Longstreth, WT; van Duijn, Cornelia M; Launer, Lenore J

2014-01-01

Background and Purpose Beyond the Framingham Stroke Risk Score (FSRS), prediction of future stroke may improve with a genetic risk score (GRS) based on Single nucleotide polymorphisms (SNPs) associated with stroke and its risk factors. Methods The study includes four population-based cohorts with 2,047 first incident strokes from 22,720 initially stroke-free European origin participants aged 55 years and older, who were followed for up to 20 years. GRS were constructed with 324 SNPs implicated in stroke and 9 risk factors. The association of the GRS to first incident stroke was tested using Cox regression; the GRS predictive properties were assessed with Area under the curve (AUC) statistics comparing the GRS to age sex, and FSRS models, and with reclassification statistics. These analyses were performed per cohort and in a meta-analysis of pooled data. Replication was sought in a case-control study of ischemic stroke (IS). Results In the meta-analysis, adding the GRS to the FSRS, age and sex model resulted in a significant improvement in discrimination (All stroke: Δjoint AUC =0.016, p-value=2.3*10-6; IS: Δ joint AUC =0.021, p-value=3.7*10−7), although the overall AUC remained low. In all studies there was a highly significantly improved net reclassification index (p-values <10−4). Conclusions The SNPs associated with stroke and its risk factors result only in a small improvement in prediction of future stroke compared to the classical epidemiological risk factors for stroke. PMID:24436238

MicroRNAs-1614-3p gene seed region polymorphisms and association analysis with chicken production traits.

PubMed

Li, Hong; Sun, Gui-Rong; Tian, Ya-Dong; Han, Rui-Li; Li, Guo-Xi; Kang, Xiang-Tao

2013-05-01

In the present study, a total of 860 chickens from a Gushi-Anka F2 resource population were used to evaluate the genetic effect of the gga-miR-1614-3p gene. A novel, silent, single nucleotide polymorphism (SNP, +5 C>T) was detected in the gga-miR-1614-3p gene seed region through AvaII polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) and PCR products sequencing methods. Associations between the SNP and chicken growth, meat quality and carcass traits were performed by association analysis. The results showed that the SNP was significantly associated with breast muscle shear force and leg muscle water loss rate, wing weight, liver weight and heart weight (p<0.05), and highly significantly associated with the weight of the abdominal fat (p<0.01). The secondary structure of gga-miR-1614 and the free energy were altered due to the variation predicted by the M-fold program.

Relatedness of Indian flax genotypes (Linum usitatissimum L.): an inter-simple sequence repeat (ISSR) primer assay.

PubMed

Rajwade, Ashwini V; Arora, Ritu S; Kadoo, Narendra Y; Harsulkar, Abhay M; Ghorpade, Prakash B; Gupta, Vidya S

2010-06-01

The objective of this study was to analyze the genetic relationships, using PCR-based ISSR markers, among 70 Indian flax (Linum usitatissimum L.) genotypes actively utilized in flax breeding programs. Twelve ISSR primers were used for the analysis yielding 136 loci, of which 87 were polymorphic. The average number of amplified loci and the average number of polymorphic loci per primer were 11.3 and 7.25, respectively, while the percent loci polymorphism ranged from 11.1 to 81.8 with an average of 63.9 across all the genotypes. The range of polymorphism information content scores was 0.03-0.49, with an average of 0.18. A dendrogram was generated based on the similarity matrix by the Unweighted Pair Group Method with Arithmetic Mean (UPGMA), wherein the flax genotypes were grouped in five clusters. The Jaccard's similarity coefficient among the genotypes ranged from 0.60 to 0.97. When the omega-3 alpha linolenic acid (ALA) contents of the individual genotypes were correlated with the clusters in the dendrogram, the high ALA containing genotypes were grouped in two clusters. This study identified SLS 50, Ayogi, and Sheetal to be the most diverse genotypes and suggested their use in breeding programs and for developing mapping populations.

Isozyme, ISSR and RAPD profiling of genotypes in marvel grass (Dichanthium annulatum).

PubMed

Saxena, Raghvendra; Chandra, Amaresh

2010-11-01

Genetic analysis of 30 accessions of marvel grass (Dichanthium annulatum Forsk.), a tropical range grass collected from grasslands and open fields of drier regions, was carried out with the objectives of identifying unique materials that could be used in developing the core germplasm for such regions as well as to explore gene (s) for drought tolerance. Five inter-simple sequence repeat (ISSR) primers [(CA)4, (AGAC), (GACA) 4; 27 random amplified polymorphic DNA (RAPD) and four enzyme systems were employed in the present study. In total, ISSR yielded 61 (52 polymorphic), RAPD 269 (253 polymorphic) and enzyme 55 isozymes (44 polymorphic) bands. The average polymorphic information content (PIC) and marker index (MI) across all polymorphic bands of 3 markers systems ranged from 0.419 to 0.480 and 4.34 to 5.25 respectively Dendrogram analysis revealed three main clusters with all three markers. Four enzymes namely esterase (EST), polyphenoloxidase (PPO), peroxidase (PRX) and superoxide dismutase (SOD) revealed 55 alleles from a total of 16 enzyme-coding loci. Of these, 14 loci and 44 alleles were polymorphic. The mean number of alleles per locus was 3.43. Mean heterozygosity observed among the polymorphic loci ranged from 0.406 (SOD) to 0.836 (EST) and accession wise from 0.679 (1G3108) to 0.743 (IGKMD-10). Though there was intermixing of few accessions of one agro-climatic region to another largely groupings of accessions were with their regions of collections. Bootstrap analysis at 1000 iterations also showed large numbers of nodes (11 to 17) having strong clustering (> 50 bootstrap values) in all three marker systems. The accessions of the arid and drier regions forming one cluster are assigned as distinct core collection of Dichanthium and can be targeted for isolation of gene (s) for drought tolerance. Variations in isozyme allele numbers and high PIC (0.48) and MI (4.98) as observed with ISSR markers indicated their usefulness for germplasm characterization.

Maternal and offspring genetic variants of AKR1C3 and the risk of childhood leukemia

PubMed Central

Liu, Chen-yu; Hsu, Yi-Hsiang; Pan, Pi-Chen; Wu, Ming-Tsang; Ho, Chi-Kung; Su, Li; Xu, Xin; Li, Yi; Christiani, David C.

2008-01-01

The aldo-keto reductase 1C3 (AKR1C3) gene located on chromosome 10p15-p14, a regulator of myeloid cell proliferation and differentiation, represents an important candidate gene for studying human carcinogenesis. In a prospectively enrolled population-based case–control study of Han Chinese conducted in Kaohsiung in southern Taiwan, a total of 114 leukemia cases and 221 controls <20 years old were recruited between November 1997 and December 2005. The present study set out to evaluate the association between childhood leukemia and both maternal and offspring's genotypes. To do so, we conducted a systematic assessment of common single-nucleotide polymorphisms (SNPs) at the 5′ flanking 10 kb to 3′ UTR of AKR1C3 gene. Gln5His and three tagSNPs (rs2245191, rs10508293 and rs3209896) and one multimarker (rs2245191, rs10508293 and rs3209896) were selected with average 90% coverage of untagged SNPs by using the HapMap II data set. Odds ratios and 95% confidence intervals were adjusted for age and gender. After correcting for multiple comparisons, we observed that risk of developing childhood leukemia is significantly associated with rs10508293 polymorphism on intron 4 of the AKR1C3 gene in both offspring alone and in the combined maternal and offspring genotypes (nominal P < 0.0001, permutation P < 0.005). The maternal methylenetetrahydrofolate reductase A1298C polymorphism was found to be an effect modifier of the maternal intron 4 polymorphism of the AKR1C3 gene (rs10508293) and the childhood leukemia risk. In conclusion, this study suggests that AKR1C3 polymorphisms may be important predictive markers for childhood leukemia susceptibility. PMID:18339682

Genetic influences on right ventricular systolic pressure (RVSP) in chronic obstructive pulmonary disease (COPD).

PubMed

Shaw, Janet G; Dent, Annette G; Passmore, Linda H; Burstow, Darryl J; Bowman, Rayleen V; Zimmerman, Paul V; Fong, Kwun M; Yang, Ian A

2012-06-13

Pulmonary hypertension (PH) is a complication of chronic obstructive pulmonary disease (COPD). This study examined genetic variations in mediators of vascular remodelling and their association with PH in patients with COPD. In patients with COPD, we genotyped 7 SNPs in 6 candidate PH genes (NOS3, ACE, EDN1, PTGIS, SLC6A4, VEGFA). We tested for association with right ventricular systolic pressure (RVSP), spirometry and gas transfer, and hypoxemia. In patients with COPD, we genotyped 7 SNPs in 6 candidate PH genes (NOS3, ACE, EDN1, PTGIS, SLC6A4, VEGFA). We tested for association with right ventricular systolic pressure (RVSP), spirometry and gas transfer, and hypoxemia. 580 COPD patients were recruited, 341 patients had a transthoracic echocardiogram, with RVSP measurable in 278 patients (mean age 69  years, mean FEV1 50% predicted, mean RVSP 44  mmHg, median history of 50 pack-years). Of the 7 tested SNPs, the NOS3-VNTR polymorphism was significantly associated with RVSP in a dose-dependent fashion for the risk allele: mean RVSP for a/a and a/b genotypes were 52.0 and 46.6  mmHg respectively, compared to 43.2  mmHg for b/b genotypes (P = 0.032). No associations were found between RVSP and other polymorphisms. ACE II or ID genotypes were associated with a lower FEV1% predicted than the ACE DD genotype (P = 0.028). The NOS3-298 TT genotype was associated with lower KCO % predicted than the NOS3-298 GG or GT genotype (P = 0.031). The NOS3-VNTR polymorphism was associated with RVSP in patients with COPD, supporting its involvement in the pathogenesis of PH in COPD. ACE and NOS3 genotypes were associated with COPD disease severity, but not with the presence of PH. Further study of these genes could lead to the development of prognostic and screening tools for PH in COPD.

Prediction of Adulthood Obesity Using Genetic and Childhood Clinical Risk Factors in the Cardiovascular Risk in Young Finns Study.

PubMed

Seyednasrollah, Fatemeh; Mäkelä, Johanna; Pitkänen, Niina; Juonala, Markus; Hutri-Kähönen, Nina; Lehtimäki, Terho; Viikari, Jorma; Kelly, Tanika; Li, Changwei; Bazzano, Lydia; Elo, Laura L; Raitakari, Olli T

2017-06-01

Obesity is a known risk factor for cardiovascular disease. Early prediction of obesity is essential for prevention. The aim of this study is to assess the use of childhood clinical factors and the genetic risk factors in predicting adulthood obesity using machine learning methods. A total of 2262 participants from the Cardiovascular Risk in YFS (Young Finns Study) were followed up from childhood (age 3-18 years) to adulthood for 31 years. The data were divided into training (n=1625) and validation (n=637) set. The effect of known genetic risk factors (97 single-nucleotide polymorphisms) was investigated as a weighted genetic risk score of all 97 single-nucleotide polymorphisms (WGRS97) or a subset of 19 most significant single-nucleotide polymorphisms (WGRS19) using boosting machine learning technique. WGRS97 and WGRS19 were validated using external data (n=369) from BHS (Bogalusa Heart Study). WGRS19 improved the accuracy of predicting adulthood obesity in training (area under the curve [AUC=0.787 versus AUC=0.744, P <0.0001) and validation data (AUC=0.769 versus AUC=0.747, P =0.026). WGRS97 improved the accuracy in training (AUC=0.782 versus AUC=0.744, P <0.0001) but not in validation data (AUC=0.749 versus AUC=0.747, P =0.785). Higher WGRS19 associated with higher body mass index at 9 years and WGRS97 at 6 years. Replication in BHS confirmed our findings that WGRS19 and WGRS97 are associated with body mass index. WGRS19 improves prediction of adulthood obesity. Predictive accuracy is highest among young children (3-6 years), whereas among older children (9-18 years) the risk can be identified using childhood clinical factors. The model is helpful in screening children with high risk of developing obesity. © 2017 American Heart Association, Inc.

Gene-gene interaction between COMT and MAOA potentially predicts the intelligence of attention-deficit hyperactivity disorder boys in China.

PubMed

Qian, Qiu-Jin; Yang, Li; Wang, Yu-Feng; Zhang, Hao-Bo; Guan, Li-Li; Chen, Yun; Ji, Ning; Liu, Lu; Faraone, S V

2010-05-01

The catechol-O-methyltransferase (COMT) gene contains a functional polymorphism (Val158Met) affecting the activity of the enzyme, and the monoamine oxidase A (MAOA) gene contains a VNTR polymorphism (MAOA-uVNTR) that affects the transcription of the gene. COMT and MAOA each contribute to the enzymatic degradation of dopamine and noradrenaline. Prefrontal cortical (PFC) function, which plays an important role in individual cognitive abilities, including intelligence, is modulated by dopamine. Since our previous association studies between attention deficit hyperactivity disorder (ADHD) and these two functional polymorphisms consistently showed the low activity alleles were preferentially transmitted to inattentive ADHD boys, the goal of the present study was to test the hypothesis that the interaction between COMT Val158Met and MAOA-uVNTR may affect the intelligence in a clinical sample of Chinese male ADHD subjects (n = 264). We found that the COMT x MAOA interaction significantly predicted full scale (FSIQ) and performance (PIQ) IQ scores (P = 0.039, 0.011); the MAOA-uVNTR significantly predicted FSIQ, PIQ and verbal IQ (VIQ) (P = 0.009, 0.019, 0.038); COMT Val158Met independently had no effect on any of the IQ scores. Only the COMT x MAOA interaction for PIQ remained significant after a Bonferroni correction. Among all combined genotypes, the valval-3R genotype predicted higher intelligence, (average 106.7 +/- 1.6, 95% C.I. 103.7-109.8 for FSIQ), and the valval-4R predicted lower intelligence (average 98.0 +/- 2.3, 95% C.I. 93.5-102.6 for FSIQ). These results suggest that there is an inverted U-shaped relationship between intelligence and dopaminergic activity in our sample. Our finding that gene-gene interaction between COMT and MAOA predicts the intelligence of ADHD boys in China is intriguing but requires replication in other samples.

Genetically elevated fetuin-A levels, fasting glucose levels, and risk of type 2 diabetes: the cardiovascular health study.

PubMed

Jensen, Majken K; Bartz, Traci M; Djoussé, Luc; Kizer, Jorge R; Zieman, Susan J; Rimm, Eric B; Siscovick, David S; Psaty, Bruce M; Ix, Joachim H; Mukamal, Kenneth J

2013-10-01

Fetuin-A levels are associated with higher risk of type 2 diabetes, but it is unknown if the association is causal. We investigated common (>5%) genetic variants in the fetuin-A gene (AHSG) fetuin-A levels, fasting glucose, and risk of type 2 diabetes. Genetic variation, fetuin-A levels, and fasting glucose were assessed in 2,893 Caucasian and 542 African American community-living individuals 65 years of age or older in 1992-1993. Common AHSG variants (rs4917 and rs2248690) were strongly associated with fetuin-A concentrations (P<0.0001). In analyses of 259 incident cases of type 2 diabetes, the single nucleotide polymorphisms (SNPs) were not associated with diabetes risk during follow-up and similar null associations were observed when 579 prevalent cases were included. As expected, higher fetuin-A levels were associated with higher fasting glucose concentrations (1.9 mg/dL [95% CI, 1.2-2.7] higher per SD in Caucasians), but Mendelian randomization analyses using both SNPs as unbiased proxies for measured fetuin-A did not support an association between genetically predicted fetuin-A levels and fasting glucose (-0.3 mg/dL [95% CI, -1.9 to 1.3] lower per SD in Caucasians). The difference between the associations of fasting glucose with actual and genetically predicted fetuin-A level was statistically significant (P=0.001). Results among the smaller sample of African Americans trended in similar directions but were statistically insignificant. Common variants in the AHSG gene are strongly associated with plasma fetuin-A concentrations, but not with risk of type 2 diabetes or glucose concentrations, raising the possibility that the association between fetuin-A and type 2 diabetes may not be causal.

Development of 11 polymorphic microsatellite markers for the blackberry rust fungus Phragmidium violaceum

USDA-ARS?s Scientific Manuscript database

Eleven polymorphic microsatellite markers were developed for the Uredinales fungus Phragmidium violaceum, which causes leaf rust on European blackberry (Rubus fruticosus L. aggregate). Allele frequency ranged between two and seventeen alleles per locus with no evidence of linkage disequilibrium amon...

CYP2D6 gene polymorphisms in Brazilian patients with breast cancer treated with adjuvant tamoxifen and its association with disease recurrence

PubMed Central

De Ameida Melo, Mariella; De Vasconcelos-Valença, Rodrigo José; Neto, Fidelis Manes; Borges, Rafael Soares; Costa-Silva, Danylo Rafhael; Da Conceição Barros-Oliveira, Maria; Borges, Umbelina Soares; Alencar, Airlane Pereira; Silva, Vladimir Costa; Da Silva, Benedito Borges

2016-01-01

At present, there is controversy regarding the efficacy of tamoxifen in breast cancer patients who are carriers of cytochrome P450 2D6 (CYP2D6) gene polymorphisms, in terms of recurrence and overall survival. Thus, the aim of the present study was to investigate the association of the CYP2D6 *4, *10 and *17 gene polymorphisms with breast cancer recurrence in a Brazilian population. The cohort comprised 40 receptor-positive breast cancer patients without recurrence and 40 with distant recurrence. A 3-ml sample of peripheral blood was collected from each patient to determine the presence of the *4, *10 and *17 single nucleotide polymorphisms of the CYP2D6 gene by quantitative polymerase chain reaction analysis. There was no statistically significant difference between the two groups regarding the polymorphism frequency (P=0.246). The results revealed that intermediate metabolizers occurred in 5% of patients without recurrence and in 15% of those with distant recurrence. Poor metabolizers occurred in only 1 patient (2.5%) per group, and there was no significant difference between the groups (P=0.789). The present study concluded that the CYP2D6 gene polymorphism in women with hormone-sensitive breast cancer treated with tamoxifen was not associated with disease recurrence. PMID:27882219

Association between genetic polymorphisms in the XRCC1, XRCC3, XPD, GSTM1, GSTT1, MSH2, MLH1, MSH3, and MGMT genes and radiosensitivity in breast cancer patients.

PubMed

Mangoni, Monica; Bisanzi, Simonetta; Carozzi, Francesca; Sani, Cristina; Biti, Giampaolo; Livi, Lorenzo; Barletta, Emanuela; Costantini, Adele Seniori; Gorini, Giuseppe

2011-09-01

Clinical radiosensitivity varies considerably among patients, and radiation-induced side effects developing in normal tissue can be therapy limiting. Some single nucleotide polymorphisms (SNPs) have been shown to correlate with hypersensitivity to radiotherapy. We conducted a prospective study of 87 female patients with breast cancer who received radiotherapy after breast surgery. We evaluated the association between acute skin reaction following radiotherapy and 11 genetic polymorphisms in DNA repair genes: XRCC1 (Arg399Gln and Arg194Trp), XRCC3 (Thr241Met), XPD (Asp312Asn and Lys751Gln), MSH2 (gIVS12-6T>C), MLH1 (Ile219Val), MSH3 (Ala1045Thr), MGMT (Leu84Phe), and in damage-detoxification GSTM1 and GSTT1 genes (allele deletion). Individual genetic polymorphisms were determined by polymerase chain reaction and single nucleotide primer extension for single nucleotide polymorphisms or by a multiplex polymerase chain reaction assay for deletion polymorphisms. The development of severe acute skin reaction (moist desquamation or interruption of radiotherapy due to toxicity) associated with genetic polymorphisms was modeled using Cox proportional hazards, accounting for cumulative biologically effective radiation dose. Radiosensitivity developed in eight patients and was increased in carriers of variants XRCC3-241Met allele (hazard ratio [HR] unquantifiably high), MSH2 gIVS12-6nt-C allele (HR=53.36; 95% confidence intervals [95% CI], 3.56-798.98), and MSH3-1045Ala allele (HR unquantifiably high). Carriers of XRCC1-Arg194Trp variant allele in combination with XRCC1-Arg399Gln wild-type allele had a significant risk of radiosensitivity (HR=38.26; 95% CI, 1.19-1232.52). To our knowledge, this is the first report to find an association between MSH2 and MSH3 genetic variants and the development of radiosensitivity in breast cancer patients. Our findings suggest the hypothesis that mismatch repair mechanisms may be involved in cellular response to radiotherapy. Genetic polymorphisms may be promising candidates for predicting acute radiosensitivity, but further studies are necessary to confirm our findings. Copyright © 2011 Elsevier Inc. All rights reserved.

Switching to nilotinib in patients with chronic myeloid leukemia in chronic phase with molecular suboptimal response to frontline imatinib: SENSOR final results and BIM polymorphism substudy.

PubMed

Miyamura, Koichi; Miyamoto, Toshihiro; Tanimoto, Mitsune; Yamamoto, Kazuhito; Kimura, Shinya; Kawaguchi, Tatsuya; Matsumura, Itaru; Hata, Tomoko; Tsurumi, Hisashi; Saito, Shigeki; Hino, Masayuki; Tadokoro, Seiji; Meguro, Kuniaki; Hyodo, Hideo; Yamamoto, Masahide; Kubo, Kohmei; Tsukada, Junichi; Kondo, Midori; Aoki, Makoto; Okada, Hikaru; Yanada, Masamitsu; Ohyashiki, Kazuma; Taniwaki, Masafumi

2016-12-01

Optimal management of patients with chronic myeloid leukemia in chronic phase with suboptimal molecular response (MR) to frontline imatinib is undefined. We report final results from SENSOR, which evaluated efficacy/safety of nilotinib in this setting. A substudy assessed whether BIM polymorphisms impacted response to nilotinib. In this single-arm, multicenter study, Japanese patients with suboptimal MR per European LeukemiaNet 2009 criteria (complete cytogenetic response, but not major MR [MMR]) after ≥18 months of frontline imatinib received nilotinib 400mg twice daily for 24 months. MR, BCR-ABL1 mutations/variants, and BIM polymorphisms were evaluated in a central laboratory. Primary endpoint was the MMR rate at 12 months (null hypothesis of 40%). Of 45 patients (median exposure, 22.08 months), 39 completed the study and six discontinued. At 12 and 24 months, 51.1% (95% CI, 35.8%-66.3%) and 66.7% (95% CI, 51.0%-80.0%) achieved MMR, respectively. Cumulative MMR incidence by 24 months was 75.6%. Of 40 patients analyzed, 10 of 12 (83.3%) with and 17 of 28 (60.7%) without BIM polymorphisms achieved MMR at 24 months. The safety profile was manageable with dose reductions and interruptions. Nilotinib provided clinical benefit for patients with suboptimal response to imatinib, and BIM polymorphisms did not influence MMR achievement. ClinicalTrials.gov: NCT01043874. Copyright © 2016 Elsevier Ltd. All rights reserved.

Cross-genera transferability of rice and finger millet genomic SSRs to barnyard millet (Echinochloa spp.).

PubMed

Kalyana Babu, B; Sood, Salej; Kumar, Dinesh; Joshi, Anjeli; Pattanayak, A; Kant, Lakshmi; Upadhyaya, H D

2018-02-01

Barnyard millet ( Echinochloa spp.) is an important crop from nutritional point of view, nevertheless, the genetic information is very scarce. In the present investigation, rice and finger millet genomic SSRs were used for assessing cross transferability, identification of polymorphic markers, syntenic regions, genetic diversity and population structure analysis of barnyard millet genotypes. We observed 100% cross transferability for finger millet SSRs, of which 91% were polymorphic, while 71% of rice markers were cross transferable with 48% polymorphic out of them. Twenty-nine and sixteen highly polymorphic finger millet and rice SSRs yielded a mean of 4.3 and 3.38 alleles per locus in barnyard millet genotypes, respectively. The PIC values varied from 0.27 to 0.73 at an average of 0.54 for finger millet SSRs, whereas it was from 0.15 to 0.67 at an average of 0.44 for rice SSRs. High synteny was observed for markers related to panicle length, yield-related traits, spikelet fertility, plant height, root traits, leaf senescence, blast and brown plant hopper resistance. Although the rice SSRs located on chromosome 10 followed by chromosome 6 and 11 were found to be more transferable to barnyard millet, the finger millet SSRs were more polymorphic and transferable to barnyard millet genotypes. These SSR data of finger millet and rice individually as well as combined together grouped the 11 barnyard millet genotypes into 2 major clusters. The results of population structure analysis were similar to cluster analysis.

Analysis of antibodies to newly described Plasmodium falciparum merozoite antigens supports MSPDBL2 as a predicted target of naturally acquired immunity.

PubMed

Tetteh, Kevin K A; Osier, Faith H A; Salanti, Ali; Kamuyu, Gathoni; Drought, Laura; Failly, Marilyne; Martin, Christophe; Marsh, Kevin; Conway, David J

2013-10-01

Prospective studies continue to identify malaria parasite genes with particular patterns of polymorphism which indicate they may be under immune selection, and the encoded proteins require investigation. Sixteen new recombinant protein reagents were designed to characterize three such polymorphic proteins expressed in Plasmodium falciparum schizonts and merozoites: MSPDBL1 (also termed MSP3.4) and MSPDBL2 (MSP3.8), which possess Duffy binding-like (DBL) domains, and SURFIN4.2, encoded by a member of the surface-associated interspersed (surf) multigene family. After testing the antigenicities of these reagents by murine immunization and parasite immunofluorescence, we analyzed naturally acquired antibody responses to the antigens in two cohorts in coastal Kenya in which the parasite was endemic (Chonyi [n = 497] and Ngerenya [n = 461]). As expected, the prevalence and levels of serum antibodies increased with age. We then investigated correlations with subsequent risk of clinical malaria among children <11 years of age during 6 months follow-up surveillance. Antibodies to the polymorphic central region of MSPDBL2 were associated with reduced risk of malaria in both cohorts, with statistical significance remaining for the 3D7 allelic type after adjustment for individuals' ages in years and antibody reactivity to whole-schizont extract (Chonyi, risk ratio, 0.51, and 95% confidence interval [CI], 0.28 to 0.93; Ngerenya, risk ratio, 0.38, and 95% CI, 0.18 to 0.82). For the MSPDBL1 Palo Alto allelic-type antigen, there was a protective association in one cohort (Ngerenya, risk ratio, 0.53, and 95% CI, 0.32 to 0.89), whereas the other antigens showed no protective associations after adjustment. These findings support the prediction that antibodies to the polymorphic region of MSPDBL2 contribute to protective immunity.

Interaction between TGF-β1 (869C/T) polymorphism and biochemical risk factor for prediction of disease progression in rheumatoid arthritis.

PubMed

Hussein, Yousri M; Mohamed, Randa H; El-Shahawy, Eman E; Alzahrani, Saad S

2014-02-25

Rheumatoid arthritis (RA) is a chronic inflammatory disease. Transforming growth factor-β1 (TGF-β1) may be a promising candidate gene for susceptibility and severity in RA. We aimed to determine whether TGF-β1 polymorphism is associated with susceptibility to RA and progression of joint destruction, as well as to identify the interaction between TGF-β1 polymorphism and biochemical risk factor. A total of 160 RA patients and 168 healthy unrelated controls were tested for the TGF-β1 (869C/T) polymorphism using polymerase chain reaction. The TGF-β1 T allele was associated with susceptibility to RA. Within the RA group, TGF-β1 T allele carriers had a significant increased risk to develop osteoporosis (OR=4.4, 95% CI=-2. 4-8.1, P<0.001), as well as more likely to develop bone erosion (OR=1.7, 95% CI=0. 99-2.7, P=0. 034). Better prediction was achieved when the TGF-β1 TT genotype was used in combination with either elevated, rheumatoid factor (RF) or C-reactive protein (CRP) (OR=6.8, 3.7 respectively). Also, they increased the risk to develop bone erosion in patients with rheumatoid arthritis (OR=3.3, 9.8, P=0.017, 0.001 respectively). Our results suggest that TGF-β1 TT genotype may determine the development of osteoporosis and bone erosion in RA. Also, our results points to a synergism between TGF-β1 TT genotype and elevated serum RF or elevated CRP that lead to the development of osteoporosis and bone erosion in patients with rheumatoid arthritis. Copyright © 2013 Elsevier B.V. All rights reserved.

Lack of association between FokI polymorphism in vitamin D receptor gene (VDR) & type 2 diabetes mellitus in the Tunisian population

PubMed Central

Mahjoubi, Imen; Kallel, Amani; Sbaï, Mohamed Hédi; Ftouhi, Bochra; ben Halima, Meriam; Jemaa, Zeineb; Feki, Moncef; Slimane, Hedia; Jemaa, Riadh; Kaabachi, Naziha

2016-01-01

Background & objectives: The impact of several environmental and genetic factors on diabetes is well documented. Though the association between the vitamin D receptor (VDR) gene polymorphisms and type 2 diabetes mellitus (T2DM) has been analyzed in different ethnic groups, the results have been inconsistent. The aim of this study was to evaluate the possible association between VDR FokI polymorphism and genetic susceptibility to T2DM in Tunisian population. Methods: A total of 439 unrelated patients with T2DM and 302 healthy controls were included in the study. Genomic DNA was extracted from blood and genotyped for the single nucleotide polymorphism (SNP) of FokI (T/C: (rs2228570) by polymerase chain reaction and restriction fragment length polymorphism (PCR-RFLP) analysis. Results: The genotype distribution and the relative allelic frequencies for the FokI polymorphism were not significantly different between T2DM and controls: in T2DM patients the frequencies of the CC, CT, and TT genotypes were 52.6, 41.0, and 6.1 per cent, respectively, and in controls the genotype frequencies were 55.6, 38.7, and 5.6 per cent, respectively. In our study, the TT genotype of the FokI polymorphism was not associated with T2DM (OR =1.19, 95% CI 0.63 - 2.25, P=0.577). Interpretation & conclusions: Our study showed no significant association of the FokI polymorphism in the vitamin D receptor gene with type 2 diabetes mellitus in Tunisian population. PMID:27834325

CHRNA7 Polymorphisms and Response to Cholinesterase Inhibitors in Alzheimer's Disease

PubMed Central

Weng, Pei-Hsuan; Chen, Jen-Hau; Chen, Ta-Fu; Sun, Yu; Wen, Li-Li; Yip, Ping-Keung; Chu, Yi-Min; Chen, Yen-Ching

2013-01-01

Background CHRNA7 encodes the α7 nicotinic acetylcholine receptor subunit, which is important to Alzheimer's disease (AD) pathogenesis and cholinergic neurotransmission. Previously, CHRNA7 polymorphisms have not been related to cholinesterase inhibitors (ChEI) response. Methods Mild to moderate AD patients received ChEIs were recruited from the neurology clinics of three teaching hospitals from 2007 to 2010 (n = 204). Nine haplotype-tagging single nucleotide polymorphisms of CHRNA7 were genotyped. Cognitive responders were those showing improvement in the Mini-Mental State Examination score ≧2 between baseline and 6 months after ChEI treatment. Results AD women carrying rs8024987 variants [GG+GC vs. CC: adjusted odds ratio (AOR) = 3.62, 95% confidence interval (CI) = 1.47–8.89] and GG haplotype in block1 (AOR = 3.34, 95% CI = 1.38–8.06) had significantly better response to ChEIs (false discovery rate <0.05). These variant carriers using galantamine were 11 times more likely to be responders than female non-carriers using donepezil or rivastigmine. Conclusion For the first time, this study found a significant association between CHRNA7 polymorphisms and better ChEI response. If confirmed by further studies, CHRNA7 polymorphisms may aid in predicting ChEI response and refining treatment choice. PMID:24391883

Differences in Cognitive Outcomes After ECT Depending on BDNF and COMT Polymorphisms.

PubMed

Bennett, Daniel Mark; Currie, James; Fernie, Gordon; Perrin, Jennifer S; Reid, Ian C

2016-12-01

The study aimed to explore cognitive outcomes after electroconvulsive therapy (ECT) depending on which version of common single nucleotide polymorphisms the patient expressed for brain-derived neurotrophic factor (BDNF) and catechol-O-methyltransferase (COMT). A total of 87 patients from the clinical ECT service in Aberdeen, Scotland, were included in the study. Cognitive function testing (using Spatial Recognition Memory task from the Cambridge Neuropsychological Test Automated Battery and Mini-Mental State Examination) and mood ratings (Montgomery-Åsberg Depression Rating Scale) were performed before ECT, after 4 treatments, at the end of ECT and 1 and 3 months after the end of treatment. These scores were compared depending on BDNF and COMT variant at each time point using the Student t test and using a time series generalized least squares random effects model. No differences were found between the val and met versions of the BDNF or COMT polymorphism in either cognitive or mood outcomes at any time point during ECT treatment or up to 3 months of follow-up. This study did not detect significant differences in cognitive or mood outcomes between patients who have the val66val or met versions of the BDNF polymorphism. Our results suggest that these polymorphisms will not be helpful in clinical practice for predicting cognitive outcomes after ECT.

Microsatellite markers for Leucobryum boninense (Leucobryaceae), endemic to the Bonin Islands, Japan1

PubMed Central

Oguri, Emiko; Yamaguchi, Tomio; Kajita, Tadashi; Murakami, Noriaki

2013-01-01

• Premise of the study: Microsatellite primers were developed for Leucobryum boninense, endemic to the Bonin Islands, Japan, to investigate its level of genetic diversity and population genetic structure. • Methods and Results: Using next-generation sequencing, 21 primer sets were developed, among which nine loci were polymorphic in the populations of the Bonin Islands. Among these polymorphic loci, the number of alleles per locus ranged from two to 10 (mean = 3.444) and the expected heterozygosity ranged from 0.066 to 0.801 (mean = 0.338). • Conclusions: These results indicate the utility of the nine microsatellite markers that we developed for population genetic studies of L. boninense. PMID:25202543

Genetic diversity and relationship analysis of Gossypium arboreum accessions.

PubMed

Liu, F; Zhou, Z L; Wang, C Y; Wang, Y H; Cai, X Y; Wang, X X; Zhang, Z S; Wang, K B

2015-11-19

Simple sequence repeat techniques were used to identify the genetic diversity of 101 Gossypium arboreum accessions collected from India, Vietnam, and the southwest of China (Guizhou, Guangxi, and Yunnan provinces). Twenty-six pairs of SSR primers produced a total of 103 polymorphic loci with an average of 3.96 polymorphic loci per primer. The average of the effective number of alleles, Nei's gene diversity, and Shannon's information index were 0.59, 0.2835, and 0.4361, respectively. The diversity varied among different geographic regions. The result of principal component analysis was consistent with that of unweighted pair group method with arithmetic mean clustering analysis. The 101 G. arboreum accessions were clustered into 2 groups.

Relationship of Genetic Polymorphisms of the Chemokine, CCL5, and Its Receptor, CCR5, with Coronary Artery Disease in Taiwan

PubMed Central

Ting, Ke-Hsin; Ueng, Kwo-Chang; Chiang, Whei-Ling; Chou, Ying-Erh; Yang, Shun-Fa; Wang, Po-Hui

2015-01-01

The chemokine receptor CCR5 polymorphism, which confers resistance to HIV infection, has been associated with reduced risk of cardiovascular disease. However, the association of the chemokine, CCL5, and its receptor, CCR5, polymorphism and coronary artery disease (CAD) in the Taiwanese has not been studied. In this study, 483 subjects who received elective coronary angiography were recruited from Chung Shan Medical University Hospital. CCL5-403 and CCR5-59029 were determined by polymerase chain reaction-restriction fragment length polymorphism. We found that CCL5-403 with TT genotype frequencies was significantly associated with the risk of CAD group (odds ratio = 3.063 and p = 0.012). Moreover, the frequencies of CCR5-59029 with GG or GA genotype were higher than AA genotype in acute coronary syndrome individuals (odds ratio = 1.853, CI = 1.176–2.921, p = 0.008). In conclusion, we found that CCL5-403 polymorphism may increase genetic susceptibility of CAD. CCL5-403 or CCR5-59029 single nucleotide polymorphism may include genotype score and it may predict cardiovascular event. PMID:26688689

Characteristics of polymorphism at a VNTR locus 3[prime] to the apolipoprotein B gene in five human populations

DOE Office of Scientific and Technical Information (OSTI.GOV)

Deka, R.; DeCroo, S.; Ferrell, R.E.

1992-12-01

The authors have analyzed the allele frequency distribution at the hypervariable locus 3[prime] to the apolipoprotein B gene (ApoB 3[prime] VNTR) in five well-defined human populations (Kacharis of northeast India, New Guinea Highlanders of Papua New Guinea, Dogrib Indians of Canada, Pehuenche Indians of Chile, and a relatively homogeneous Caucasian population of northern German extraction) by using the PCR technique. A total of 12 segregating alleles were detected in the pooled sample of 319 individuals. A fairly consistent bimodal pattern of allele frequency distribution, apparent in most of these geographically and genetically diverse populations, suggests that the ApoB 3[prime] VNTRmore » polymorphism predates the geographic dispersal of ancestral human populations. In spite of the observed high degree of polymorphism at this locus (expected heterozygosity levels 55%-78%), the genotype distributions in all populations (irrespective of their tribal or cosmopolitan nature) conform to their respective Hardy-Weinberg predictions. Furthermore, analysis of the congruence between expected heterozygosity and the observed number of alleles reveals that, in general, the allele frequency distributions at this locus are in agreement with the predictions of the classical mutation-drift models. The data also show that alleles that are shared by all populations have the highest average frequency within populations. These findings demonstrate the potential utility of highly informative hypervariable loci such as the ApoB 3[prime] VNTR locus in population genetic research, as well as in forensic medicine and determination of biological relatedness of individuals. 38 refs., 2 figs., 3 tabs.« less

Investigation of the Sensitivity of Transmission Raman Spectroscopy for Polymorph Detection in Pharmaceutical Tablets.

PubMed

Feng, Hanzhou; Bondi, Robert W; Anderson, Carl A; Drennen, James K; Igne, Benoît

2017-08-01

Polymorph detection is critical for ensuring pharmaceutical product quality in drug substances exhibiting polymorphism. Conventional analytical techniques such as X-ray powder diffraction and solid-state nuclear magnetic resonance are utilized primarily for characterizing the presence and identity of specific polymorphs in a sample. These techniques have encountered challenges in analyzing the constitution of polymorphs in the presence of other components commonly found in pharmaceutical dosage forms. Laborious sample preparation procedures are usually required to achieve satisfactory data interpretability. There is a need for alternative techniques capable of probing pharmaceutical dosage forms rapidly and nondestructively, which is dictated by the practical requirements of applications such as quality monitoring on production lines or when quantifying product shelf lifetime. The sensitivity of transmission Raman spectroscopy for detecting polymorphs in final tablet cores was investigated in this work. Carbamazepine was chosen as a model drug, polymorph form III is the commercial form, whereas form I is an undesired polymorph that requires effective detection. The concentration of form I in a direct compression tablet formulation containing 20% w/w of carbamazepine, 74.00% w/w of fillers (mannitol and microcrystalline cellulose), and 6% w/w of croscarmellose sodium, silicon dioxide, and magnesium stearate was estimated using transmission Raman spectroscopy. Quantitative models were generated and optimized using multivariate regression and data preprocessing. Prediction uncertainty was estimated for each validation sample by accounting for all the main variables contributing to the prediction. Multivariate detection limits were calculated based on statistical hypothesis testing. The transmission Raman spectroscopic model had an absolute prediction error of 0.241% w/w for the independent validation set. The method detection limit was estimated at 1.31% w/w. The results demonstrated that transmission Raman spectroscopy is a sensitive tool for polymorphs detection in pharmaceutical tablets.

Association of Functional Polymorphisms from Brain-Derived Neurotrophic Factor and Serotonin-Related Genes with Depressive Symptoms after a Medical Stressor in Older Adults

PubMed Central

Rawson, Kerri S.; Dixon, David; Nowotny, Petra; Ricci, William M.; Binder, Ellen F.; Rodebaugh, Thomas L.; Wendleton, Leah; Doré, Peter; Lenze, Eric J.

2015-01-01

Depressive symptoms are common in older adults after a disabling medical event and interfere with rehabilitation and recovery from the disability. This prospective study examined the role of genetic polymorphisms implicated in synaptic integrity and stress-associated depression as predictors of depressive symptoms after hip fracture. We recruited healthy comparisons from the community and participants with hip fracture after surgical fixation from Saint Louis, Missouri hospitals. We examined the valine (Val) to methionine (Met) polymorphism in brain-derived neurotrophic factor (BDNF), serotonin 1A receptor (5HT1a-rs6295) polymorphism, and the serotonin transporter-linked polymorphic region (5HTTLPR) interaction with the rs25531 A to G single nucleotide polymorphism (5HTTLPR-rs25531) as predictors of depressive symptoms. We also examined whether depressive symptoms mediate the influence of BDNF genotype on functional recovery. Among 429 participants with hip fracture, BDNF Met/Met carriers developed significantly more depressive symptoms than Val/Val carriers during a four-week period after the fracture (p=.012). BDNF genotype also predicted functional recovery over the ensuing year, mediated by its effects on depressive symptoms (CI: 0.07-3.37). Unlike prior studies of stressful life events, the S′ 5HTTLPR-rs25531 variant did not predict higher levels of depressive symptoms; instead, we report an exploratory finding of an epistatic effect between BDNF and 5HTTLPR-rs25531 whereby the compounded effects of two LA alleles and BDNF Met/Met genotype elevate risk of depressive symptoms after hip fracture (p=.006). No differences between 5HT1a genotypes were found. Our findings suggest plasticity-related genetic factors contribute to the neural mechanisms of mental and functional well-being after a disabling medical stressor. PMID:25781924

Ab initio NMR Confirmed Evolutionary Structure Prediction for Organic Molecular Crystals

NASA Astrophysics Data System (ADS)

Pham, Cong-Huy; Kucukbenli, Emine; de Gironcoli, Stefano

2015-03-01

Ab initio crystal structure prediction of even small organic compounds is extremely challenging due to polymorphism, molecular flexibility and difficulties in addressing the dispersion interaction from first principles. We recently implemented vdW-aware density functionals and demonstrated their success in energy ordering of aminoacid crystals. In this work we combine this development with the evolutionary structure prediction method to study cholesterol polymorphs. Cholesterol crystals have paramount importance in various diseases, from cancer to atherosclerosis. The structure of some polymorphs (e.g. ChM, ChAl, ChAh) have already been resolved while some others, which display distinct NMR spectra and are involved in disease formation, are yet to be determined. Here we thoroughly assess the applicability of evolutionary structure prediction to address such real world problems. We validate the newly predicted structures with ab initio NMR chemical shift data using secondary referencing for an improved comparison with experiments.

Genetic polymorphisms of the drug-metabolizing enzyme cytochrome P450 3A5 in a Uyghur Chinese population.

PubMed

Chen, Zhengshuai; Li, Jingjie; Chen, Peng; Wang, Fengjiao; Zhang, Ning; Yang, Min; Jin, Tianbo; Chen, Chao

2016-09-01

1.  Detection of CYP3A5 variant alleles, and knowledge about their allelic frequency in Uyghur ethnic groups, is important to establish the clinical relevance of screening for these polymorphisms to optimize pharmacotherapy. 2. We used DNA sequencing to investigate the promoter, exons and surrounding introns, and 3'-untranslated region of the CYP3A5 gene in 96 unrelated healthy Uyghur individuals. We also used SIFT and PolyPhen-2 to predict the protein function of the novel non-synonymous mutation in CYP3A5 coding regions. 3. We found 24 different CYP3A5 polymorphisms in the Uyghur population, three of which were novel: the synonymous mutation 43C > T in exon 1, two mutations 32120C > G and 32245T > C in 3'-untranslated region, and we detected the allele frequencies of CYP3A5*1 and *3 as 64.58% and 35.42%, respectively. While no subjects with CYP3A5*6 were identified. Other identified genotypes included the heterozygous genotype 1A/3A (59.38%) and 1A/3E (11.46%), which lead to decreased enzyme activity. In addition, the frequency of haplotype "TTAGGT" was the most prevalent with 0.781. 4. Our data provide new information regarding CYP3A5 genetic polymorphisms in Uyghur individuals, which may help to improve individualization of drug therapy and offer a preliminary basis for more rational use of drugs.

Systematic review: genetic biomarkers associated with anti-TNF treatment response in inflammatory bowel diseases.

PubMed

Bek, S; Nielsen, J V; Bojesen, A B; Franke, A; Bank, S; Vogel, U; Andersen, V

2016-09-01

Personalised medicine, including biomarkers for treatment selection, may provide new algorithms for more effective treatment of patients. Genetic variation may impact drug response and genetic markers could help selecting the best treatment strategy for the individual patient. To identify polymorphisms and candidate genes from the literature that are associated with anti-tumour necrosis factor (TNF) treatment response in patients with inflammatory bowel diseases (IBD), Crohn's disease (CD) and ulcerative colitis. We performed a PubMed literature search and retrieved studies reporting original data on association between polymorphisms and anti-TNF treatment response and conducted a meta-analysis. A functional polymorphism in FCGR3A was significantly associated with anti-TNF treatment response among CD patients using biological response criterion (decrease in C-reactive protein, levels). Meta-analyses showed that polymorphisms in TLR2 (rs3804099, OR (95% CI) = 2.17 (1.35-3.47)], rs11938228 [OR = 0.64 (0.43-0.96)], TLR4 (rs5030728) [OR = 3.18 (1.63-6.21)], TLR9 (rs352139) [OR = 0.43 (0.21-0.88)], TNFRSF1A (rs4149570) [OR = 2.06 (1.02-4.17)], IFNG (rs2430561) [OR = 1.66 (1.05-2.63)], IL6 (rs10499563) [OR = 1.65 (1.04-2.63)] and IL1B (rs4848306) [OR = 1.88 (1.05-3.35)] were significantly associated with response among IBD patients using clinical response criteria. A positive predictive value of 0.96 was achieved by combining five genetic markers in an explorative analysis. There are no genetic markers currently available which are adequately predictive of anti-TNF response for use in the clinic. Genetic markers bear the advantage that they do not change over time. Therefore, hypothesis-free approaches, testing a large number of polymorphisms in large, well-characterised cohorts, are required in order to identify genetic profiles with larger effect sizes, which could be employed as biomarkers for treatment selection in clinical settings. © 2016 The Authors. Alimentary Pharmacology & Therapeutics published by John Wiley & Sons Ltd.

Examining ERBB2 as a candidate gene for susceptibility to leprosy (Hansen’s disease) in Brazil

PubMed Central

Araújo, Sérgio Ricardo Fernandes; Jamieson, Sarra Elisabeth; Dupnik, Kathryn Margaret; Monteiro, Glória Regina; Nobre, Maurício Lisboa; Dias, Márcia Sousa; Trindade, Pedro Bezerra; Queiroz, Maria do Carmo Palmeira; Gomes, Carlos Eduardo Maia; Blackwell, Jenefer Mary; Jeronimo, Selma Maria Bezerra

2014-01-01

Leprosy remains prevalent in Brazil. ErbB2 is a receptor for leprosy bacilli entering Schwann cells, which mediates Mycobacterium leprae-induced demyelination and the ERBB2 gene lies within a leprosy susceptibility locus on chromosome 17q11-q21. To determine whether polymorphisms at the ERBB2 locus contribute to this linkage peak, three haplotype tagging single nucleotide polymorphisms (tag-SNPs) (rs2517956, rs2952156, rs1058808) were genotyped in 72 families (208 cases; 372 individuals) from the state of Pará (PA). All three tag-SNPs were associated with leprosy per se [best SNP rs2517959 odds ratio (OR) = 2.22; 95% confidence interval (CI) 1.37-3.59; p = 0.001]. Lepromatous (LL) (OR = 3.25; 95% CI 1.37-7.70; p = 0.007) and tuberculoid (TT) (OR = 1.79; 95% CI 1.04-3.05; p = 0.034) leprosy both contributed to the association, which is consistent with the previous linkage to chromosome 17q11-q21 in the population from PA and supports the functional role of ErbB2 in disease pathogenesis. To attempt to replicate these findings, six SNPs (rs2517955, rs2517956, rs1810132, rs2952156, rs1801200, rs1058808) were genotyped in a population-based sample of 570 leprosy cases and 370 controls from the state of Rio Grande do Norte (RN) and the results were analysed using logistic regression analysis. However, none of the associations were replicated in the RN sample, whether analysed for leprosy per se, LL leprosy, TT leprosy, erythema nodosum leprosum or reversal reaction conditions. The role of polymorphisms at ERBB2 in controlling susceptibility to leprosy in Brazil therefore remains unclear. PMID:24676663

Microsatellite analysis of genetic diversity and population structure of hermaphrodite ridge gourd (Luffa hermaphrodita).

PubMed

Pandey, Sudhakar; Ansari, W A; Choudhary, B R; Pandey, Maneesh; Jena, S N; Singh, A K; Dubey, R K; Singh, Bijendra

2018-01-01

Out of 103 microsatellite markers used for studying the genetic diversity among local landraces of Luffa species, 56 were found polymorphic, including 38 gSSR and 18 eSSR, respectively. A total of 197 amplification products were obtained. The mean number of alleles per locus was 3.52. The PIC ranged from 0.037 to 0.986, while size of amplified product ranged from 105 to 500 bp. Cucumber-derived SSRs were amplified within L. acutangula (68%), L. aegyptiaca (61.16%), and L. hermaphrodita (60.2%), with an average of 63.12% cross-transferability. The Jaccard's coefficient ranged from 0.66 to 0.97, with an average of 0.81. High genetic variability was observed for node of 1st hermaphrodite flower (6.4-17), days to 1st hermaphrodite flower (38-52.1), days to 1st fruit harvest (43-65), number of fruit per cluster (1-5.9), fruit length (3.9-25 cm), fruit weight (18.4-175 g), number of fruit per plant (20-147.5), and yield per plant (2.2-4.7 kg). Two sub-populations were identified including 21 genotypes (sub-population I) and 06 genotypes (sub-population II), these two sub-populations showed 0.608-0.395% of the ancestral relationship to each other. This study provides information for future exploration, collection, and utilization of Luffa genotypes, as well as the polymorphic markers identified could be available for the study of landmarks in linkages, genomic structures, evolutionary ecology, and marker-assisted selection (MAS) in Luffa species.

Simple Decision-Analytic Functions of the AUC for Ruling Out a Risk Prediction Model and an Added Predictor.

PubMed

Baker, Stuart G

2018-02-01

When using risk prediction models, an important consideration is weighing performance against the cost (monetary and harms) of ascertaining predictors. The minimum test tradeoff (MTT) for ruling out a model is the minimum number of all-predictor ascertainments per correct prediction to yield a positive overall expected utility. The MTT for ruling out an added predictor is the minimum number of added-predictor ascertainments per correct prediction to yield a positive overall expected utility. An approximation to the MTT for ruling out a model is 1/[P (H(AUC model )], where H(AUC) = AUC - {½ (1-AUC)} ½ , AUC is the area under the receiver operating characteristic (ROC) curve, and P is the probability of the predicted event in the target population. An approximation to the MTT for ruling out an added predictor is 1 /[P {(H(AUC Model:2 ) - H(AUC Model:1 )], where Model 2 includes an added predictor relative to Model 1. The latter approximation requires the Tangent Condition that the true positive rate at the point on the ROC curve with a slope of 1 is larger for Model 2 than Model 1. These approximations are suitable for back-of-the-envelope calculations. For example, in a study predicting the risk of invasive breast cancer, Model 2 adds to the predictors in Model 1 a set of 7 single nucleotide polymorphisms (SNPs). Based on the AUCs and the Tangent Condition, an MTT of 7200 was computed, which indicates that 7200 sets of SNPs are needed for every correct prediction of breast cancer to yield a positive overall expected utility. If ascertaining the SNPs costs $500, this MTT suggests that SNP ascertainment is not likely worthwhile for this risk prediction.

Heated oligonucleotide ligation assay (HOLA): an affordable single nucleotide polymorphism assay.

PubMed

Black, W C; Gorrochotegui-Escalante, N; Duteau, N M

2006-03-01

Most single nucleotide polymorphism (SNP) detection requires expensive equipment and reagents. The oligonucleotide ligation assay (OLA) is an inexpensive SNP assay that detects ligation between a biotinylated "allele-specific detector" and a 3' fluorescein-labeled "reporter" oligonucleotide. No ligation occurs unless the 3' detector nucleotide is complementary to the SNP nucleotide. The original OLA used chemical denaturation and neutralization. Heated OLA (HOLA) instead uses a thermal stable ligase and cycles of denaturing and hybridization for ligation and SNP detection. The cost per genotype is approximately US$1.25 with two-allele SNPs or approximately US$1.75 with three-allele SNPs. We illustrate the development of HOLA for SNP detection in the Early Trypsin and Abundant Trypsin loci in the mosquito Aedes aegypti (L.) and at the a-glycerophosphate dehydrogenase locus in the mosquito Anopheles gambiae s.s.

Note of the methodological flaws in the paper entitled "GSTT1 and GSTM1 polymorphisms predict treatment outcome for breast cancer: a systematic review and meta-analysis".

PubMed

Qiu, Mali; Wu, Xu; Qu, Xiaobing

2016-09-01

With great interest, we read the paper "GSTT1 and GSTM1 polymorphisms predict treatment outcome for breast cancer: a systematic review and meta-analysis" (by Hu XY et al.), which has reached important conclusions that GSTM1 null and GSTT1/GSTM1 double null polymorphisms might be significantly associated with an increased tumor response in breast cancer. The result is encouraging. Nevertheless, several methodological flaws in this meta-analysis are worth noticing.

CYP2C9*3 polymorphism presenting as lethal subdural hematoma with low-dose warfarin

PubMed Central

Karnik, Niteen D.; Sridharan, Kannan; Tiwari, D.; Gupta, V.

2014-01-01

Warfarin is the most common and cheap oral anticoagulant currently used in clinical practice. A high inter-individual variation is seen in the response to warfarin. Recently, pharmacogenetics has gained importance in managing patients on warfarin, both in predicting the optimum required dose as well as in decreasing the risk of bleeding. This case report is a description of a 49-year-old patient who had a lethal subdural hematoma with low-dose warfarin. He was subsequently found to have CYP2C9 gene polymorphism (*1/*3). This case report stresses the importance of pre-prescription assessment of genetic analysis for those initiated on warfarin. PMID:25298588

Cardiovascular Genetic Risk Testing for Targeting Statin Therapy in the Primary Prevention of Atherosclerotic Cardiovascular Disease: A Cost-Effectiveness Analysis.

PubMed

Jarmul, Jamie; Pletcher, Mark J; Hassmiller Lich, Kristen; Wheeler, Stephanie B; Weinberger, Morris; Avery, Christy L; Jonas, Daniel E; Earnshaw, Stephanie; Pignone, Michael

2018-04-01

It is unclear whether testing for novel risk factors, such as a cardiovascular genetic risk score (cGRS), improves clinical decision making or health outcomes when used for targeting statin initiation in the primary prevention of atherosclerotic cardiovascular disease (ASCVD). Our objective was to estimate the cost-effectiveness of cGRS testing to inform clinical decision making about statin initiation in individuals with low-to-intermediate (2.5%-7.5%) 10-year predicted risk of ASCVD. We evaluated the cost-effectiveness of testing for a 27-single-nucleotide polymorphism cGRS comparing 4 test/treat strategies: treat all, treat none, test/treat if cGRS is high, and test/treat if cGRS is intermediate or high. We tested a set of clinical scenarios of men and women, aged 45 to 65 years, with 10-year ASCVD risks between 2.5% and 7.5%. Our primary outcome measure was cost per quality-adjusted life-year gained. Under base case assumptions for statin disutility and cost, the preferred strategy is to treat all patients with ASCVD risk >2.5% without cGRS testing. For certain clinical scenarios, such as a 57-year-old man with a 10-year ASCVD risk of 7.5%, cGRS testing can be cost-effective under a limited set of assumptions; for example, when statins cost $15 per month and statin disutility is 0.013 (ie, willing to trade 3 months of life in perfect health to avoid 20 years of statin therapy), the preferred strategy (using a willingness-to-pay threshold of $50 000 per quality-adjusted life-year gained) is to test and treat if cGRS is intermediate or high. Overall, the results were not sensitive to assumptions about statin efficacy and harms. Testing for a 27-single-nucleotide polymorphism cGRS is generally not a cost-effective approach for targeting statin therapy in the primary prevention of ASCVD for low- to intermediate-risk patients. © 2018 American Heart Association, Inc.

Quantitative trait loci markers derived from whole genome sequence data increases the reliability of genomic prediction.

PubMed

Brøndum, R F; Su, G; Janss, L; Sahana, G; Guldbrandtsen, B; Boichard, D; Lund, M S

2015-06-01

This study investigated the effect on the reliability of genomic prediction when a small number of significant variants from single marker analysis based on whole genome sequence data were added to the regular 54k single nucleotide polymorphism (SNP) array data. The extra markers were selected with the aim of augmenting the custom low-density Illumina BovineLD SNP chip (San Diego, CA) used in the Nordic countries. The single-marker analysis was done breed-wise on all 16 index traits included in the breeding goals for Nordic Holstein, Danish Jersey, and Nordic Red cattle plus the total merit index itself. Depending on the trait's economic weight, 15, 10, or 5 quantitative trait loci (QTL) were selected per trait per breed and 3 to 5 markers were selected to tag each QTL. After removing duplicate markers (same marker selected for more than one trait or breed) and filtering for high pairwise linkage disequilibrium and assaying performance on the array, a total of 1,623 QTL markers were selected for inclusion on the custom chip. Genomic prediction analyses were performed for Nordic and French Holstein and Nordic Red animals using either a genomic BLUP or a Bayesian variable selection model. When using the genomic BLUP model including the QTL markers in the analysis, reliability was increased by up to 4 percentage points for production traits in Nordic Holstein animals, up to 3 percentage points for Nordic Reds, and up to 5 percentage points for French Holstein. Smaller gains of up to 1 percentage point was observed for mastitis, but only a 0.5 percentage point increase was seen for fertility. When using a Bayesian model accuracies were generally higher with only 54k data compared with the genomic BLUP approach, but increases in reliability were relatively smaller when QTL markers were included. Results from this study indicate that the reliability of genomic prediction can be increased by including markers significant in genome-wide association studies on whole genome sequence data alongside the 54k SNP set. Copyright © 2015 American Dairy Science Association. Published by Elsevier Inc. All rights reserved.

Polymorphism in molecular solids: an extraordinary system of red, orange, and yellow crystals.

PubMed

Yu, Lian

2010-09-21

Diamond and graphite are polymorphs of each other: they have the same composition but different structures and properties. Many other substances exhibit polymorphism: inorganic and organic, natural and manmade. Polymorphs are encountered in studies of crystallization, phase transition, materials synthesis, and biomineralization and in the manufacture of specialty chemicals. Polymorphs can provide valuable insights into crystal packing and structure-property relationships. 5-Methyl-2-[(2-nitrophenyl)amino]-3-thiophenecarbonitrile, known as ROY for its red, orange, and yellow crystals, has seven polymorphs with solved structures, the largest number in the Cambridge Structural Database. First synthesized by medicinal chemists, ROY has attracted attention from solid-state chemists because it demonstrates the remarkable diversity possible in organic solids. Many structures of ROY polymorphs and their thermodynamic properties are known, making ROY an important model system for testing computational models. Though not the most polymorphic substance on record, ROY is extraordinary in that many of its polymorphs can crystallize simultaneously from the same liquid and are kinetically stable under the same conditions. Studies of ROY polymorphs have revealed a new crystallization mechanism that invalidates the common view that nucleation defines the polymorph of crystallization. A slow-nucleating polymorph can still dominate the product if it grows rapidly and nucleates on another polymorph. Studies of ROY have also helped understand a new, surprisingly fast mode of crystal growth in organic liquids cooled to the glass transition temperature. This growth mode exists only for those polymorphs that have more isotropic, and perhaps more liquid-like, packing. The rich polymorphism of ROY results from a combination of favorable thermodynamics and kinetics. Not only must there be many polymorphs of comparable energies or free energies, many polymorphs must be kinetically stable and crystallize at comparable rates to be observed. This system demonstrates the unique insights that polymorphism provides into solid-state structures and properties, as well as the inadequacy of our current understanding of the phenomenon. Despite many studies of ROY, it is still impossible to predict the next molecule that is equally or more polymorphic. ROY is a lucky gift from medicinal chemists.

The Third Ambient Aspirin Polymorph

DOE Office of Scientific and Technical Information (OSTI.GOV)

Shtukenberg, Alexander G.; Hu, Chunhua T.; Zhu, Qiang

Polymorphism in aspirin (acetylsalicylic acid), one of the most widely consumed medications, was equivocal until the structure of a second polymorph II, similar in structure to the original form I, was reported in 2005. Here, the third ambient polymorph of aspirin is described. Lastly, it was crystallized from the melt and its structure was determined using a combination of X-ray powder diffraction analysis and crystal structure prediction algorithms.

The Third Ambient Aspirin Polymorph

DOE PAGES

Shtukenberg, Alexander G.; Hu, Chunhua T.; Zhu, Qiang; ...

2017-05-17

Polymorphism in aspirin (acetylsalicylic acid), one of the most widely consumed medications, was equivocal until the structure of a second polymorph II, similar in structure to the original form I, was reported in 2005. Here, the third ambient polymorph of aspirin is described. Lastly, it was crystallized from the melt and its structure was determined using a combination of X-ray powder diffraction analysis and crystal structure prediction algorithms.

DOE Office of Scientific and Technical Information (OSTI.GOV)

Mangoni, Monica; Bisanzi, Simonetta; Carozzi, Francesca

Purpose: Clinical radiosensitivity varies considerably among patients, and radiation-induced side effects developing in normal tissue can be therapy limiting. Some single nucleotide polymorphisms (SNPs) have been shown to correlate with hypersensitivity to radiotherapy. We conducted a prospective study of 87 female patients with breast cancer who received radiotherapy after breast surgery. We evaluated the association between acute skin reaction following radiotherapy and 11 genetic polymorphisms in DNA repair genes: XRCC1 (Arg399Gln and Arg194Trp), XRCC3 (Thr241Met), XPD (Asp312Asn and Lys751Gln), MSH2 (gIVS12-6T>C), MLH1 (Ile219Val), MSH3 (Ala1045Thr), MGMT (Leu84Phe), and in damage-detoxification GSTM1 and GSTT1 genes (allele deletion). Methods and Materials: Individualmore » genetic polymorphisms were determined by polymerase chain reaction and single nucleotide primer extension for single nucleotide polymorphisms or by a multiplex polymerase chain reaction assay for deletion polymorphisms. The development of severe acute skin reaction (moist desquamation or interruption of radiotherapy due to toxicity) associated with genetic polymorphisms was modeled using Cox proportional hazards, accounting for cumulative biologically effective radiation dose. Results: Radiosensitivity developed in eight patients and was increased in carriers of variants XRCC3-241Met allele (hazard ratio [HR] unquantifiably high), MSH2 gIVS12-6nt-C allele (HR = 53.36; 95% confidence intervals [95% CI], 3.56-798.98), and MSH3-1045Ala allele (HR unquantifiably high). Carriers of XRCC1-Arg194Trp variant allele in combination with XRCC1-Arg399Gln wild-type allele had a significant risk of radiosensitivity (HR = 38.26; 95% CI, 1.19-1232.52). Conclusions: To our knowledge, this is the first report to find an association between MSH2 and MSH3 genetic variants and the development of radiosensitivity in breast cancer patients. Our findings suggest the hypothesis that mismatch repair mechanisms may be involved in cellular response to radiotherapy. Genetic polymorphisms may be promising candidates for predicting acute radiosensitivity, but further studies are necessary to confirm our findings.« less

Association of GSTM1, GSTT1 and GSTP1 Ile105Val polymorphisms with clinical response to imatinib mesylate treatment among Malaysian chronic myeloid leukaemia patients.

PubMed

Makhtar, Siti Maziras; Husin, Azlan; Baba, Abdul Aziz; Ankathil, Ravindran

2017-09-01

The detoxifying activity of glutathione S-transferases (GST) enzymes not only protect cells from the adverse effects of xenobiotics, but also alters the effectiveness of drugs in cancer cells, resulting in toxicity or drug resistance. In this study, we aimed to evaluate the association of GSTM1, GSTT1 and GSTP1 Ile105Val polymorphisms with treatment response among Malaysian chronic myeloid leukaemia (CML) patients who everyday undergo 400 mg of imatinib mesylate (IM) therapy. Multiplex polymerase chain reaction (multiplex-PCR) was performed to detect GSTM1 and GSTT1 polymorphisms simultaneously and polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) analysis was conducted to detect the GSTP1 Ile195Val polymorphism. On evaluating the association of the variant genotype with treatment outcome, heterozygous variant (AG) and homozygous variant (GG) of GSTP1 Ile105Val showed significantly a higher risk for the development of resistance to IM with OR: 1.951 (95% CI: 1.186-3.209, P = 0.009) and OR: 3.540 (95% CI: 1.305-9.606, P = 0.013), respectively. Likewise, GSTT1 null genotype was also associated with a significantly higher risk for the development of resistance to IM with OR = 1.664 (95% CI: 1.011-2.739, P = 0.045). Our results indicate the potential usefulness of GST polymorphism genotyping in predicting the IM treatment response among CML patients.

Efficiency of RAPD versus SSR markers for determining genetic diversity among popcorn lines.

PubMed

Leal, A A; Mangolin, C A; do Amaral, A T; Gonçalves, L S A; Scapim, C A; Mott, A S; Eloi, I B O; Cordovés, V; da Silva, M F P

2010-01-05

Using only one type of marker to quantify genetic diversity generates results that have been questioned in terms of reliability, when compared to the combined use of different markers. To compare the efficiency of the use of single versus multiple markers, we quantified genetic diversity among 10 S(7) inbred popcorn lines using both RAPD and SSR markers, and we evaluated how well these two types of markers discriminated the popcorn genotypes. These popcorn genotypes: "Yellow Pearl Popcorn" (P1-1 and P1-5), "Zélia" (P1-2 and P1-4), "Curagua" (P1-3), "IAC 112" (P9-1 and P9-2), "Avati Pichinga" (P9-3 and P9-5), and "Pisankalla" (P9-4) have different soil and climate adaptations. Using RAPD marker analysis, each primer yielded bands of variable intensities that were easily detected, as well as non-specific bands, which were discarded from the analysis. The nine primers used yielded 126 bands, of which 104 were classified as polymorphic, giving an average of 11.6 polymorphisms per primer. Using SSR procedures, the number of alleles per locus ranged from two to five, giving a total of 47 alleles for the 14 SSR loci. When comparing the groups formed using SSR and RAPD markers, there were similarities in the combinations of genotypes from the same genealogy. Correlation between genetic distances obtained through RAPD and SSR markers was relatively high (0.5453), indicating that both techniques are efficient for evaluating genetic diversity in the genotypes of popcorn that we evaluated, though RAPDs yielded more polymorphisms.

Comparative pharmacogenetic analysis of risk polymorphisms in Caucasian and Vietnamese children with acute lymphoblastic leukemia: prediction of therapeutic outcome?

PubMed

Hoang, Phuong Thu Vu; Ambroise, Jérôme; Dekairelle, Anne-France; Durant, Jean-François; Butoescu, Valentina; Chi, Vu Luan Dang; Huynh, Nghia; Nguyen, Tan Binh; Robert, Annie; Vermylen, Christiane; Gala, Jean-Luc

2015-03-01

Acute lymphoblastic leukemia (ALL) is the most common of all paediatric cancers. Aside from predisposing to ALL, polymorphisms could also be associated with poor outcome. Indeed, genetic variations involved in drug metabolism could, at least partially, be responsible for heterogeneous responses to standardized leukemia treatments, hence requiring more personalized therapy. The aims of this study were to (a) to determine the prevalence of seven common genetic polymorphisms including those that affect the folate and/or thiopurine metabolic pathways, i.e. cyclin D1 (CCND1-G870A), γ-glutamyl hydrolase (GGH-C452T), methylenetetrahydrofolate reductase (MTHFR-C677T and MTHFR-A1298C), thymidylate synthase promoter (TYMS-TSER), thiopurine methyltransferase (TPMT*3A and TPMT*3C) and inosine triphosphate pyrophosphatase (ITPA-C94A), in Caucasian (n = 94, age < 20) and Vietnamese (n = 141, age < 16 years) childhood ALL and (b) to assess the impact of a multilocus genetic risk score (MGRS) on relapse-free survival (RFS) using a Cox proportional-hazards regression model. The prevalence of MTHFR-677TT genotype was significantly higher in Caucasians (P = 0.008), in contrast to the prevalence of TYMS-TSER*3R/3R and ITPA-94AA/AC genotypes which were significantly higher in Vietnamese (P < 0.001 and P = 0.02, respectively). Compared with children with a low MGRS (≤ 3), those with a high MGRS (≥ 4) were 2.06 (95% CI = 1.01, 4.22; P = 0.04) times more likely to relapse. Adding MGRS into a multivariate Cox regression model with race/ethnicity and four clinical variables improved the predictive accuracy of the model (AUC from 0.682 to 0.709 at 24 months). Including MGRS into a clinical model improved the predictive accuracy of short and medium term prognosis, hence confirming the association between well determined pharmacogenotypes and outcome of paediatric ALL. Whether variants on other genes associated with folate metabolism can substantially improve the predictive value of current MGRS is not known but deserves further evaluation. © 2014 The British Pharmacological Society.

Comparative pharmacogenetic analysis of risk polymorphisms in Caucasian and Vietnamese children with acute lymphoblastic leukemia: prediction of therapeutic outcome?

PubMed Central

Vu Hoang, Phuong Thu; Ambroise, Jérôme; Dekairelle, Anne-France; Durant, Jean-François; Butoescu, Valentina; Dang Chi, Vu Luan; Huynh, Nghia; Nguyen, Tan Binh; Robert, Annie; Vermylen, Christiane; Gala, Jean-Luc

2015-01-01

Aims Acute lymphoblastic leukemia (ALL) is the most common of all paediatric cancers. Aside from predisposing to ALL, polymorphisms could also be associated with poor outcome. Indeed, genetic variations involved in drug metabolism could, at least partially, be responsible for heterogeneous responses to standardized leukemia treatments, hence requiring more personalized therapy. The aims of this study were to (a) to determine the prevalence of seven common genetic polymorphisms including those that affect the folate and/or thiopurine metabolic pathways, i.e. cyclin D1 (CCND1-G870A), γ-glutamyl hydrolase (GGH-C452T), methylenetetrahydrofolate reductase (MTHFR-C677T and MTHFR-A1298C), thymidylate synthase promoter (TYMS-TSER), thiopurine methyltransferase (TPMT*3A and TPMT*3C) and inosine triphosphate pyrophosphatase (ITPA-C94A), in Caucasian (n = 94, age < 20) and Vietnamese (n = 141, age < 16 years) childhood ALL and (b) to assess the impact of a multilocus genetic risk score (MGRS) on relapse-free survival (RFS) using a Cox proportional-hazards regression model. Results The prevalence of MTHFR-677TT genotype was significantly higher in Caucasians (P = 0.008), in contrast to the prevalence of TYMS-TSER*3R/3R and ITPA-94AA/AC genotypes which were significantly higher in Vietnamese (P < 0.001 and P = 0.02, respectively). Compared with children with a low MGRS (≤3), those with a high MGRS (≥4) were 2.06 (95% CI = 1.01, 4.22; P = 0.04) times more likely to relapse. Adding MGRS into a multivariate Cox regression model with race/ethnicity and four clinical variables improved the predictive accuracy of the model (AUC from 0.682 to 0.709 at 24 months). Conclusion Including MGRS into a clinical model improved the predictive accuracy of short and medium term prognosis, hence confirming the association between well determined pharmacogenotypes and outcome of paediatric ALL. Whether variants on other genes associated with folate metabolism can substantially improve the predictive value of current MGRS is not known but deserves further evaluation. PMID:25099492

The 223A>G polymorphism of the leptin receptor gene is associated with macroangiopathy in type 2 diabetes mellitus.

PubMed

Gan, Run-Tao; Yang, Shu-Sen

2012-04-01

To determine whether leptin receptor (LEPR) 223A>G polymorphism has an effect on the plasma leptin levels and the macroangiopathic complications in type 2 diabetes mellitus (T2DM). The genotypes and allelic frequencies of the LEPR 223A>G were examined with polymerase chain reaction and restriction fragment length polymorphism in 301 patients with T2DM and 172 unrelated healthy subjects. The plasma concentrations of leptin were determined in all subjects. The mean plasma leptin levels in the T2DM group were significantly higher than that of controls and the plasma levels of leptin were higher in diabetic patients with macroangiopathy than in patients without macroangiopathy (P < 0.05). The genotype (GG, AG and AA) distribution of 223A>G polymorphism was 58.3, 32.5, and 9.2% in diabetic patients with macroangiopathy, 75.3, 22.1, and 2.6% in patients without macroangiopathy, and 70.3, 27.5, 2.2% in controls respectively, a significant difference was found between diabetic patients with and without macroangiopathy (P < 0.05). The frequency of the allele A was higher in patients with macroangiopathy than in patients without macroangiopathy (25.6 vs. 16.3%; P < 0.05). Moreover, the plasma leptin levels were markedly higher in patients with AA genotype than those with AG or GG genotype in patients with macroangiopathy (P < 0.05). The LEPR 223A>G gene polymorphism associated with a predisposition to increased plasma leptin levels could constitute a useful predictive marker for diabetic macroangiopathy.

Genetic Polymorphisms in Cytokine Genes in Colombian Patients with Ocular Toxoplasmosis.

PubMed

Naranjo-Galvis, C A; de-la-Torre, A; Mantilla-Muriel, L E; Beltrán-Angarita, L; Elcoroaristizabal-Martín, X; McLeod, R; Alliey-Rodriguez, N; Begeman, I J; López de Mesa, C; Gómez-Marín, J E; Sepúlveda-Arias, J C

2018-04-01

Toxoplasmosis is caused by infection with the protozoan parasite Toxoplasma gondii , which has the capacity to infect all warm-blooded animals worldwide. Toxoplasmosis is a major cause of visual defects in the Colombian population; however, the association between genetic polymorphisms in cytokine genes and susceptibility to ocular toxoplasmosis has not been studied in this population. This work evaluates the associations between polymorphisms in genes coding for the cytokines tumor necrosis factor alpha (TNF-α) (rs1799964, rs1800629, rs1799724, rs1800630, and rs361525), interleukin 1β (IL-1β) (rs16944, rs1143634, and rs1143627), IL-1α (rs1800587), gamma interferon (IFN-γ) (rs2430561), and IL-10 (rs1800896 and rs1800871) and the presence of ocular toxoplasmosis (OT) in a sample of a Colombian population (61 patients with OT and 116 healthy controls). Genotyping was performed with the "dideoxynucleotide (ddNTP) primer extension" technique. Functional-effect predictions of single nucleotide polymorphisms (SNPs) were done by using FuncPred. A polymorphism in the IL-10 gene promoter (-1082G/A) was significantly more prevalent in OT patients than in controls ( P = 1.93e-08; odds ratio [OR] = 5.27e+03; 95% confidence interval [CI] = 3.18 to 8.739; Bonferroni correction [BONF] = 3.48e-07). In contrast, haplotype "AG" of the IL-10 gene promoter polymorphisms (rs1800896 and rs1800871) was present at a lower frequency in OT patients ( P = 7e-04; OR = 0.10; 95% CI = 0.03 to 0.35). The +874A/T polymorphism of IFN-γ was associated with OT ( P = 3.37e-05; OR = 4.2; 95% CI = 2.478 to 7.12; BONF = 6.07e-04). Haplotype "GAG" of the IL-1β gene promoter polymorphisms (rs1143634, rs1143627, and rs16944) appeared to be significantly associated with OT ( P = 0.0494). The IL-10, IFN-γ, and IL-1β polymorphisms influence the development of OT in the Colombian population. Copyright © 2018 American Society for Microbiology.

Novel microsatellite loci for Agave parryi and cross-amplification in Agave palmeri (Agavaceae).

PubMed

Lindsay, Denise L; Edwards, Christine E; Jung, Michael G; Bailey, Pamela; Lance, Richard F

2012-07-01

To examine the foraging behavior of nectarivorous bats in southeastern Arizona, we developed microsatellite primers in Agave parryi. These markers were also tested for cross-amplification and applicability to assess patterns of genetic diversity and structure in A. palmeri. Utilizing DNA sequence data from 454 shotgun sequencing, we identified seven novel polymorphic microsatellite loci in A. parryi and screened them for cross-amplification in A. palmeri. These markers were characterized in two populations of 30 individuals each for each species. In A. parryi, all primers were polymorphic and amplified between three and 12 alleles per population. In A. palmeri, all primers amplified, six were polymorphic, and allelic diversity ranged from one to 16 alleles per population. Our results demonstrate the applicability of these microsatellite primers for population genetics studies in both A. parryi and A. palmeri.

Longevity-associated mitochondrial DNA 5178 C/A polymorphism modulates the effects of coffee consumption on erythrocytic parameters in Japanese men: an exploratory cross-sectional analysis.

PubMed

Kokaze, Akatsuki; Ishikawa, Mamoru; Matsunaga, Naomi; Karita, Kanae; Yoshida, Masao; Ohtsu, Tadahiro; Ochiai, Hirotaka; Shirasawa, Takako; Nanri, Hinako; Saga, Nobuyuki; Ohtsu, Iichiro; Hoshino, Hiromi; Takashima, Yutaka

2014-12-20

Mitochondrial DNA 5178 cytosine/adenine (Mt5178 C/A) polymorphism reportedly modulates the effects of coffee consumption on the risk of hypertension, dyslipidemia and abnormal glucose tolerance. The objective of this analysis was to investigate whether Mt5178 C/A polymorphism modifies the effects of coffee consumption on erythrocytic parameters in male Japanese health check-up examinees. A total of 436 men (mean age ± standard deviation, 54.1 ± 7.8 years) were selected from among individuals visiting the hospital for regular medical check-ups. After Mt5178 C/A genotyping, an exploratory cross-sectional analysis assessing the joint effects of Mt5178 C/A polymorphism and coffee consumption on red blood cell counts, hematocrit and hemoglobin was conducted. For Mt5178C genotypic men, after adjustment for age, body mass index, alcohol consumption, habitual smoking and green tea consumption, coffee consumption significantly decreased red blood cell counts (P for trend = 0.022) and hemoglobin (P for trend = 0.035). The risk of anemia, defined as hemoglobin of <14 g/dL, after the aforementioned adjustment, appeared to depend on coffee consumption (P for trend = 0.078), and the adjusted odds ratio for anemia was significantly higher in men who consumed ≥4 cups of coffee per day than in those who consumed <1 cup per day (odds ratio = 3.771, 95% confidence interval: 1.088 to 13.06, P = 0.036). For Mt5178A genotypic men, coffee consumption possibly reduced the risk of anemia (P for trend = 0.049). However, after the aforementioned adjustment, the statistical significance disappeared (P for trend = 0.137). This exploratory cross-sectional analysis suggests that Mt5178 C/A polymorphism modulates the effects of coffee consumption on erythrocytic parameters and the risk of anemia in male Japanese health check-up examinees.

Single Nucleotide Polymorphisms Predict Symptom Severity of Autism Spectrum Disorder

ERIC Educational Resources Information Center

Jiao, Yun; Chen, Rong; Ke, Xiaoyan; Cheng, Lu; Chu, Kangkang; Lu, Zuhong; Herskovits, Edward H.

2012-01-01

Autism is widely believed to be a heterogeneous disorder; diagnosis is currently based solely on clinical criteria, although genetic, as well as environmental, influences are thought to be prominent factors in the etiology of most forms of autism. Our goal is to determine whether a predictive model based on single-nucleotide polymorphisms (SNPs)…

Genetically-Predicted Adult Height and Alzheimer's Disease.

PubMed

Larsson, Susanna C; Traylor, Matthew; Burgess, Stephen; Markus, Hugh S

2017-01-01

Observational studies have linked increased adult height with better cognitive performance and reduced risk of Alzheimer's disease (AD). It is unclear whether the associations are due to shared biological processes that influence height and AD or due to confounding by early life exposures or environmental factors. To use a genetic approach to investigate the association between adult height and AD. We selected 682 single nucleotide polymorphisms (SNPs) associated with height at genome-wide significance (p < 5×10-8) in the Genetic Investigation of ANthropometric Traits (GIANT) consortium. Summary statistics for each of these SNPs on AD were obtained from the International Genomics of Alzheimer's Project (IGAP) of 17,008 individuals with AD and 37,154 controls. The estimate of the association between genetically predicted height and AD was calculated using the inverse-variance weighted method. The odds ratio of AD was 0.91 (95% confidence interval, 0.86-0.95; p = 9.8×10-5) per one standard deviation increase (about 6.5 cm) in genetically predicted height based on 682 SNPs, which were clustered in 419 loci. In an analysis restricted to one SNP from each height-associated locus (n = 419 SNPs), the corresponding OR was 0.92 (95% confidence interval, 0.86-0.97; p = 4.8×10-3). This finding suggests that biological processes that influence adult height may have a role in the etiology of AD.

Race/Ethnicity and the Pharmacogenetics of Reported Suicidality With Efavirenz Among Clinical Trials Participants.

PubMed

Mollan, Katie R; Tierney, Camlin; Hellwege, Jacklyn N; Eron, Joseph J; Hudgens, Michael G; Gulick, Roy M; Haubrich, Richard; Sax, Paul E; Campbell, Thomas B; Daar, Eric S; Robertson, Kevin R; Ventura, Diana; Ma, Qing; Edwards, Digna R Velez; Haas, David W

2017-09-01

We examined associations between suicidality and genotypes that predict plasma efavirenz exposure among AIDS Clinical Trials Group study participants in the United States. Four clinical trials randomly assigned treatment-naive participants to efavirenz-containing regimens; suicidality was defined as reported suicidal ideation or attempted or completed suicide. Genotypes that predict plasma efavirenz exposure were defined by CYP2B6 and CYP2A6 polymorphisms. Associations were evaluated with weighted Cox proportional hazards models stratified by race/ethnicity. Additional analyses adjusted for genetic ancestry and selected covariates. Among 1833 participants, suicidality was documented in 41 in exposed analyses, and 34 in on-treatment analyses. In unadjusted analyses based on 12 genotype levels, suicidality increased per level in exposed (hazard ratio, 1.11; 95% confidence interval, .96-1.27) and on-treatment 1.16; 1.01-1.34) analyses. In the on-treatment analysis, the association was strongest among white but nearly null among black participants. Considering 3 metabolizer levels (extensive, intermediate and slow), slow metabolizers were at increased risk. Results were similar after baseline covariate-adjustment for genetic ancestry, sex, age, weight, injection drug use history, and psychiatric history or recent psychoactive medication. Genotypes that predict higher plasma efavirenz exposure were associated with increased risk of suicidality. Strength of association varied by race/ethnicity. © The Author 2017. Published by Oxford University Press for the Infectious Diseases Society of America.

DFT-Assisted Polymorph Identification from Lattice Raman Fingerprinting

PubMed Central

2017-01-01

A combined experimental and theoretical approach, consisting of lattice phonon Raman spectroscopy and density functional theory (DFT) calculations, is proposed as a tool for lattice dynamics characterization and polymorph phase identification. To illustrate the reliability of the method, the lattice phonon Raman spectra of two polymorphs of the molecule 2,7-dioctyloxy[1]benzothieno[3,2-b]benzothiophene are investigated. We show that DFT calculations of the lattice vibrations based on the known crystal structures, including many-body dispersion van der Waals (MBD-vdW) corrections, predict experimental data within an accuracy of ≪5 cm–1 (≪0.6 meV). Due to the high accuracy of the simulations, they can be used to unambiguously identify different polymorphs and to characterize the nature of the lattice vibrations and their relationship to the structural properties. More generally, this work implies that DFT-MBD-vdW is a promising method to describe also other physical properties that depend on lattice dynamics like charge transport. PMID:28731723

Modification of menopausal hormone therapy-associated colorectal cancer risk by polymorphisms in sex steroid signaling, metabolism and transport related genes.

PubMed

Rudolph, Anja; Sainz, Juan; Hein, Rebecca; Hoffmeister, Michael; Frank, Bernd; Försti, Asta; Brenner, Hermann; Hemminki, Kari; Chang-Claude, Jenny

2011-06-01

The mechanisms underlying the association of menopausal hormone therapy (MHT) with reduced colorectal cancer (CRC) risk are unknown and the identification of genetic modifiers may yield further insight. We explored the effect modification of MHT-associated CRC risk in postmenopausal women by 47 polymorphisms with known or putative functional relevance in 16 candidate genes related to hormone metabolism (COMT, CYP1A1, CYP1A2, CYP1B1, CYP2C9, CYP2C19, CYP3A4, CYP17A1, GSTP, and HSD17B1), transport (ABCB1), and signaling (ESR1, ESR2, SHBG, PGR, and NR1I2). A total of 685 CRC patients and 684 healthy controls from a German population-based case-control study (DACHS) were genotyped. Multiplicative statistical interaction between polymorphisms and ever MHT use as well as duration of use was assessed using multivariate logistic regression. CRC risk associated with ever MHT use as well as with duration was significantly modified by rs1202168 in the transporter gene ABCB1 (P interaction=0.04). The MHT-associated risk reduction was not significant in homozygous non-carriers (odds ratio (OR) ever use=0.84, 95% confidence interval (CI) 0.53-1.34; OR per 5 year duration=0.94, 95% CI 0.83-1.08), while homozygous carriers of the minor T allele had a 57% lower risk with ever use of MHT (95% CI 0.21-0.88) and a 22% lower risk per 5 years of MHT use (95% CI 0.62-0.97). Significant effect modification was also observed for the ESR1_rs910416 polymorphism (P interaction=0.03 for ever use and 0.07 for duration of use), whereby the decreased risk was attenuated in homozygous carriers of the minor C allele (OR ever use=0.87, 95% CI 0.48-1.60, OR per 5 year duration=0.99, 95% CI 0.83-1.18). Results of this exploratory study provide first evidence that polymorphisms in genes related to estrogen transport and signaling may modify MHT-associated CRC risk but warrant replication in an independent population.

Impact of Genetic Polymorphisms on 6-Thioguanine Nucleotide Levels and Toxicity in Pediatric Patients with IBD Treated with Azathioprine.

PubMed

Lee, Mi-Na; Kang, Ben; Choi, So Yoon; Kim, Mi Jin; Woo, Sook Young; Kim, Jong-Won; Choe, Yon Ho; Lee, Soo-Youn

2015-12-01

Thiopurine-related toxicity results in discontinuation of therapy in up to 30% of patients with inflammatory bowel disease. Although thiopurine S-methyltransferase (TPMT) is implicated in toxicity, not all toxicity can be attributed to TPMT polymorphisms. We investigated the effects of polymorphisms of genes involved in thiopurine and folate metabolism pathways on 6-thioguanine nucleotide levels and toxicity. Retrospective clinical data and blood samples were collected from 132 pediatric patients with inflammatory bowel disease treated with azathioprine. Eighty-seven genetic polymorphisms of 30 genes were screened using the MassARRAY system, and 70 polymorphisms of 28 genes were selected for further analysis. TPMT genotype (P < 0.001), concurrent use of mesalazine (P = 0.006), ABCC5 (rs2293001) (P < 0.001), ITPA (rs2236206 and rs8362) (P = 0.010 and P = 0.003), and ABCB1 (rs2032582) (P = 0.028) were all associated with the ratio of 6-thioguanine nucleotides to azathioprine dose. ADK (rs10824095) (P = 0.004, odds ratio [OR] = 6.220), SLC29A1 (rs747199) (P = 0.016, OR = 5.681), and TYMS (rs34743033) (P = 0.045, OR = 3.846) were associated with neutropenia. ABCC1 (rs2074087) (P = 0.022, OR = 3.406), IMPDH1 (rs2278294) (P = 0.027, OR = 0.276), and IMPDH2 (rs11706052) (P = 0.034, OR = 3.639) had a significant impact on lymphopenia. This study describes genetic polymorphisms in genes whose products may affect pharmacokinetics and which may predict the relative likelihood of benefit or risk from thiopurine treatment. These findings may serve as a basis for personalized thiopurine therapy in pediatric patients with inflammatory bowel disease, although our data need to be validated in further studies.

Polymorphism and thermodynamic ground state of silver fulminate studied from van der Waals density functional calculations

DOE Office of Scientific and Technical Information (OSTI.GOV)

Yedukondalu, N.; Vaitheeswaran, G., E-mail: gvsp@uohyd.ernet.in

2014-06-14

Silver fulminate (AgCNO) is a primary explosive, which exists in two polymorphic phases, namely, orthorhombic (Cmcm) and trigonal (R3{sup ¯}) forms at ambient conditions. In the present study, we have investigated the effect of pressure and temperature on relative phase stability of the polymorphs using planewave pseudopotential approaches based on Density Functional Theory (DFT). van der Waals interactions play a significant role in predicting the phase stability and they can be effectively captured by semi-empirical dispersion correction methods in contrast to standard DFT functionals. Based on our total energy calculations using DFT-D2 method, the Cmcm structure is found to bemore » the preferred thermodynamic equilibrium phase under studied pressure and temperature range. Hitherto Cmcm and R3{sup ¯} phases denoted as α- and β-forms of AgCNO, respectively. Also a pressure induced polymorphic phase transition is seen using DFT functionals and the same was not observed with DFT-D2 method. The equation of state and compressibility of both polymorphic phases were investigated. Electronic structure and optical properties were calculated using full potential linearized augmented plane wave method within the Tran-Blaha modified Becke-Johnson potential. The calculated electronic structure shows that α, β phases are indirect bandgap insulators with a bandgap values of 3.51 and 4.43 eV, respectively. The nature of chemical bonding is analyzed through the charge density plots and partial density of states. Optical anisotropy, electric-dipole transitions, and photo sensitivity to light of the polymorphs are analyzed from the calculated optical spectra. Overall, the present study provides an early indication to experimentalists to avoid the formation of unstable β-form of AgCNO.« less

Association of endothelial nitric oxide synthase gene variants (-786 T>C, intron 4 b/a VNTR and 894 G>T) with idiopathic recurrent pregnancy loss: A case-control study with haplotype and in silico analysis.

PubMed

Azani, Alireza; Hosseinzadeh, Asghar; Azadkhah, Roya; Zonouzi, Ali Akbar Poursadegh; Zonouzi, Ahmad Poursadegh; Aftabi, Younes; Khani, Hourieh; Heidary, Leida; Danaii, Shahla; Bargahi, Nasrin; Pouladi, Nasser; Hosseini, Sayed Mostafa

2017-08-01

Many lines of evidence suggest that reduced production of nitric oxide (NO) due to single nucleotide polymorphisms in endothelial nitric oxide synthase (eNOS) gene may affect the implantation and maintenance of pregnancy. Accordingly, our objective was to investigate whether the eNOS polymorphisms (-786 T>C, intron 4 b/a VNTR and 894 G>T) and haplotypes may be associated with increased susceptibility to recurrent pregnancy loss (RPL). A total of 130 women with a history of two or more unexplained consecutive first trimester miscarriages and 110 ethnically matched women with at least two normal pregnancies and no history of pregnancy loss were included in the study as cases and controls, respectively. To identify the genotypes, we used polymerase chain reaction (PCR) and PCR-restriction fragment length polymorphism (PCR-RFLP) methods In addition, an in silico analysis was conducted to predict the possible effects of the eNOS 894 G>T polymorphism on the structure and function of eNOS mRNA and protein using prediction servers. Our findings revealed that the prevalence of eNOS -786 T>C polymorphism, eNOS -786C allele and TC+CC genotype in cases were significantly higher than those in healthy controls (p<0.05). Also, the combination genotypes -786TT/4b4a and -786TT/894GG were significantly associated with reduced risk of RPL. We also found that the C-4a-G haplotype of the eNOS gene studied polymorphisms was significantly associated with a predisposition to RPL (odds ratio, 3.219; 95% confidence interval, 1.649-6.282; p=0.0003). The in silico analysis showed that the eNOS 894 G>T polymorphism couldn't affects eNOS mRNA and protein significantly. Our findings provide evidence to support the hypothesis that eNOS -786 T>C polymorphism and the -786C-4a-894G haplotype are associated with the high risk of RPL. Copyright © 2017 Elsevier B.V. All rights reserved.

Do polymorphisms in chemosensory genes matter for human ingestive behavior?

PubMed Central

Hayes, John E.; Feeney, Emma L.; Allen, Alissa L.

2013-01-01

In the last decade, basic research in chemoreceptor genetics and neurobiology have revolutionized our understanding of individual differences in chemosensation. From an evolutionary perspective, chemosensory variations appear to have arisen in response to different living environments, generally in the avoidance of toxins and to better detect vital food sources. Today, it is often assumed that these differences may drive variable food preferences and choices, with downstream effects on health and wellness. A growing body of evidence indicates chemosensory variation is far more complex than previously believed. However, just because a genetic polymorphism results in altered receptor function in cultured cells or even behavioral phenotypes in the laboratory, this variation may not be sufficient to influence food choice in free living humans. Still, there is ample evidence to indicate allelic variation in TAS2R38 predicts variation in bitterness of synthetic pharmaceuticals (e.g., propylthiouracil) and natural plant compounds (e.g., goitrin), and this variation associates with differential intake of alcohol and vegetables. Further, this is only one of 25 unique bitter taste genes (TAS2Rs) in humans, and emerging evidence suggests other TAS2Rs may also contain polymorphisms that a functional with respect to ingestive behavior. For example, TAS2R16 polymorphisms are linked to the bitterness of naturally occurring plant compounds and alcoholic beverage intake, a TAS2R19 polymorphism predicts differences in quinine bitterness and grapefruit bitterness and liking, and TAS2R31 polymorphisms associate with differential bitterness of plant compounds like aristolochic acid and the sulfonyl amide sweeteners saccharin and acesulfame-K. More critically with respect to food choices, these polymorphisms may vary independently from each other within and across individuals, meaning a monolithic one-size-fits-all approach to bitterness needs to be abandoned. Nor are genetic differences restricted to bitterness. Perceptual variation has also been associated with polymorphisms in genes involved in odors associated with meat defects (boar taint), green/grassy notes, and cilantro, as well as umami and sweet tastes (TAS1R1/2/3). Here, a short primer on receptor genetics is provided, followed by a summary of current knowledge, and implications for human ingestive behavior are discussed. PMID:23878414

Fc gamma receptor 3a genotype predicts overall survival in follicular lymphoma patients treated on SWOG trials with combined monoclonal antibody plus chemotherapy but not chemotherapy alone

PubMed Central

Persky, Daniel O.; Dornan, David; Goldman, Bryan H.; Braziel, Rita M.; Fisher, Richard I.; LeBlanc, Michael; Maloney, David G.; Press, Oliver W.; Miller, Thomas P.; Rimsza, Lisa M.

2012-01-01

Background Fc gamma receptor polymorphisms were linked to outcome in follicular lymphoma patients treated with single-agent rituximab, an anti-CD20 monoclonal antibody. In particular, 158F/F genotype of Fc gamma receptor 3A and 131R/R genotype of Fc gamma receptor 2A correlated with worse outcome compared to high-affinity 158V/V and 131H/H, respectively. We examined this association in the context of anti-CD20 monoclonal antibody combined with chemotherapy, as compared to chemotherapy alone, in follicular lymphoma patients treated on SWOG clinical trials. Design and Methods Tissue from 142 SWOG patients treated with chemotherapy alone (protocol S8809, n=70) or combined chemotherapy and anti-CD20 monoclonal antibody (rituximab and Iodine I-131 tositumomab on protocols S9800 and S9911, n=30 and 42, respectively) was analyzed. DNA was extracted and assayed for Fc gamma receptor 3A V158F and 2A R131H polymorphisms using a TaqMan SNP assay. Stratified Cox’s regression was used to assess association with overall survival. Results For Fc gamma receptor 3A, there was an association with overall survival in the combination therapy trials but not in the chemotherapy-only trial. Having at least one Fc gamma receptor 3A V allele was associated with improved overall survival versus F/F (HR=0.33, 95% CI, 0.11, 0.96, P=0.042). For overall survival, there was evidence of a statistical interaction between the use of mAb and the number of V alleles (0, 1, or 2) (P=0.006). There was no such association for Fc gamma receptor 2A. Conclusions Fc gamma receptor 3A polymorphism status may be predictive of survival in follicular lymphoma patients receiving treatments containing an anti-CD20 antibody but not treatment with chemotherapy alone. Thus, Fc gamma receptor 3A polymorphisms may be important to consider in designing new follicular lymphoma trials and new anti-CD20 monoclonal antibodies. PMID:22271896

A Genomics-Based Model for Prediction of Severe Bioprosthetic Mitral Valve Calcification.

PubMed

Ponasenko, Anastasia V; Khutornaya, Maria V; Kutikhin, Anton G; Rutkovskaya, Natalia V; Tsepokina, Anna V; Kondyukova, Natalia V; Yuzhalin, Arseniy E; Barbarash, Leonid S

2016-08-31

Severe bioprosthetic mitral valve calcification is a significant problem in cardiovascular surgery. Unfortunately, clinical markers did not demonstrate efficacy in prediction of severe bioprosthetic mitral valve calcification. Here, we examined whether a genomics-based approach is efficient in predicting the risk of severe bioprosthetic mitral valve calcification. A total of 124 consecutive Russian patients who underwent mitral valve replacement surgery were recruited. We investigated the associations of the inherited variation in innate immunity, lipid metabolism and calcium metabolism genes with severe bioprosthetic mitral valve calcification. Genotyping was conducted utilizing the TaqMan assay. Eight gene polymorphisms were significantly associated with severe bioprosthetic mitral valve calcification and were therefore included into stepwise logistic regression which identified male gender, the T/T genotype of the rs3775073 polymorphism within the TLR6 gene, the C/T genotype of the rs2229238 polymorphism within the IL6R gene, and the A/A genotype of the rs10455872 polymorphism within the LPA gene as independent predictors of severe bioprosthetic mitral valve calcification. The developed genomics-based model had fair predictive value with area under the receiver operating characteristic (ROC) curve of 0.73. In conclusion, our genomics-based approach is efficient for the prediction of severe bioprosthetic mitral valve calcification.

A Genomics-Based Model for Prediction of Severe Bioprosthetic Mitral Valve Calcification

PubMed Central

Ponasenko, Anastasia V.; Khutornaya, Maria V.; Kutikhin, Anton G.; Rutkovskaya, Natalia V.; Tsepokina, Anna V.; Kondyukova, Natalia V.; Yuzhalin, Arseniy E.; Barbarash, Leonid S.

2016-01-01

Severe bioprosthetic mitral valve calcification is a significant problem in cardiovascular surgery. Unfortunately, clinical markers did not demonstrate efficacy in prediction of severe bioprosthetic mitral valve calcification. Here, we examined whether a genomics-based approach is efficient in predicting the risk of severe bioprosthetic mitral valve calcification. A total of 124 consecutive Russian patients who underwent mitral valve replacement surgery were recruited. We investigated the associations of the inherited variation in innate immunity, lipid metabolism and calcium metabolism genes with severe bioprosthetic mitral valve calcification. Genotyping was conducted utilizing the TaqMan assay. Eight gene polymorphisms were significantly associated with severe bioprosthetic mitral valve calcification and were therefore included into stepwise logistic regression which identified male gender, the T/T genotype of the rs3775073 polymorphism within the TLR6 gene, the C/T genotype of the rs2229238 polymorphism within the IL6R gene, and the A/A genotype of the rs10455872 polymorphism within the LPA gene as independent predictors of severe bioprosthetic mitral valve calcification. The developed genomics-based model had fair predictive value with area under the receiver operating characteristic (ROC) curve of 0.73. In conclusion, our genomics-based approach is efficient for the prediction of severe bioprosthetic mitral valve calcification. PMID:27589735

Development of a physiologically based pharmacokinetic model to predict the effects of flavin-containing monooxygenase 3 (FMO3) polymorphisms on itopride exposure.

PubMed

Zhou, Wangda; Humphries, Helen; Neuhoff, Sibylle; Gardner, Iain; Masson, Eric; Al-Huniti, Nidal; Zhou, Diansong

2017-09-01

Itopride, a substrate of FMO3, has been used for the symptomatic treatment of various gastrointestinal disorders. Physiologically based pharmacokinetic (PBPK) modeling was applied to evaluate the impact of FMO3 polymorphism on itopride pharmacokinetics (PK). The Asian populations within the Simcyp simulator were updated to incorporate information on the frequency, activity and abundance of FMO3 enzyme with different phenotypes. A meta-analysis of relative enzyme activities suggested that FMO3 activity in subjects with homozygous Glu158Lys and Glu308Gly mutations (Lys158 and Gly308) in both alleles is ~47% lower than those carrying two wild-type FMO3 alleles. Individuals with homozygous Lys158 and Gly308 mutations account for about 5% of the total population in Asian populations. A CL int of 9 μl/min/pmol was optimised for itopride via a retrograde approach as human liver microsomal results would under-predict its clearance by ~7.9-fold. The developed itopride PBPK model was first verified with three additional clinical studies in Korean and Japanese subjects resulting in a predicted clearance of 52 to 69 l/h, which was comparable to those observed (55 to 88 l/h). The model was then applied to predict plasma concentration-time profiles of itopride in Chinese subjects with wild type or homozygous Lys158 and Gly308 FMO3 genotypes. The ratios of predicted to observed AUC of itopride in subjects with each genotype were 1.23 and 0.94, respectively. In addition, the results also suggested that for FMO3 metabolised drugs with a safety margin of 2 or more, proactive genotyping FMO3 to exclude subjects with homozygous Lys158/Gly308 alleles may not be necessary. Copyright © 2017 John Wiley & Sons, Ltd.

Predictive Value of Gene Polymorphisms on Recurrence after the Withdrawal of Antithyroid Drugs in Patients with Graves’ Disease

PubMed Central

Liu, Jia; Fu, Jing; Duan, Yan; Wang, Guang

2017-01-01

Graves’ disease (GD) is one of the most common endocrine diseases. Antithyroid drugs (ATDs) treatment is frequently used as the first-choice therapy for GD patients in most countries due to the superiority in safety and tolerance. However, GD patients treated with ATD have a relatively high recurrence rate after drug withdrawal, which is a main limitation for ATD treatment. It is of great importance to identify some predictors of the higher recurrence risk for GD patients, which may facilitate an appropriate therapeutic approach for a given patient at the time of GD diagnosis. The genetic factor was widely believed to be an important pathogenesis for GD. Increasing studies were conducted to investigate the relationship between gene polymorphisms and the recurrence risk in GD patients. In this article, we updated the current literatures to highlight the predictive value of gene polymorphisms on recurrence risk in GD patients after ATD withdrawal. Some gene polymorphisms, such as CTLA4 rs231775, human leukocyte antigen polymorphisms (DRB1*03, DQA1*05, and DQB1*02) might be associated with the high recurrence risk in GD patients. Further prospective studies on patients of different ethnicities, especially studies with large sample sizes, and long-term follow-up, should be conducted to confirm the predictive roles of gene polymorphism. PMID:29085334

Gender Interacts with Opioid Receptor Polymorphism A118G and Serotonin Receptor Polymorphism -1438 A/G on Speed-Dating Success.

PubMed

Wu, Karen; Chen, Chuansheng; Moyzis, Robert K; Greenberger, Ellen; Yu, Zhaoxia

2016-09-01

We examined an understudied but potentially important source of romantic attraction-genetics-using a speed-dating paradigm. The mu opioid receptor (OPRM1) polymorphism A118G (rs1799971) and the serotonin receptor (HTR2A) polymorphism -1438 A/G (rs6311) were studied because they have been implicated in social affiliation. Guided by the social role theory of mate selection and prior genetic evidence, we examined these polymorphisms' gender-specific associations with speed-dating success (i.e., date offers, mate desirability). A total of 262 single Asian Americans went on speed-dates with members of the opposite gender and completed interaction questionnaires about their partners. Consistent with our prediction, significant gender-by-genotype interactions were found for speed-dating success. Specifically, the minor variant of A118G (G-allele), which has been linked to submissiveness/social sensitivity, predicted greater speed-dating success for women, whereas the minor variant of -1438 A/G (G-allele), which has been linked to leadership/social dominance, predicted greater speed-dating success for men. For both polymorphisms, reverse "dampening" effects of minor variants were found for opposite-gender counterparts. These results support previous research on the importance of the opioid and serotonergic systems in social affiliation, indicating that their influence extends to dating success, with opposite, yet gender-norm consistent, effects for men and women.

Evaluation and identification of damaged single nucleotide polymorphisms in COL1A1 gene involved in osteoporosis

PubMed Central

Alsaif, Mohammed A.; Al Shammari, Sulaiman A.; Alhamdan, Adel A.

2012-01-01

Introduction Single-nucleotide polymorphisms (SNPs) are biomarkers for exploring the genetic basis of many complex human diseases. The prediction of SNPs is promising in modern genetic analysis but it is still a great challenge to identify the functional SNPs in a disease-related gene. The computational approach has overcome this challenge and an increase in the successful rate of genetic association studies and reduced cost of genotyping have been achieved. The objective of this study is to identify deleterious non-synonymous SNPs (nsSNPs) associated with the COL1A1 gene. Material and methods The SNPs were retrieved from the Single Nucleotide Polymorphism Database (dbSNP). Using I-Mutant, protein stability change was calculated. The potentially functional nsSNPs and their effect on proteins were predicted by PolyPhen and SIFT respectively. FASTSNP was used for estimation of risk score. Results Our analysis revealed 247 SNPs as non-synonymous, out of which 5 nsSNPs were found to be least stable by I-Mutant 2.0 with a DDG value of > –1.0. Four nsSNPs, namely rs17853657, rs17857117, rs57377812 and rs1059454, showed a highly deleterious tolerance index score of 0.00 with a change in their physicochemical properties by the SIFT server. Seven nsSNPs, namely rs1059454, rs8179178, rs17853657, rs17857117, rs72656340, rs72656344 and rs72656351, were found to be probably damaging with a PSIC score difference between 2.0 and 3.5 by the PolyPhen server. Three nsSNPs, namely rs1059454, rs17853657 and rs17857117, were found to be highly polymorphic with a risk score of 3-4 with a possible effect of non-conservative change and splicing regulation by FASTSNP. Conclusions Three nsSNPs, namely rs1059454, rs17853657 and rs17857117, are potential functional polymorphisms that are likely to have a functional impact on the COL1A1 gene. PMID:24273577

Determination of genetic polymorphism in Guney Karaman local Turkish sheep breed by using STR markers

NASA Astrophysics Data System (ADS)

Karslı, Taki; Balcıoǧlu, Murat Soner

2017-04-01

The objective of this study was to assess genetic diversity of Güney Karaman Turkish local sheep breed. A total of 29 samples were genotyped by using 14 STR markers. All markers were polymorphic. The number of alleles in Güney Karaman sheep breed ranged from 3 to 11 per locus, with a mean of 7.42. The average observed and expected heterozygosity was 0.659 and 0.794, respectively. Mean inbreeding coefficient (Fis) value was found 0.175. The PIC values ranged from 0.569 to 0.860 with a mean of 0.743. The findings of this research demonstrate at moderate level gene diversity and heterozygosity with lower inbreeding in Güney Karaman sheep breed.

Isolation and characterization of 12 microsatellite loci in soapbark, Quillaja saponaria (Quillajaceae)1

PubMed Central

Letelier, Luis; Harvey, Nick; Valderrama, Aly; Stoll, Alexandra; González-Rodríguez, Antonio

2015-01-01

Premise of the study: Microsatellite primers were developed for the endemic Chilean tree Quillaja saponaria (Quillajaceae), a common member of the sclerophyllous Mediterranean forest, to investigate intraspecific patterns of genetic diversity and structure. Methods and Results: Using an enriched library, 12 polymorphic microsatellite loci were developed in Q. saponaria. All loci consisted of dinucleotide repeats. The average number of alleles per locus was 5.3 (2–13), with a total of 64 alleles recorded in 39 individuals from three populations. Conclusions: The microsatellite markers described here are the first characterized for Q. saponaria. The polymorphic loci will be useful in studies of genetic diversity and genetic population differentiation in natural populations of this species. PMID:25995980

Implications of the angiotensin converting enzyme gene insertion/deletion polymorphism in health and disease: a snapshot review

PubMed Central

Gard, Paul R

2010-01-01

This review considers the 250+ papers concerning the association of the angiotensin converting enzyme (ACE) gene insertion/deletion polymorphism (rs1799752) and various disease conditions published in 2009. The deletion allele occurs in approximately 55% of the population and is associated with increased activity of the ACE enzyme. It might be predicted that the D allele, therefore, might be associated with pathologies involving increased activity of the renin-angiotensin system. The D allele was seen to be associated with an increased risk of hypertension, pre-eclampsia, heart failure, cerebral infarct, diabetic nephropathy, encephalopathy, asthma, severe hypoglycaemia in diabetes, gastric cancer (in Caucasians) and poor prognosis following kidney transplant. On the positive side, the D allele appears to offer protection against schizophrenia and chronic periodontitis and confers greater up-per-body strength in old age. The I allele, meanwhile, offers improved endurance/athletic performance and aerobic capacity as determined by lung function tests, although it does increase the risk of oral squamous cell carcinoma and obstructive sleep apnoea in hypertensives. PMID:21537387

Cortical Dopamine Transmission as Measured with the [11C]FLB 457 – Amphetamine PET Imaging Paradigm Is Not Influenced by COMT Genotype

PubMed Central

Narendran, Rajesh; Tumuluru, Divya; May, Maureen A.; Chowdari, Kodavali V.; Himes, Michael L.; Fasenmyer, Kelli; Frankle, W. Gordon; Nimgaonkar, Vishwajit L.

2016-01-01

Basic investigations link a Val158Met polymorphism (rs4680) in the catechol-O-methyltransferase (COMT) gene to not only its enzymatic activity, but also to its dopaminergic tone in the prefrontal cortex. Previous PET studies have documented the relationship between COMT Val158Met polymorphism and D1 and D2/3 receptor binding potential (BP), and interpreted them in terms of dopaminergic tone. The use of baseline dopamine D1 and D2/3 receptor binding potential (BPND) as a proxy for dopaminergic tone is problematic because they reflect both endogenous dopamine levels (a change in radiotracer's apparent affinity) and receptor density. In this analysis of 31 healthy controls genotyped for the Val158Met polymorphism (Val/Val, Val/Met, and Met/Met), we used amphetamine-induced displacement of [11C]FLB 457 as a direct measure of dopamine release. Our analysis failed to show a relationship between COMT genotype status and prefrontal cortical dopamine release. COMT genotype was also not predictive of baseline dopamine D2/3 receptor BPND. PMID:27322568

Genomic Variation by Whole-Genome SNP Mapping Arrays Predicts Time-to-Event Outcome in Patients with Chronic Lymphocytic Leukemia

PubMed Central

Schweighofer, Carmen D.; Coombes, Kevin R.; Majewski, Tadeusz; Barron, Lynn L.; Lerner, Susan; Sargent, Rachel L.; O'Brien, Susan; Ferrajoli, Alessandra; Wierda, William G.; Czerniak, Bogdan A.; Medeiros, L. Jeffrey; Keating, Michael J.; Abruzzo, Lynne V.

2013-01-01

Genomic abnormalities, such as deletions in 11q22 or 17p13, are associated with poorer prognosis in patients with chronic lymphocytic leukemia (CLL). We hypothesized that unknown regions of copy number variation (CNV) affect clinical outcome and can be detected by array-based single-nucleotide polymorphism (SNP) genotyping. We compared SNP genotypes from 168 untreated patients with CLL with genotypes from 73 white HapMap controls. We identified 322 regions of recurrent CNV, 82 of which occurred significantly more often in CLL than in HapMap (CLL-specific CNV), including regions typically aberrant in CLL: deletions in 6q21, 11q22, 13q14, and 17p13 and trisomy 12. In univariate analyses, 35 of total and 11 of CLL-specific CNVs were associated with unfavorable time-to-event outcomes, including gains or losses in chromosomes 2p, 4p, 4q, 6p, 6q, 7q, 11p, 11q, and 17p. In multivariate analyses, six CNVs (ie, CLL-specific variations in 11p15.1-15.4 or 6q27) predicted time-to-treatment or overall survival independently of established markers of prognosis. Moreover, genotypic complexity (ie, the number of independent CNVs per patient) significantly predicted prognosis, with a median time-to-treatment of 64 months versus 23 months in patients with zero to one versus two or more CNVs, respectively (P = 3.3 × 10−8). In summary, a comparison of SNP genotypes from patients with CLL with HapMap controls allowed us to identify known and unknown recurrent CNVs and to determine regions and rates of CNV that predict poorer prognosis in patients with CLL. PMID:23273604

Development of microsatellite primers of the largest seagrass, Enhalus acoroides (Hydrocharitaceae).

PubMed

Gao, Hui; Jiang, Kai; Geng, Yan; Chen, Xiao-Yong

2012-03-01

Microsatellite primers were developed for the seagrass Enhalus acoroides to investigate genetic variation and identify clonal structure. Four polymorphic loci and 32 monomorphic loci were developed in E. acoroides. Two to four alleles per locus were observed at the polymorphic loci across 60 individuals of two E. acoroides populations. The observed and expected heterozygosities within populations ranged from 0.100 to 0.5667 and from 0.0977 to 0.5079, respectively. Our study revealed very low polymorphism in E. acoroides, even at the polymorphic loci. Nevertheless, these primers are a useful tool to study genetic variation, clonal structure, and mating system.

Development and characterization of polymorphic microsatellite markers in Dysosma pleiantha (Berberidaceae).

PubMed

Guan, Bi-Cai; Gong, Xi; Zhou, Shi-Liang

2011-08-01

The development of compound microsatellite markers was conducted in Dysosma pleiantha to investigate genetic diversity and population genetic structure of this threatened medicinal plant. Using the compound microsatellite marker technique, 14 microsatellite markers that were successfully amplified showed polymorphism when tested on 38 individuals from three populations in eastern China. Overall, the number of alleles per locus ranged from 2 to 14, with an average of 7.71 alleles per locus. These results indicate that these microsatellite markers are adequate for detecting and characterizing population genetic structure and genetic diversity in Dysosma pleiantha.

Genome-wide association study identifies phospholipase C zeta 1 (PLCz1) as a stallion fertility locus in Hanoverian warmblood horses.

PubMed

Schrimpf, Rahel; Dierks, Claudia; Martinsson, Gunilla; Sieme, Harald; Distl, Ottmar

2014-01-01

A consistently high level of stallion fertility plays an economically important role in modern horse breeding. We performed a genome-wide association study for estimated breeding values of the paternal component of the pregnancy rate per estrus cycle (EBV-PAT) in Hanoverian stallions. A total of 228 Hanoverian stallions were genotyped using the Equine SNP50 Beadchip. The most significant association was found on horse chromosome 6 for a single nucleotide polymorphism (SNP) within phospholipase C zeta 1 (PLCz1). In the close neighbourhood to PLCz1 is located CAPZA3 (capping protein (actin filament) muscle Z-line, alpha 3). The gene PLCz1 encodes a protein essential for spermatogenesis and oocyte activation through sperm induced Ca2+-oscillation during fertilization. We derived equine gene models for PLCz1 and CAPZA3 based on cDNA and genomic DNA sequences. The equine PLCz1 had four different transcripts of which two contained a premature termination codon. Sequencing all exons and their flanking sequences using genomic DNA samples from 19 Hanoverian stallions revealed 47 polymorphisms within PLCz1 and one SNP within CAPZA3. Validation of these 48 polymorphisms in 237 Hanoverian stallions identified three intronic SNPs within PLCz1 as significantly associated with EBV-PAT. Bioinformatic analysis suggested regulatory effects for these SNPs via transcription factor binding sites or microRNAs. In conclusion, non-coding polymorphisms within PLCz1 were identified as conferring stallion fertility and PLCz1 as candidate locus for male fertility in Hanoverian warmblood. CAPZA3 could be eliminated as candidate gene for fertility in Hanoverian stallions.

Genome-Wide Association Study Identifies Phospholipase C zeta 1 (PLCz1) as a Stallion Fertility Locus in Hanoverian Warmblood Horses

PubMed Central

Schrimpf, Rahel; Dierks, Claudia; Martinsson, Gunilla; Sieme, Harald; Distl, Ottmar

2014-01-01

A consistently high level of stallion fertility plays an economically important role in modern horse breeding. We performed a genome-wide association study for estimated breeding values of the paternal component of the pregnancy rate per estrus cycle (EBV-PAT) in Hanoverian stallions. A total of 228 Hanoverian stallions were genotyped using the Equine SNP50 Beadchip. The most significant association was found on horse chromosome 6 for a single nucleotide polymorphism (SNP) within phospholipase C zeta 1 (PLCz1). In the close neighbourhood to PLCz1 is located CAPZA3 (capping protein (actin filament) muscle Z-line, alpha 3). The gene PLCz1 encodes a protein essential for spermatogenesis and oocyte activation through sperm induced Ca2+-oscillation during fertilization. We derived equine gene models for PLCz1 and CAPZA3 based on cDNA and genomic DNA sequences. The equine PLCz1 had four different transcripts of which two contained a premature termination codon. Sequencing all exons and their flanking sequences using genomic DNA samples from 19 Hanoverian stallions revealed 47 polymorphisms within PLCz1 and one SNP within CAPZA3. Validation of these 48 polymorphisms in 237 Hanoverian stallions identified three intronic SNPs within PLCz1 as significantly associated with EBV-PAT. Bioinformatic analysis suggested regulatory effects for these SNPs via transcription factor binding sites or microRNAs. In conclusion, non-coding polymorphisms within PLCz1 were identified as conferring stallion fertility and PLCz1 as candidate locus for male fertility in Hanoverian warmblood. CAPZA3 could be eliminated as candidate gene for fertility in Hanoverian stallions. PMID:25354211

Serotonin Transporter-Linked Polymorphic Region (5-HTTLPR) Genotype and Stressful Life Events Interact to Predict Preschool-Onset Depression: A Replication and Developmental Extension

ERIC Educational Resources Information Center

Bogdan, Ryan; Agrawal, Arpana; Gaffrey, Michael S.; Tillman, Rebecca; Luby, Joan L.

2014-01-01

Background: Scientific enthusiasm about gene × environment interactions, spurred by the 5-HTTLPR (serotonin transporter-linked polymorphic region) × SLEs (stressful life events) interaction predicting depression, have recently been tempered by sober realizations of small effects and meta-analyses reaching opposing conclusions. These mixed findings…

Functional polymorphisms in UDP-glucuronosyltransferases and recurrence in tamoxifen-treated breast cancer survivors

PubMed Central

Ahern, Thomas P.; Christensen, Mariann; Cronin-Fenton, Deirdre P.; Lunetta, Kathryn L.; Søiland, Håvard; Gjerde, Jennifer; Garne, Jens Peter; Rosenberg, Carol L.; Silliman, Rebecca A.; Sørensen, Henrik Toft; Lash, Timothy L.; Hamilton-Dutoit, Stephen

2011-01-01

Background Tamoxifen is oxidized by cytochrome-P450 enzymes (e.g., CYP2D6) to two active metabolites, which are eliminated via glucuronidation by UDP-glucuronosyltransferases (UGTs). We measured the association between functional polymorphisms in key UGTs (UGT2B15*2, UGT2B7*2, and UGT1A8*3) and the recurrence rate among breast cancer survivors. Methods We used the Danish Breast Cancer Cooperative Group registry to identify 541 cases of recurrent breast cancer among women with estrogen receptor-positive tumors treated with tamoxifen for at least one year (ER+/TAM+), and 300 cases of recurrent breast cancer among women with estrogen receptor-negative tumors who were not treated with tamoxifen (ER−/TAM−). We matched 1 control to each case on ER status, menopausal status, stage, calendar period, and county. UGT polymorphisms were genotyped from archived primary tumors. We estimated the recurrence odds ratio for the UGT polymorphisms using logistic regression models, with and without stratification on CYP2D6*4 genotype. Results No UGT polymorphism was associated with breast cancer recurrence in either the ER+/TAM+ or ER-/TAM- groups [in the ER+TAM+ group, compared with two normal alleles: adjusted OR for two UGT2B15*2 variant alleles = 1.0 (95% CI: 0.70, 1.5); adjusted OR for two for UGT2B7*2 variant alleles = 0.91 (95% CI: 0.65, 1.3); adjusted OR for 1 or 2 UGT1A8*3 variant alleles = 0.75 (0.41, 1.4)]. Associations were similar within strata of CYP2D6*4 genotype. Conclusions Functional polymorphisms in key tamoxifen-metabolizing enzymes were not associated with breast cancer recurrence risk. Impact Our results do not support the genotyping of key metabolic enzyme polymorphisms to predict response to tamoxifen therapy. PMID:21750172

The BIM Deletion Polymorphism and its Clinical Implication in Patients with EGFR-Mutant Non-Small-Cell Lung Cancer Treated with EGFR Tyrosine Kinase Inhibitors.

PubMed

Lee, Ji Yun; Ku, Bo Mi; Lim, Sung Hee; Lee, Min-Young; Kim, Haesu; Kim, Moonjin; Kim, Sungmin; Jung, Hyun Ae; Sun, Jong-Mu; Ahn, Jin Seok; Park, Keunchil; Ahn, Myung-Ju

2015-06-01

A germline BIM deletion polymorphism has been proposed to predict poor treatment response to certain kinase inhibitors. The purpose of this study was to explore whether the BIM deletion polymorphism predicts treatment efficacy of epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) in Korean patients with EGFR-mutant non-small-cell lung cancer (NSCLC). Peripheral blood samples from a total of 205 patients with EGFR-mutant NSCLC who were treated with EGFR TKIs between July 2008 and April 2013 were included. The incidence of BIM deletions in these samples was detected by polymerase chain reaction. We compared the clinical outcomes in patients with and without the polymorphism after treatment with EGFR TKIs (gefitinib or erlotinib). The BIM deletion polymorphism was present in 15.6% (32 of 205) of patients. One patient was homozygous for the deletion, and the remaining 31 had heterozygous deletions. The majority of patients were younger than 65 years (74%), female (68%), never smokers (76%), and had stage IV NSCLC (67%). There were no associations between the BIM deletion polymorphism and clinicopathological features including gender, age, smoking status, histology, stage, and number of metastasis sites. Patients with and without the BIM deletion polymorphism had similar objective response rates (91 vs. 84%, p = 0.585). Progression-free survival and overall survival did not differ significantly between patients with and without the BIM deletion polymorphism (median progression-free survival 12 vs. 11 months, p = 0.160; median overall survival 31 vs. 30 months, p = 0.452). Multivariate analysis identified significantly predictive markers for clinical outcomes of EGFR TKIs including Eastern Cooperative Oncology Group performance status 0-1, adenocarcinoma histology, recurrent disease, and EGFR mutation type. The results were validated in an independent cohort of 69 NSCLC patients. It remains to be determined whether the BIM deletion polymorphism provides intrinsic resistance or decreased sensitivity to EGFR TKIs in EGFR-mutant NSCLC patients.

Polymorphic microsatellite markers for the rare and endangered cactus Uebelmannia pectinifera (Cactaceae) and its congeneric species.

PubMed

Moraes, E M; Cidade, F W; Silva, G A R; Machado, M C

2014-12-04

The cactus genus Uebelmannia includes 3 narrow endemic species associated with rocky savanna habitats in eastern South America. Because of their rarity and illegal over-collection, all of these species are endangered. Taxonomic uncertainties resulting from dramatic local variation in morphology within Uebelmannia species preclude effective conservation efforts, such as the reintroduction or translocation of plants, to restore declining populations. In this study, we developed and characterized 18 perfect, dinucleotide simple-sequence repeat markers for U. pectinifera, the most widely distributed species in the genus, and tested the cross-amplification of these markers in the remaining congeneric species and subspecies. All markers were polymorphic in a sample from 2 U. pectinifera populations. The effective number of alleles ranged from 1.6 to 8.7, with an average per population of 3.3 (SE ± 0.30) and 4.5 (SE ± 0.50). Expected heterozygosity ranged from 0.375 to 0.847 and 8-10 loci showed departures from Hardy- Weinberg equilibrium in the analyzed populations. Based on the observed polymorphism level of each marker, as well as the analysis of null allele presence and evidence of amplification of duplicate loci, a subset of 12 loci can be used as reliable markers to investigate the genetic structure, diversity, and species limits of the Uebelmannia genus.

Prediction of Adult Dyslipidemia Using Genetic and Childhood Clinical Risk Factors: The Cardiovascular Risk in Young Finns Study.

PubMed

Nuotio, Joel; Pitkänen, Niina; Magnussen, Costan G; Buscot, Marie-Jeanne; Venäläinen, Mikko S; Elo, Laura L; Jokinen, Eero; Laitinen, Tomi; Taittonen, Leena; Hutri-Kähönen, Nina; Lyytikäinen, Leo-Pekka; Lehtimäki, Terho; Viikari, Jorma S; Juonala, Markus; Raitakari, Olli T

2017-06-01

Dyslipidemia is a major modifiable risk factor for cardiovascular disease. We examined whether the addition of novel single-nucleotide polymorphisms for blood lipid levels enhances the prediction of adult dyslipidemia in comparison to childhood lipid measures. Two thousand four hundred and twenty-two participants of the Cardiovascular Risk in Young Finns Study who had participated in 2 surveys held during childhood (in 1980 when aged 3-18 years and in 1986) and at least once in a follow-up study in adulthood (2001, 2007, and 2011) were included. We examined whether inclusion of a lipid-specific weighted genetic risk score based on 58 single-nucleotide polymorphisms for low-density lipoprotein cholesterol, 71 single-nucleotide polymorphisms for high-density lipoprotein cholesterol, and 40 single-nucleotide polymorphisms for triglycerides improved the prediction of adult dyslipidemia compared with clinical childhood risk factors. Adjusting for age, sex, body mass index, physical activity, and smoking in childhood, childhood lipid levels, and weighted genetic risk scores were associated with an increased risk of adult dyslipidemia for all lipids. Risk assessment based on 2 childhood lipid measures and the lipid-specific weighted genetic risk scores improved the accuracy of predicting adult dyslipidemia compared with the approach using only childhood lipid measures for low-density lipoprotein cholesterol (area under the receiver-operating characteristic curve 0.806 versus 0.811; P =0.01) and triglycerides (area under the receiver-operating characteristic curve 0.740 versus area under the receiver-operating characteristic curve 0.758; P <0.01). The overall net reclassification improvement and integrated discrimination improvement were significant for all outcomes. The inclusion of weighted genetic risk scores to lipid-screening programs in childhood could modestly improve the identification of those at highest risk of dyslipidemia in adulthood. © 2017 American Heart Association, Inc.

A polymorphism in the gene encoding carnosinase (CNDP1) as a predictor of mortality and progression from nephropathy to end-stage renal disease in type 1 diabetes mellitus.

PubMed

Alkhalaf, A; Bakker, S J L; Bilo, H J G; Gans, R O B; Navis, G J; Postmus, D; Forsblom, C; Groop, P H; Vionnet, N; Hadjadj, S; Marre, M; Parving, H H; Rossing, P; Tarnow, L

2010-12-01

Homozygosity for a five leucine repeat (5L-5L) in the carnosinase gene (CNDP1) has been found to be cross-sectionally associated with a low frequency of diabetic nephropathy (DN), mainly in type 2 diabetes. We prospectively investigated in patients with type 1 diabetes whether: (1) 5L-5L is associated with mortality; (2) there is an interaction of 5L-5L with DN or sex for prediction of mortality; and (3) 5L-5L is associated with progression to end-stage renal disease (ESRD). In this prospective study in white European patients with type 1 diabetes, individuals with DN were defined by persistent albuminuria ≥ 300 mg/24 h. Controls without nephropathy were defined by persistent (>15 years) normoalbuminuria < 30 mg/24 h. Leucine repeats were assessed with a fluorescent DNA analysis system. Onset of ESRD was defined by need to start chronic dialysis or kidney transplantation. The study involved 916 patients with DN and 1,170 controls. During follow-up for 8.8 years, 107 patients (14%) with 5L-5L died compared with 182 patients (13.8%) with other genotypes (p = 0.99). There was no significant interaction of 5L-5L with DN for prediction of mortality (p = 0.57), but a trend towards interaction with sex (p = 0.08). In patients with DN, HR for ESRD in 5L-5L vs other genotypes was not constant over time, with increased risk for 5L-5L beyond 8 years of follow-up (p = 0.03). CNDP1 polymorphism was not associated with mortality, and nor was there an interaction of this polymorphism with DN for prediction of mortality in patients with type 1 diabetes. CNDP1 polymorphism predicts progression to ESRD in patients with DN, but only late after baseline measurements.

PPARA intron polymorphism associated with power performance in 30-s anaerobic Wingate Test.

PubMed

Petr, Miroslav; Stastny, Petr; Št'astný, Petr; Pecha, Ondřej; Šteffl, Michal; Šeda, Ondřej; Kohlíková, Eva

2014-01-01

To date, polymorphisms in several genes have been associated with a strength/power performance including alpha 3 actinin, ciliary neurotrophic factor, vitamin D receptor, or angiotensin I converting enzyme, underlining the importance of genetic component of the multifactorial strength/power-related phenotypes. The single nucleotide variation in peroxisome proliferator-activated receptor alpha gene (PPARA) intron 7 G/C (rs4253778; g.46630634G>C) has been repeatedly found to play a significant role in response to different types of physical activity. We investigated the effect of PPARA intron 7 G/C polymorphism specifically on anaerobic power output in a group of 77 elite male Czech ice hockey players (18-36 y). We determined the relative peak power per body weight (Pmax.kg(-1)) and relative peak power per fat free mass (W.kg(-1)FFM) during the 30-second Wingate Test (WT30) on bicycle ergometer (Monark 894E Peak bike, MONARK, Sweden). All WT30s were performed during the hockey season. Overall genotype frequencies were 50.6% GG homozygotes, 40.3% CG heterozygotes, and 9.1% CC homozygotes. We found statistically significant differences in Pmax.kg(-1) and marginally significant differences in Pmax.kg(-1)FFM values in WT30 between carriers and non-carriers for C allele (14.6 ± 0.2 vs. 13.9 ± 0.3 W.kg(-1) and 15.8 ± 0.2 vs. 15.2 ± 0.3 W.kg(-1)FFM, P = 0.036 and 0.12, respectively). Furthermore, Pmax.kg(-1)FFM strongly positively correlated with the body weight only in individuals with GG genotypes (R = 0.55; p<0.001). Our results indicate that PPARA 7C carriers exhibited higher speed strength measures in WT30. We hypothesize that C allele carriers within the cohort of trained individuals may possess a metabolic advantage towards anaerobic metabolism.

Single nucleotide polymorphisms in the mitochondrial displacement loop and outcome of esophageal squamous cell carcinoma.

PubMed

Zhang, Ruixing; Wang, Rui; Zhang, Fengbin; Wu, Chensi; Fan, Haiyan; Li, Yan; Wang, Cuiju; Guo, Zhanjun

2010-11-26

Accumulation of single nucleotide polymorphisms (SNPs) in the displacement loop (D-loop) of mitochondrial DNA (mtDNA) has been described for different types of cancers and might be associated with cancer risk and disease outcome. We used a population-based series of esophageal squamous cell carcinoma (ESCC) patients for investigating the prediction power of SNPs in mitochondrial D-loop. The D-loop region of mtDNA was sequenced for 60 ESCC patients recorded in the Fourth Hospital of Hebei Medical University between 2003 and 2004. The 5 year survival curve were calculated with the Kaplan-Meier method and compared by the log-rank test at each SNP site, a multivariate survival analysis was also performed with the Cox proportional hazards method. The SNP sites of nucleotides 16274G/A, 16278C/T and 16399A/G were identified for prediction of post-operational survival by the log-rank test. In an overall multivariate analysis, the 16278 and 16399 alleles were identified as independent predictors of ESCC outcome. The length of survival of patients with the minor allele 16278T genotype was significantly shorter than that of patients with 16278C at the 16278 site (relative risk, 3.001; 95% CI, 1.029 - 8.756; p = 0.044). The length of survival of patients with the minor allele 16399G genotype was significantly shorter than that of patients with the more frequent allele 16399A at the 16399 site in ESCC patients (relative risk, 3.483; 95% CI, 1.068 - 11.359; p = 0.039). Genetic polymorphisms in the D-loop are independent prognostic markers for patients with ESCC. Accordingly, the analysis of genetic polymorphisms in the mitochondrial D-loop can help identify patient subgroups at high risk of a poor disease outcome.

Novel association of the obesity risk-allele near Fas Apoptotic Inhibitory Molecule 2 (FAIM2) gene with heart rate and study of its effects on myocardial infarction in diabetic participants of the PREDIMED trial.

PubMed

Corella, Dolores; Sorlí, Jose V; González, José I; Ortega, Carolina; Fitó, Montserrat; Bulló, Monica; Martínez-González, Miguel Angel; Ros, Emilio; Arós, Fernando; Lapetra, José; Gómez-Gracia, Enrique; Serra-Majem, Lluís; Ruiz-Gutierrez, Valentina; Fiol, Miquel; Coltell, Oscar; Vinyoles, Ernest; Pintó, Xavier; Martí, Amelia; Saiz, Carmen; Ordovás, José M; Estruch, Ramón

2014-01-06

The Fas apoptotic pathway has been implicated in type 2 diabetes and cardiovascular disease. Although a polymorphism (rs7138803; G > A) near the Fas apoptotic inhibitory molecule 2 (FAIM2) locus has been related to obesity, its association with other cardiovascular risk factors and disease remains uncertain. We analyzed the association between the FAIM2-rs7138803 polymorphism and obesity, blood pressure and heart rate in 7,161 participants (48.3% with type 2 diabetes) in the PREDIMED study at baseline. We also explored gene-diet interactions with adherence to the Mediterranean diet (MedDiet) and examined the effects of the polymorphism on cardiovascular disease incidence per diabetes status after a median 4.8-year dietary intervention (MedDiet versus control group) follow-up. We replicated the association between the FAIM2-rs7138803 polymorphism and greater obesity risk (OR: 1.08; 95% CI: 1.01-1.16; P = 0.011; per-A allele). Moreover, we detected novel associations of this polymorphism with higher diastolic blood pressure (DBP) and heart rate at baseline (B = 1.07; 95% CI: 0.97-1.28 bmp in AA vs G-carriers for the whole population), that remained statistically significant even after adjustment for body mass index (P = 0.012) and correction for multiple comparisons. This association was greater and statistically significant in type-2 diabetic subjects (B = 1.44: 95% CI: 0.23-2.56 bmp; P = 0.010 for AA versus G-carriers). Likewise, these findings were also observed longitudinally over 5-year follow-up. Nevertheless, we found no statistically significant gene-diet interactions with MedDiet for this trait. On analyzing myocardial infarction risk, we detected a nominally significant (P = 0.041) association in type-2 diabetic subjects (HR: 1.86; 95% CI:1.03-3.37 for AA versus G-carriers), although this association did not remain statistically significant following correction for multiple comparisons. We confirmed the FAIM2-rs7138803 relationship with obesity and identified novel and consistent associations with heart rate in particular in type 2 diabetic subjects. Furthermore, our results suggest a possible association of this polymorphism with higher myocardial infarction risk in type-2 diabetic subjects, although this result needs to be replicated as it could represent a false positive.

Chemical and physical controls on the transformation of amorphous calcium carbonate into crystalline CaCO3 polymorphs

NASA Astrophysics Data System (ADS)

Blue, C. R.; Giuffre, A.; Mergelsberg, S.; Han, N.; De Yoreo, J. J.; Dove, P. M.

2017-01-01

Calcite and other crystalline polymorphs of CaCO3 can form by pathways involving amorphous calcium carbonate (ACC). Apparent inconsistencies in the literature indicate the relationships between ACC composition, local conditions, and the subsequent crystalline polymorphs are not yet established. This experimental study quantifies the control of solution composition on the transformation of ACC into crystalline polymorphs in the presence of magnesium. Using a mixed flow reactor to control solution chemistry, ACC was synthesized with variable Mg contents by tuning input pH, Mg/Ca, and total carbonate concentration. ACC products were allowed to transform within the output suspension under stirred or quiescent conditions while characterizing the evolving solutions and solids. As the ACC transforms into a crystalline phase, the solutions record a polymorph-specific evolution of pH and Mg/Ca. The data provide a quantitative framework for predicting the initial polymorph that forms from ACC based upon the solution aMg2+/aCa2+ and aCO32-/aCa2+ and stirring versus quiescent conditions. This model reconciles discrepancies among previous studies that report on the nature of the polymorphs produced from ACC and supports the previous claim that monohydrocalcite may be an important, but overlooked, transient phase on the way to forming some aragonite and calcite deposits. By this construct, organic additives and extreme pH are not required to tune the composition and nature of the polymorph that forms. Our measurements show that the Mg content of ACC is recorded in the resulting calcite with a ≈1:1 dependence. By correlating composition of these calcite products with the Mgtot/Catot of the initial solutions, we find a ≈3:1 dependence that is approximately linear and general to whether calcite is formed via an ACC pathway or by the classical step-propagation process. Comparisons to calcite grown in synthetic seawater show a ≈1:1 dependence. The relationships suggest that the local Mg2+/Ca2+ at the time of precipitation determines the calcite composition, independent of whether growth occurs via an amorphous intermediate or classical pathway for a range of supersaturations and pH conditions. The findings reiterate the need to revisit the traditional picture of chemical and physical controls on CaCO3 polymorph selection. Mineralization by pathways involving ACC can lead to the formation of crystalline phases whose polymorphs and compositions are out of equilibrium with local growth media. As such, classical thermodynamic equilibria may not provide a reliable predictor of observed compositions.

Aromatase gene polymorphism does not influence clinical phenotype and response to oral contraceptive pills in polycystic ovary syndrome women.

PubMed

Maier, Polyana S; Spritzer, Poli Mara

2012-01-01

To assess whether a single nucleotide polymorphism (SNP50) of the aromatase gene (CYP19) is associated with polycystic ovary syndrome (PCOS) phenotypes and to investigate the influence of this polymorphism on the response of PCOS to treatment with oral contraceptive pills (OCP). 162 hirsute women were stratified into a classic PCOS group (hyperandrogenism, ovulatory dysfunction, c-PCOS) and an ovulatory PCOS group (hyperandrogenism, ovulatory cycles, polycystic ovaries, ov-PCOS). 51 women completed a 6-month OCP trial (20 µg ethinyl estradiol + 75 µg gestodene, 21/28 days per cycle, plus 100 mg spironolactone in 32 women with moderate to severe hirsutism). We considered the presence of the polymorphic allele A (AG+AA) in comparison to the absence of the polymorphism (GG) to express results and to perform the comparisons regarding clinical variables. Mean age was 23.3 ± 6.9 years. Hirsutism score was similar in c-PCOS and ov-PCOS (15 (11-20) vs. 13 (11-20)). The differences in hormone and metabolic variables between phenotypes were independent of the presence of allele A. In the OCP trial subsample, no differences were observed between genotypes after 6 months' treatment. The differences between c-PCOS and ov-PCOS cannot be explained by the genetic variation at SNP50 in the CYP19 gene. Copyright © 2012 S. Karger AG, Basel.

C-reactive protein (+1444C>T) polymorphism influences CRP response following a moderate inflammatory stimulus.

PubMed

D'Aiuto, Francesco; Casas, Juan P; Shah, Tina; Humphries, Steve E; Hingorani, Aroon D; Tonetti, Maurizio S

2005-04-01

Elevations in C-reactive protein (CRP) concentration are associated with an increased risk of future coronary events in prospective studies and it has been suggested that CRP could be used to aid risk prediction. A +1444C>T polymorphism in the CRP gene has been associated with differences in CRP concentration. We investigated the effect of this polymorphism on the CRP response to periodontal therapy, an intermediate inflammatory stimulus. Clinical parameters, CRP, and interleukin-6 (IL-6) concentrations were evaluated in 55 consecutive patients suffering from periodontitis at baseline, 1, 7 and 30 days after an intensive course of periodontal treatment. In a multivariate analysis individuals homozygous for the +1444T allele showed higher CRP concentrations (day 1, 21.10+/-4.81 mg/L and day 7, 4.89+/-0.74 mg/L) compared with C-allele carriers (day 1, 12.37+/-1.61 mg/L and day 7, 3.08+/-2.00 mg/L). This effect was independent of conventional cardiovascular risk factors and inflammatory factors known to affect CRP concentrations. CRP genotype may need to be considered when CRP values are used in coronary risk prediction.

Analysis of CYP3A4 genetic polymorphisms in Han Chinese.

PubMed

Zhou, Qing; Yu, Xiaomin; Shu, Chang; Cai, Yimei; Gong, Wei; Wang, Xumin; Wang, Duen-mei; Hu, Songnian

2011-06-01

Our study aimed to comprehensively investigate the genetic polymorphisms of CYP3A4 in Han Chinese. We sequenced the gene regions of CYP3A4, including its promoter, exons, surrounding introns and 3' untranslated region (3'UTR), from 100 unrelated-healthy Han Chinese individuals. We detected 11 SNPs, three of which are novel. According to in silico functional prediction of novel variants, 20148 A>G in exon 10, resulting in substitution of Tyr319 with Cys (CYP3A4*21), may induce dramatic alteration of protein conformation, and 26908 G>A in 3'UTR may disrupt post-transcriptional regulation. We identified five alleles in Han Chinese, the allele frequencies of CYP3A4*1, *5, *6, *18 and *21 are 97, 0.5, 1, 1 and 0.5%, respectively. Haplotype inference revealed 14 haplotypes, of which the major haplotype CYP3A4*1A constitutes 59% of the total chromosomes. We also examined the possible role of natural selection in shaping the variation of CYP3A4 and confirmed a trend, consistent with the action of positive selection. We systematically screened the genetic polymorphisms of CYP3A4 in Han Chinese, highlighted possible functional impairment of the novel allele and summarized the distinct allele and haplotype frequency distribution, with an emphasis on detecting the footprint of recent positive selection on the CYP3A4 gene in Han Chinese.

Using reweighting and free energy surface interpolation to predict solid-solid phase diagrams

NASA Astrophysics Data System (ADS)

Schieber, Natalie P.; Dybeck, Eric C.; Shirts, Michael R.

2018-04-01

Many physical properties of small organic molecules are dependent on the current crystal packing, or polymorph, of the material, including bioavailability of pharmaceuticals, optical properties of dyes, and charge transport properties of semiconductors. Predicting the most stable crystalline form at a given temperature and pressure requires determining the crystalline form with the lowest relative Gibbs free energy. Effective computational prediction of the most stable polymorph could save significant time and effort in the design of novel molecular crystalline solids or predict their behavior under new conditions. In this study, we introduce a new approach using multistate reweighting to address the problem of determining solid-solid phase diagrams and apply this approach to the phase diagram of solid benzene. For this approach, we perform sampling at a selection of temperature and pressure states in the region of interest. We use multistate reweighting methods to determine the reduced free energy differences between T and P states within a given polymorph and validate this phase diagram using several measures. The relative stability of the polymorphs at the sampled states can be successively interpolated from these points to create the phase diagram by combining these reduced free energy differences with a reference Gibbs free energy difference between polymorphs. The method also allows for straightforward estimation of uncertainties in the phase boundary. We also find that when properly implemented, multistate reweighting for phase diagram determination scales better with the size of the system than previously estimated.

Human cardiovascular disease IBC chip-wide association with weight loss and weight regain in the look AHEAD trial.

PubMed

McCaffery, Jeanne M; Papandonatos, George D; Huggins, Gordon S; Peter, Inga; Erar, Bahar; Kahn, Steven E; Knowler, William C; Lipkin, Edward W; Kitabchi, Abbas E; Wagenknecht, Lynne E; Wing, Rena R

2013-01-01

The present study identified genetic predictors of weight change during behavioral weight loss treatment. Participants were 3,899 overweight/obese individuals with type 2 diabetes from Look AHEAD, a randomized controlled trial to determine the effects of intensive lifestyle intervention (ILI), including weight loss and physical activity, relative to diabetes support and education, on cardiovascular outcomes. Analyses focused on associations of single nucleotide polymorphisms (SNPs) on the Illumina CARe iSelect (IBC) chip (minor allele frequency >5%; n = 31,959) with weight change at year 1 and year 4, and weight regain at year 4, among individuals who lost ≥ 3% at year 1. Two novel regions of significant chip-wide association with year-1 weight loss in ILI were identified (p < 2.96E-06). ABCB11 rs484066 was associated with 1.16 kg higher weight per minor allele at year 1, whereas TNFRSF11A, or RANK, rs17069904 was associated with 1.70 kg lower weight per allele at year 1. This study, the largest to date on genetic predictors of weight loss and regain, indicates that SNPs within ABCB11, related to bile salt transfer, and TNFRSF11A, implicated in adipose tissue physiology, predict the magnitude of weight loss during behavioral intervention. These results provide new insights into potential biological mechanisms and may ultimately inform weight loss treatment. © 2013 S. Karger AG, Basel.

Meta-Prediction of the Effect of Methylenetetrahydrofolate Reductase Polymorphisms and Air Pollution on Alzheimer's Disease Risk.

PubMed

Wu, Suh-Mian; Chen, Zhao-Feng; Young, Lufei; Shiao, S Pamela K

2017-01-11

Background : Alzheimer's disease (AD) is a significant public health issue. AD has been linked with methylenetetrahydrofolate reductase ( MTHFR ) C677T polymorphism, but the findings have been inconsistent. The purpose of this meta-predictive analysis is to examine the associations between MTHFR polymorphisms and epigenetic factors, including air pollution, with AD risk using big data analytics approaches. Methods and Results : Forty-three studies (44 groups) were identified by searching various databases. MTHFR C677T TT and CT genotypes had significant associations with AD risk in all racial populations (RR = 1.13, p = 0.0047; and RR = 1.12, p < 0.0001 respectively). Meta-predictive analysis showed significant increases of percentages of MTHFR C677T polymorphism with increased air pollution levels in both AD case group and control group ( p = 0.0021-0.0457); with higher percentages of TT and CT genotypes in the AD case group than that in the control group with increased air pollution levels. Conclusions : The impact of MTHFR C677T polymorphism on susceptibility to AD was modified by level of air pollution. Future studies are needed to further examine the effects of gene-environment interactions including air pollution on AD risk for world populations.

Meta-Prediction of the Effect of Methylenetetrahydrofolate Reductase Polymorphisms and Air Pollution on Alzheimer’s Disease Risk

PubMed Central

Wu, Suh-Mian; Chen, Zhao-Feng; Young, Lufei; Shiao, S. Pamela K.

2017-01-01

Background: Alzheimer’s disease (AD) is a significant public health issue. AD has been linked with methylenetetrahydrofolate reductase (MTHFR) C677T polymorphism, but the findings have been inconsistent. The purpose of this meta-predictive analysis is to examine the associations between MTHFR polymorphisms and epigenetic factors, including air pollution, with AD risk using big data analytics approaches. Methods and Results: Forty-three studies (44 groups) were identified by searching various databases. MTHFR C677T TT and CT genotypes had significant associations with AD risk in all racial populations (RR = 1.13, p = 0.0047; and RR = 1.12, p < 0.0001 respectively). Meta-predictive analysis showed significant increases of percentages of MTHFR C677T polymorphism with increased air pollution levels in both AD case group and control group (p = 0.0021–0.0457); with higher percentages of TT and CT genotypes in the AD case group than that in the control group with increased air pollution levels. Conclusions: The impact of MTHFR C677T polymorphism on susceptibility to AD was modified by level of air pollution. Future studies are needed to further examine the effects of gene-environment interactions including air pollution on AD risk for world populations. PMID:28085050

MAOA, MTHFR, and TNF-β genes polymorphisms and personality traits in the pathogenesis of migraine.

PubMed

Ishii, Masakazu; Shimizu, Shunichi; Sakairi, Yuki; Nagamine, Ayumu; Naito, Yuika; Hosaka, Yukiko; Naito, Yuko; Kurihara, Tatsuya; Onaya, Tomomi; Oyamada, Hideto; Imagawa, Atsuko; Shida, Kenji; Takahashi, Johji; Oguchi, Katsuji; Masuda, Yutaka; Hara, Hajime; Usami, Shino; Kiuchi, Yuji

2012-04-01

Migraine is a multifactorial disease with various factors, such as genetic polymorphisms and personality traits, but the contribution of those factors is not clear. To clarify the pathogenesis of migraine, the contributions of genetic polymorphisms and personality traits were simultaneously investigated using multivariate analysis. Ninety-one migraine patients and 119 non-headache healthy volunteers were enrolled. The 12 gene polymorphisms analysis and NEO-FFI personality test were performed. At first, the univariate analysis was performed to extract the contributing factors to pathogenesis of migraine. We then extracted the factors that independently contributed to the pathogenesis of migraine using multivariate stepwise logistic regression analysis. Using the multivariate analysis, three gene polymorphisms including monoamine oxidase A (MAOA) T941G, methylenetetrahydrofolate reductase (MTHFR) C677T, and tumor necrosis factor beta (TNF-β) G252Α, and the neuroticism and conscientiousness scores in NEO-FFI were selected as significant factors that independently contributed to the pathogenesis of migraine. Their odds ratios were 1.099 (per point of neuroticism score), 1.080 (per point of conscientiousness score), 2.272 (T and T/T or T/G vs G and G/G genotype of MAOA), 1.939 (C/T or T/T vs C/C genotype of MTHFR), and 2.748 (G/A or A/A vs G/G genotype of TNF-β), respectively. We suggested that multiple factors, such as gene polymorphisms and personality traits, contribute to the pathogenesis of migraine. The contribution of polymorphisms, such as MAOA T941G, MTHFR C677T, and TNF-β G252A, were more important than personality traits in the pathogenesis of migraine, a multifactorial disorder.

Catalog of MicroRNA Seed Polymorphisms in Vertebrates

PubMed Central

Calin, George Adrian; Horvat, Simon; Jiang, Zhihua; Dovc, Peter; Kunej, Tanja

2012-01-01

MicroRNAs (miRNAs) are a class of non-coding RNA that plays an important role in posttranscriptional regulation of mRNA. Evidence has shown that miRNA gene variability might interfere with its function resulting in phenotypic variation and disease susceptibility. A major role in miRNA target recognition is ascribed to complementarity with the miRNA seed region that can be affected by polymorphisms. In the present study, we developed an online tool for the detection of miRNA polymorphisms (miRNA SNiPer) in vertebrates (http://www.integratomics-time.com/miRNA-SNiPer) and generated a catalog of miRNA seed region polymorphisms (miR-seed-SNPs) consisting of 149 SNPs in six species. Although a majority of detected polymorphisms were due to point mutations, two consecutive nucleotide substitutions (double nucleotide polymorphisms, DNPs) were also identified in nine miRNAs. We determined that miR-SNPs are frequently located within the quantitative trait loci (QTL), chromosome fragile sites, and cancer susceptibility loci, indicating their potential role in the genetic control of various complex traits. To test this further, we performed an association analysis between the mmu-miR-717 seed SNP rs30372501, which is polymorphic in a large number of standard inbred strains, and all phenotypic traits in these strains deposited in the Mouse Phenome Database. Analysis showed a significant association between the mmu-miR-717 seed SNP and a diverse array of traits including behavior, blood-clinical chemistry, body weight size and growth, and immune system suggesting that seed SNPs can indeed have major pleiotropic effects. The bioinformatics analyses, data and tools developed in the present study can serve researchers as a starting point in testing more targeted hypotheses and designing experiments using optimal species or strains for further mechanistic studies. PMID:22303453

Powder diffraction and crystal structure prediction identify four new coumarin polymorphs

DOE Office of Scientific and Technical Information (OSTI.GOV)

Shtukenberg, Alexander G.; Zhu, Qiang; Carter, Damien J.

Coumarin, a simple, commodity chemical isolated from beans in 1820, has, to date, only yielded one solid state structure. Here, we report a rich polymorphism of coumarin grown from the melt. Four new metastable forms were identified and their crystal structures were solved using a combination of computational crystal structure prediction algorithms and X-ray powder diffraction. With five crystal structures, coumarin has become one of the few rigid molecules showing extensive polymorphism at ambient conditions. We demonstrate the crucial role of advanced electronic structure calculations including many-body dispersion effects for accurate ranking of the stability of coumarin polymorphs and themore » need to account for anharmonic vibrational contributions to their free energy. As such, coumarin is a model system for studying weak intermolecular interactions, crystallization mechanisms, and kinetic effects.« less

Powder diffraction and crystal structure prediction identify four new coumarin polymorphs

DOE PAGES

Shtukenberg, Alexander G.; Zhu, Qiang; Carter, Damien J.; ...

2017-05-15

Coumarin, a simple, commodity chemical isolated from beans in 1820, has, to date, only yielded one solid state structure. Here, we report a rich polymorphism of coumarin grown from the melt. Four new metastable forms were identified and their crystal structures were solved using a combination of computational crystal structure prediction algorithms and X-ray powder diffraction. With five crystal structures, coumarin has become one of the few rigid molecules showing extensive polymorphism at ambient conditions. We demonstrate the crucial role of advanced electronic structure calculations including many-body dispersion effects for accurate ranking of the stability of coumarin polymorphs and themore » need to account for anharmonic vibrational contributions to their free energy. As such, coumarin is a model system for studying weak intermolecular interactions, crystallization mechanisms, and kinetic effects.« less

The TNF-α -308 polymorphism may affect the severity of Crohn's disease

PubMed Central

Santana, Genoile; Bendicho, Maria Teresita; Santana, Tamara Celi; dos Reis, Lidiane Bianca; Lemaire, Denise; Lyra, André Castro

2011-01-01

OBJECTIVE: The goal of this project was to analyze the association between Crohn's disease, its clinical features, and the tumor necrosis factor alpha (TNF-α) -308 polymorphism. METHODS: This is a case-control and cross-sectional study that enrolled 91 patients with Crohn's disease and 91 controls. Patients with Crohn's disease were characterized according to the Montreal Classification, along with their clinical and surgical treatment history. Analysis of the TNF-α -308 polymorphism was performed using a commercial kit. A stratified analysis was applied using an OR (odds ratio) with a 95% confidence interval. The chi-square and Fisher's exact tests were utilized for analysis of the association between the polymorphism and the clinical features of Crohn's disease. RESULTS: The low producer predicted phenotype was present in 76.9% of Crohn's disease cases and 75.8% of controls (OR 0.94 [0.45-1.97]). The TNF2 allele and the high producer predicted phenotype were more frequent among patients with Crohn's disease penetrating behavior (p = 0.004). The TNF2 allele and the high producer predicted phenotype were also associated with a history of colectomy (p = 0.02), and the TNF2 allele was associated with small bowel resection (p = 0.03). CONCLUSIONS: The TNF-α -308 polymorphism appears to affect the severity of the disease. However, TNF-α -308 polymorphism does not appear to be important for the susceptibility in the development of Crohn's disease. PMID:21915486

Circadian-relevant genes are highly polymorphic in autism spectrum disorder patients.

PubMed

Yang, Zhiliang; Matsumoto, Ayumi; Nakayama, Kazuhiro; Jimbo, Eriko F; Kojima, Karin; Nagata, Koh-ichi; Iwamoto, Sadahiko; Yamagata, Takanori

2016-01-01

The genetic background of autism spectrum disorder (ASD) is considered a multi-genetic disorder with high heritability. Autistic children present with a higher prevalence of sleep disorders than has been observed in children with normal development. Some circadian-relevant genes have been associated with ASD (e.g., PER1, PER2, NPAS2, MTNR1A, and MTNR1B). We analyzed 28 ASD patients (14 with sleep disorders and 14 without) and 23 control subjects of Japanese descent. The coding regions of 18 canonical clock genes and clock-controlled genes were sequenced. Detected mutations were verified by direct sequencing analysis, and additional control individuals were screened. Thirty-six base changes with amino acid changes were detected in 11 genes. Six missense changes were detected only in individuals with ASD with sleep disturbance: p.F498S in TIMELESS, p.S20R in NR1D1, p.R493C in PER3, p.H542R in CLOCK, p.L473S in ARNTL2, and p.A325V in MTNR1B. Six missense changes were detected only in individuals with ASD without sleep disturbance: p.S1241N in PER1, p.A325T in TIMELESS, p.S13T in ARNTL, p.G24E in MTNR1B, p.G24E in PER2, and p.T1177A in PER3. The p.R493C mutation in PER3 was detected in both groups. One missense change, p.P932L in PER2, was detected only in the control group. Mutations in NR1D1, CLOCK, and ARNTL2 were detected only in individuals with ASD with sleep disorder. The prevalence of the mutations detected only single time differed significantly among all ASD patients and controls (p=0.003). Two kinds of mutations detected only in individuals with ASD with sleep disorder, p.F498S in TIMELESS and p.R366Q in PER3, were considered to affect gene function by three different methods: PolyPhen-2, scale-invariant feature transform (SIFT) prediction, and Mutation Taster (www.mutationtaster.org). The mutations p.S20R in NR1D1, p.H542R in CLOCK, p.L473S in ARNTL2, p.A325T in TIMELESS, p.S13T in ARNTL, and p.G24E in PER2 were diagnosed to negatively affect gene function by more than one of these methods. Mutations in circadian-relevant genes affecting gene function are more frequent in patients with ASD than in controls. Circadian-relevant genes may be involved in the psychopathology of ASD. Copyright © 2015 The Japanese Society of Child Neurology. Published by Elsevier B.V. All rights reserved.

Inflammatory gene polymorphisms and risk of postoperative myocardial infarction after cardiac surgery.

PubMed

Podgoreanu, M V; White, W D; Morris, R W; Mathew, J P; Stafford-Smith, M; Welsby, I J; Grocott, H P; Milano, C A; Newman, M F; Schwinn, D A

2006-07-04

The inflammatory response triggered by cardiac surgery with cardiopulmonary bypass (CPB) is a primary mechanism in the pathogenesis of postoperative myocardial infarction (PMI), a multifactorial disorder with significant inter-patient variability poorly predicted by clinical and procedural factors. We tested the hypothesis that candidate gene polymorphisms in inflammatory pathways contribute to risk of PMI after cardiac surgery. We genotyped 48 polymorphisms from 23 candidate genes in a prospective cohort of 434 patients undergoing elective cardiac surgery with CPB. PMI was defined as creatine kinase-MB isoenzyme level > or = 10x upper limit of normal at 24 hours postoperatively. A 2-step analysis strategy was used: marker selection, followed by model building. To minimize false-positive associations, we adjusted for multiple testing by permutation analysis, Bonferroni correction, and controlling the false discovery rate; 52 patients (12%) experienced PMI. After adjusting for multiple comparisons and clinical risk factors, 3 polymorphisms were found to be independent predictors of PMI (adjusted P<0.05; false discovery rate <10%). These gene variants encode the proinflammatory cytokine interleukin 6 (IL6 -572G>C; odds ratio [OR], 2.47), and 2 adhesion molecules: intercellular adhesion molecule-1 (ICAM1 Lys469Glu; OR, 1.88), and E-selectin (SELE 98G>T; OR, 0.16). The inclusion of genotypic information from these polymorphisms improved prediction models for PMI based on traditional risk factors alone (C-statistic 0.764 versus 0.703). Functional genetic variants in cytokine and leukocyte-endothelial interaction pathways are independently associated with severity of myonecrosis after cardiac surgery. This may aid in preoperative identification of high-risk cardiac surgical patients and development of novel cardioprotective strategies.

Microsatellite primers for vulnerable seagrass Halophila beccarii (Hydrocharitaceae).

PubMed

Jiang, Kai; Shi, Yi-Su; Zhang, Jian; Xu, Na-Na

2011-06-01

Polymorphic microsatellite primers were developed in the vulnerable seagrass Halophila beccarii to investigate genetic variation and provide necessary markers for studying its population genetic structure. Six polymorphic and six monomorphic microsatellite loci were developed in H. beccarii. Most loci were successfully amplified across 40 H. beccarii individuals collected from three populations from coastal regions of southern China. Two to four alleles per locus were observed at the six polymorphic loci. The highest expected heterozygosity was 0.5737. The results demonstrate low levels of polymorphism in H. beccarii from coastal regions of southern China. They also illustrate that these primers may be useful for studying the mating system and population genetics of H. beccarii on a global scale.

Characterization of polymorphic microsatellites for the invasive grass Microstegium vimineum (Poaceae).

PubMed

Novy, Ari; Flory, S Luke; Honig, Joshua A; Bonos, Stacy; Hartman, Jean Marie

2012-02-01

Microsatellite markers were developed for the invasive plant Microstegium vimineum (Poaceae) to assess its population structure and to facilitate tracking of invasion expansion. Using 454 sequencing, 11 polymorphic and six monomorphic microsatellite primer sets were developed for M. vimineum. The primer sets were tested on individuals sampled from six populations in the United States and China. The polymorphic primers amplified di-, tri-, and tetranucleotide repeats with three to 10 alleles per locus. These markers will be useful for a variety of applications including tracking of invasion dynamics and population genetics studies.

Prediction for Intravenous Immunoglobulin Resistance by Using Weighted Genetic Risk Score Identified From Genome-Wide Association Study in Kawasaki Disease.

PubMed

Kuo, Ho-Chang; Wong, Henry Sung-Ching; Chang, Wei-Pin; Chen, Ben-Kuen; Wu, Mei-Shin; Yang, Kuender D; Hsieh, Kai-Sheng; Hsu, Yu-Wen; Liu, Shih-Feng; Liu, Xiao; Chang, Wei-Chiao

2017-10-01

Intravenous immunoglobulin (IVIG) is the treatment of choice in Kawasaki disease (KD). IVIG is used to prevent cardiovascular complications related to KD. However, a proportion of KD patients have persistent fever after IVIG treatment and are defined as IVIG resistant. To develop a risk scoring system based on genetic markers to predict IVIG responsiveness in KD patients, a total of 150 KD patients (126 IVIG responders and 24 IVIG nonresponders) were recruited for this study. A genome-wide association analysis was performed to compare the 2 groups and identified risk alleles for IVIG resistance. A weighted genetic risk score was calculated by the natural log of the odds ratio multiplied by the number of risk alleles. Eleven single-nucleotide polymorphisms were identified by genome-wide association study. The KD patients were categorized into 3 groups based on their calculated weighted genetic risk score. Results indicated a significant association between weighted genetic risk score (groups 3 and 4 versus group 1) and the response to IVIG (Fisher's exact P value 4.518×10 - 03 and 8.224×10 - 10 , respectively). This is the first weighted genetic risk score study based on a genome-wide association study in KD. The predictive model integrated the additive effects of all 11 single-nucleotide polymorphisms to provide a prediction of the responsiveness to IVIG. © 2017 The Authors.

Gene Polymorphisms in the CCL5/CCR5 Pathway as a Genetic Biomarker for Outcome and Hand-Foot Skin Reaction in Metastatic Colorectal Cancer Patients Treated With Regorafenib.

PubMed

Suenaga, Mitsukuni; Schirripa, Marta; Cao, Shu; Zhang, Wu; Yang, Dongyun; Ning, Yan; Cremolini, Chiara; Antoniotti, Carlotta; Borelli, Beatrice; Mashima, Tetsuo; Okazaki, Satoshi; Berger, Martin D; Miyamoto, Yuji; Gopez, Roel; Barzi, Afsaneh; Lonardi, Sara; Yamaguchi, Toshiharu; Falcone, Alfredo; Loupakis, Fotios; Lenz, Heinz-Josef

2018-06-01

The C-C motif chemokine ligand 5/C-C motif chemokine receptor 5 (CCL5/CCR5) pathway has been shown to induce endothelial progenitor cell migration, resulting in increased vascular endothelial growth factor A expression. We hypothesized that genetic polymorphisms in the CCL5/CCR5 pathway predict efficacy and toxicity in patients with metastatic colorectal cancer (mCRC) treated with regorafenib. We analyzed genomic DNA extracted from 229 tumor samples from 2 different cohorts of patients who received regorafenib: an evaluation cohort of 79 Japanese patients and a validation cohort of 150 Italian patients. Single nucleotide polymorphisms of CCL5/CCR5 pathway-related genes were analyzed by PCR-based direct sequencing. CCL4 rs1634517 and CCL3 rs1130371 were associated with progression-free survival in the evaluation cohort (hazard ratio [HR] 1.54, P = .043; HR 1.48, P = .064), and progression-free survival (HR 1.74, P < .001; HR 1.66, P = .002) and overall survival (HR 1.65, P = .004; HR 1.65, P = .004) in the validation cohort. The allelic frequencies of CCL5 single nucleotide polymorphisms varied between the evaluation and validation cohorts (G/G variant in rs2280789, 21.5% vs. 1.3%, P < .001; T/T variant in rs3817655, 22.8% vs. 2.7%, P < .001). In the evaluation cohort, patients with the G/G variant in rs2280789 had a higher incidence of grade 3+ hand-foot skin reaction compared to any A allele (53% vs. 27%, P = .078), and similarly to the T/T variant in rs3817655 compared to any A allele (56% vs. 26%, P = .026). Genetic variants in the CCL5/CCR5 pathway may serve as prognostic markers and may predict severe hand-foot skin reaction in mCRC patients receiving regorafenib therapy. Copyright © 2018 Elsevier Inc. All rights reserved.

Developing and Evaluating the HRM Technique for Identifying Cytochrome P450 2D6 Polymorphisms.

PubMed

Lu, Hsiu-Chin; Chang, Ya-Sian; Chang, Chun-Chi; Lin, Ching-Hsiung; Chang, Jan-Gowth

2015-05-01

Cytochrome P450 2D6 is one of the important enzymes involved in the metabolism of many widely used drugs. Genetic polymorphisms of CYP2D6 can affect its activity. Therefore, an efficient method for identifying CYP2D6 polymorphisms is clinically important. We developed a high-resolution melting (HRM) analysis to investigate CYP2D6 polymorphisms. Genomic DNA was extracted from peripheral blood samples from 71 healthy individuals. All nine exons of the CYP2D6 gene were sequenced before screening by HRM analysis. This method can detect the most genotypes (*1, *2, *4, *10, *14, *21 *39, and *41) of CYP2D6 in Chinese. All samples were successfully genotyped. The four most common mutant CYP2D6 alleles (*1, *2, *10, and *41) can be genotyped. The single nucleotides polymorphism (SNP) frequencies of 100C > T (rs1065852), 1039C > T (rs1081003), 1661G > C (rs1058164), 2663G > A (rs28371722), 2850C > T (rs16947), 2988G > A (rs28371725), 3181A > G, and 4180G > C (rs1135840) were 58%, 61%, 73%, 1%, 13%, 3%, 1%, 73%, respectively. We identified 100% of all heterozygotes without any errors. The two homozygous genotypes (1661G > C and 4180G > C) can be distinguished by mixing with a known genotype sample to generate an artificial heterozygote for HRM analysis. Therefore, all samples could be identified using our HRM method, and the results of HRM analysis are identical to those obtained by sequencing. Our method achieved 100% sensitivity, specificity, positive prediction value and negative prediction value. HRM analysis is a nongel resolution method that is faster and less expensive than direct sequencing. Our study shows that it is an efficient tool for typing CYP2D6 polymorphisms. © 2014 Wiley Periodicals, Inc.

Whole-genome scan to detect quantitative trait loci associated with milk protein composition in 3 French dairy cattle breeds.

PubMed

Sanchez, M P; Govignon-Gion, A; Ferrand, M; Gelé, M; Pourchet, D; Amigues, Y; Fritz, S; Boussaha, M; Capitan, A; Rocha, D; Miranda, G; Martin, P; Brochard, M; Boichard, D

2016-10-01

In the context of the PhénoFinLait project, a genome-wide analysis was performed to detect quantitative trait loci (QTL) that affect milk protein composition estimated using mid-infrared spectrometry in the Montbéliarde (MO), Normande (NO), and Holstein (HO) French dairy cattle breeds. The 6 main milk proteins (α-lactalbumin, β-lactoglobulin, and αS1-, αS2-, β-, and κ-caseins) expressed as grams per 100g of milk (% of milk) or as grams per 100g of protein (% of protein) were estimated in 848,068 test-day milk samples from 156,660 cows. Genotyping was performed for 2,773 MO, 2,673 NO, and 2,208 HO cows using the Illumina BovineSNP50 BeadChip (Illumina Inc., San Diego, CA). Individual test-day records were adjusted for environmental effects and then averaged per cow to define the phenotypes analyzed. Quantitative trait loci detection was performed within each breed using a linkage disequilibrium and linkage analysis approach. A total of 39 genomic regions distributed on 20 of the 29 Bos taurus autosomes (BTA) were significantly associated with milk protein composition at a genome-wide level of significance in at least 1 of the 3 breeds. The 9 most significant QTL were located on BTA2 (133 Mbp), BTA6 (38, 47, and 87 Mbp), BTA11 (103 Mbp), BTA14 (1.8 Mbp), BTA20 (32 and 58 Mbp), and BTA29 (8 Mbp). The BTA6 (87 Mbp), BTA11, and BTA20 (58 Mbp) QTL were found in all 3 breeds, and they had highly significant effects on κ-casein, β-lactoglobulin, and α-lactalbumin, expressed as a percentage of protein, respectively. Each of these QTL explained between 13% (BTA14) and 51% (BTA11) of the genetic variance of the trait. Many other QTL regions were also identified in at least one breed. They were located on 14 additional chromosomes (1, 3, 4, 5, 7, 15, 17, 19, 21, 22, 24, 25, 26, and 27), and they explained 2 to 8% of the genetic variance of 1 or more protein composition traits. Concordance analyses, performed between QTL status and sequence-derived polymorphisms from 13 bulls, revealed previously known causal polymorphisms in LGB (BTA11) and GHR (BTA20 at 32 Mbp) and excluded some other previously described mutations. These results constitute a first step in identifying causal mutations and using routinely collected mid-infrared predictions in future genomic selection programs to improve bovine milk protein composition. Copyright © 2016 American Dairy Science Association. Published by Elsevier Inc. All rights reserved.

Association of the glucocorticoid receptor gene polymorphisms and their interaction with stressful life events in Polish adolescent girls with anorexia nervosa.

PubMed

Dmitrzak-Weglarz, Monika; Szczepankiewicz, Aleksandra; Slopien, Agnieszka; Tyszkiewicz, Marta; Maciukiewicz, Malgorzata; Zaremba, Dorota; Twarowska-Hauser, Joanna

2016-03-01

Disturbances in stress response mechanisms and hypothalamic-pituitary-adrenal axis (HPA) functioning are considered important factors involved in the pathophysiology of anorexia nervosa (AN). Thus, genetic variations in the end effector of HPA - glucocorticoid receptor gene and relationships to stressful life events (SLE) may be connected to a higher risk of illness. The aim of the study was examining the association between glucocorticoid receptor gene (NR3C1) polymorphisms and risk factors among stressful life events in AN patients. This study comprised 256 patients with AN and 167 control subjects. The questionnaires examining brief history of the mother's pregnancy and long-acting stress factors, as well as life events checklist to assess stressful life events during the 6 months prior to hospitalization were used. The eight common SNPs (rs6198, rs6191, rs6196, rs258813, rs33388, rs41423247, rs56149945 and rs10052957) of NR3C1 gene were genotyped. The association of five polymorphisms (rs6191, rs258813, rs33388, rs41423247 and rs10052957) and one complex allele (TCAGT) of NR3C1 gene with increased risk of AN were found. However, no significant correlations between early, long-acting and predicting hospitalization SLE and any of the analyzed polymorphisms were observed. The results confirm that the NR3C1 gene is associated with AN risk regardless of the type of stressful triggering factors.

Coarse-grained modeling of crystal growth and polymorphism of a model pharmaceutical molecule.

PubMed

Mandal, Taraknath; Marson, Ryan L; Larson, Ronald G

2016-10-04

We describe a systematic coarse-graining method to study crystallization and predict possible polymorphs of small organic molecules. In this method, a coarse-grained (CG) force field is obtained by inverse-Boltzmann iteration from the radial distribution function of atomistic simulations of the known crystal. With the force field obtained by this method, we show that CG simulations of the drug phenytoin predict growth of a crystalline slab from a melt of phenytoin, allowing determination of the fastest-growing surface, as well as giving the correct lattice parameters and crystal morphology. By applying meta-dynamics to the coarse-grained model, a new crystalline form of phenytoin (monoclinic, space group P2 1 ) was predicted which is different from the experimentally known crystal structure (orthorhombic, space group Pna2 1 ). Atomistic simulations and quantum calculations then showed the polymorph to be meta-stable at ambient temperature and pressure, and thermodynamically more stable than the conventional orthorhombic crystal at high pressure. The results suggest an efficient route to study crystal growth of small organic molecules that could also be useful for identification of possible polymorphs as well.

SMAD3 rs17228212 Gene Polymorphism Is Associated with Reduced Risk to Cerebrovascular Accidents and Subclinical Atherosclerosis in Anti-CCP Negative Spanish Rheumatoid Arthritis Patients

PubMed Central

Genre, Fernanda; Castañeda, Santos; González-Juanatey, Carlos; Llorca, Javier; Corrales, Alfonso; Miranda-Filloy, José A.; Rueda-Gotor, Javier; Gómez-Vaquero, Carmen; Rodríguez-Rodríguez, Luis; Fernández-Gutiérrez, Benjamín; Pascual-Salcedo, Dora; Balsa, Alejandro; López-Longo, Francisco J.; Carreira, Patricia; Blanco, Ricardo; González-Álvaro, Isidoro; Martín, Javier; González-Gay, Miguel A.

2013-01-01

Rheumatoid arthritis (RA) is a complex polygenic inflammatory disease associated with accelerated atherosclerosis and increased risk of cardiovascular (CV) disease. Previous genome-wide association studies have described SMAD3 rs17228212 polymorphism as an important signal associated with CV events. The aim of the present study was to evaluate for the first time the relationship between this gene polymorphism and the susceptibility to CV manifestations and its potential association with the presence of subclinical atherosclerosis assessed by the evaluation of carotid intima-media thickness (cIMT) in patients with RA. Methods One thousand eight hundred and ninety-seven patients fulfilling classification criteria for RA were genotyped for SMAD3 rs17228212 gene polymorphism through TaqMan genotyping assay. Also, subclinical atherosclerosis determined by the assessment of cIMT was analyzed in a subgroup of these patients by carotid ultrasonography. Results No statistically significant differences were observed when allele frequencies of RA patients with or without CV events were compared. Nevertheless, when RA patients were stratified according to anti-cyclic citrullinated peptide (anti-CCP) status, we found that in RA patients who were negative for anti-CCP antibodies, the presence of C allele of SMAD3 rs17228212 polymorphism conferred a protective effect against the risk of cerebrovascular accident (CVA) after adjustment for demographic and classic CV risk factors (HR [95%CI]=0.36 [0.14–0.94], p=0.038) in a Cox regression model. Additionally, correlation between the presence of C allele of SMAD3 rs17228212 polymorphism and lower values of cIMT was found after adjustment for demographic and classic CV risk factors (p-value=0.0094) in the anti-CCP negative RA patients. Conclusions Our results revealed that SMAD3 rs17228212 gene variant is associated with lower risk of CVA and less severe subclinical atherosclerosis in RA patients negative for anti-CCP antibodies. These findings may have importance to establish predictive models of CV disease in RA patients according to anti-CCP status. PMID:24204921

SMAD3 rs17228212 gene polymorphism is associated with reduced risk to cerebrovascular accidents and subclinical atherosclerosis in anti-CCP negative Spanish rheumatoid arthritis patients.

PubMed

García-Bermúdez, Mercedes; López-Mejías, Raquel; Genre, Fernanda; Castañeda, Santos; González-Juanatey, Carlos; Llorca, Javier; Corrales, Alfonso; Miranda-Filloy, José A; Rueda-Gotor, Javier; Gómez-Vaquero, Carmen; Rodríguez-Rodríguez, Luis; Fernández-Gutiérrez, Benjamín; Pascual-Salcedo, Dora; Balsa, Alejandro; López-Longo, Francisco J; Carreira, Patricia; Blanco, Ricardo; González-Álvaro, Isidoro; Martín, Javier; González-Gay, Miguel A

2013-01-01

Rheumatoid arthritis (RA) is a complex polygenic inflammatory disease associated with accelerated atherosclerosis and increased risk of cardiovascular (CV) disease. Previous genome-wide association studies have described SMAD3 rs17228212 polymorphism as an important signal associated with CV events. The aim of the present study was to evaluate for the first time the relationship between this gene polymorphism and the susceptibility to CV manifestations and its potential association with the presence of subclinical atherosclerosis assessed by the evaluation of carotid intima-media thickness (cIMT) in patients with RA. One thousand eight hundred and ninety-seven patients fulfilling classification criteria for RA were genotyped for SMAD3 rs17228212 gene polymorphism through TaqMan genotyping assay. Also, subclinical atherosclerosis determined by the assessment of cIMT was analyzed in a subgroup of these patients by carotid ultrasonography. No statistically significant differences were observed when allele frequencies of RA patients with or without CV events were compared. Nevertheless, when RA patients were stratified according to anti-cyclic citrullinated peptide (anti-CCP) status, we found that in RA patients who were negative for anti-CCP antibodies, the presence of C allele of SMAD3 rs17228212 polymorphism conferred a protective effect against the risk of cerebrovascular accident (CVA) after adjustment for demographic and classic CV risk factors (HR [95%CI]=0.36 [0.14-0.94], p=0.038) in a Cox regression model. Additionally, correlation between the presence of C allele of SMAD3 rs17228212 polymorphism and lower values of cIMT was found after adjustment for demographic and classic CV risk factors (p-value=0.0094) in the anti-CCP negative RA patients. Our results revealed that SMAD3 rs17228212 gene variant is associated with lower risk of CVA and less severe subclinical atherosclerosis in RA patients negative for anti-CCP antibodies. These findings may have importance to establish predictive models of CV disease in RA patients according to anti-CCP status.

Artificial neural network model for predicting the bioavailability of tacrolimus in patients with renal transplantation

PubMed Central

Thishya, Kalluri; Vattam, Kiran Kumar; Naushad, Shaik Mohammad; Raju, Shree Bhushan

2018-01-01

The objective of the current study was to explore the role of ABCB1 and CYP3A5 genetic polymorphisms in predicting the bioavailability of tacrolimus and the risk for post-transplant diabetes. Artificial neural network (ANN) and logistic regression (LR) models were used to predict the bioavailability of tacrolimus and risk for post-transplant diabetes, respectively. The five-fold cross-validation of ANN model showed good correlation with the experimental data of bioavailability (r2 = 0.93–0.96). Younger age, male gender, optimal body mass index were shown to exhibit lower bioavailability of tacrolimus. ABCB1 1236 C>T and 2677G>T/A showed inverse association while CYP3A5*3 showed a positive association with the bioavailability of tacrolimus. Gender bias was observed in the association with ABCB1 3435 C>T polymorphism. CYP3A5*3 was shown to interact synergistically in increasing the bioavailability in combination with ABCB1 1236 TT or 2677GG genotypes. LR model showed an independent association of ABCB1 2677 G>T/A with post transplant diabetes (OR: 4.83, 95% CI: 1.22–19.03). Multifactor dimensionality reduction analysis (MDR) revealed that synergistic interactions between CYP3A5*3 and ABCB1 2677 G>T/A as the determinants of risk for post-transplant diabetes. To conclude, the ANN and MDR models explore both individual and synergistic effects of variables in modulating the bioavailability of tacrolimus and risk for post-transplant diabetes. PMID:29621269

Isolation and characterization of microsatellite loci in the whale shark (Rhincodon typus)

USGS Publications Warehouse

Ramirez-Macias, D.; Shaw, K.; Ward, R.; Galvan-Magana, F.; Vazquez-Juarez, R.

2009-01-01

In preparation for a study on population structure of the whale shark (Rhincodon typus), nine species-specific polymorphic microsatellite DNA markers were developed. An initial screening of 50 individuals from Holbox Island, Mexico found all nine loci to be polymorphic, with two to 17 alleles observed per locus. Observed and expected heterozygosity per locus ranged from 0.200 to 0.826 and from 0.213 to 0.857, respectively. Neither statistically significant deviations from Hardy–Weinberg expectations nor statistically significant linkage disequilibrium between loci were observed. These microsatellite loci appear suitable for examining population structure, kinship assessment and other applications.

Genetic models of homosexuality: generating testable predictions

PubMed Central

Gavrilets, Sergey; Rice, William R

2006-01-01

Homosexuality is a common occurrence in humans and other species, yet its genetic and evolutionary basis is poorly understood. Here, we formulate and study a series of simple mathematical models for the purpose of predicting empirical patterns that can be used to determine the form of selection that leads to polymorphism of genes influencing homosexuality. Specifically, we develop theory to make contrasting predictions about the genetic characteristics of genes influencing homosexuality including: (i) chromosomal location, (ii) dominance among segregating alleles and (iii) effect sizes that distinguish between the two major models for their polymorphism: the overdominance and sexual antagonism models. We conclude that the measurement of the genetic characteristics of quantitative trait loci (QTLs) found in genomic screens for genes influencing homosexuality can be highly informative in resolving the form of natural selection maintaining their polymorphism. PMID:17015344

Allelic association of a dopamine transporter gene polymorphism with antisocial behaviour in heroin-dependent patients.

PubMed

Gerra, Gilberto; Garofano, Luciano; Pellegrini, Caterina; Bosari, Silvano; Zaimovic, Amir; Moi, Gabriele; Avanzini, Paola; Talarico, Enrica; Gardini, Federica; Donnini, Claudia

2005-09-01

Polymorphism of a variable number of tandem repeats (VNTR) in the 3' untranslated region of exon 15 of the SLC6A3 gene, coding for the dopamine transporter (DAT), was analysed to test whether length variation contributes to differences in the individual susceptibility to aggressive - criminal behaviour and liability to heroin dependence. The repeat number of the DAT polymorphism was assessed in 125 healthy subjects and 104 heroin-dependent subjects (including 52 addicted individuals with violent behaviour and criminal records). There was no significant difference in the frequencies of genotypes and alleles between heroin-dependent subjects and control subjects. On the contrary, there was a significant difference between offenders and non-offenders, p = 0.004 and p = 0.002, respectively, among heroin-dependent subjects. No association was found between DAT polymorphism and history of suicide. Buss - Durkee Hostility Inventory (BDHI) mean total scores were significantly higher in heroin addicts than in controls (p < 0.001) and in antisocial - violent heroin addicts in comparison with addicted individuals without antisocial behaviour (p < 0.005). The regression analysis of BDHI subscales, performed to provide an estimate of the magnitude of any potential effect on the risk of aggressiveness associated with the variants in DAT VNTR, showed that the presence of the 9 - 9 genotype significantly increases the risk of irritability and direct aggressiveness more than six and 10 times with respect to the 9 - 10 genotype. Our findings suggest that the 9-repeat allele of the DAT polymorphism confers increased susceptibility to antisocial - violent behaviour and aggressiveness, rather than drug dependence per se in heroin-dependent males.

Meta-prediction of MTHFR gene polymorphism-mutations, air pollution, and risks of leukemia among world populations.

PubMed

Lien, Shin-Yu A; Young, Lufei; Gau, Bih-Shya; K Shiao, S Pamela

2017-01-17

The major objective of this study was to examine the association between Methylenetetrahydrofolate Reductase (MTHFR) polymorphisms and the risk of various types of leukemias across the lifespans of children and adults by using the meta-predictive techniques. The secondary objective was to examine the interactions among epigenetic risk factors (including air pollution), MTHFR polymorphisms, and the risks of developing leukemia. We completed a comprehensive search of 6 databases to find 54 studies (10,033 leukemia cases and 15,835 controls) for MTHFR 677, and 43 studies (8,868 cases and 14,301 controls) for MTHFR 1298, published from 1999 to 2014. The results revealed that, in European populations; childhood populations; children from Europe, East Asia, and America; and children with acute lymphocytic leukemia (ALL), MTHFR 677 polymorphisms (both TT and CT types together and individually) are protective, while CC wildtype was leukemogenic. In addition, MTHFR 1298 polymorphisms were protective against ALL and acute myeloid leukemia in European children, and in chronic myeloid leukemia in all adults worldwide and American adults. Air pollution played a role in the increased polymorphisms of MTHFR 677 genotypes in childhood leukemia.

Meta-prediction of MTHFR gene polymorphism-mutations, air pollution, and risks of leukemia among world populations

PubMed Central

Lien, Shin-Yu A.; Young, Lufei; Gau, Bih-Shya; Shiao, S. Pamela K.

2017-01-01

The major objective of this study was to examine the association between Methylenetetrahydrofolate Reductase (MTHFR) polymorphisms and the risk of various types of leukemias across the lifespans of children and adults by using the meta-predictive techniques. The secondary objective was to examine the interactions among epigenetic risk factors (including air pollution), MTHFR polymorphisms, and the risks of developing leukemia. We completed a comprehensive search of 6 databases to find 54 studies (10,033 leukemia cases and 15,835 controls) for MTHFR 677, and 43 studies (8,868 cases and 14,301 controls) for MTHFR 1298, published from 1999 to 2014. The results revealed that, in European populations; childhood populations; children from Europe, East Asia, and America; and children with acute lymphocytic leukemia (ALL), MTHFR 677 polymorphisms (both TT and CT types together and individually) are protective, while CC wildtype was leukemogenic. In addition, MTHFR 1298 polymorphisms were protective against ALL and acute myeloid leukemia in European children, and in chronic myeloid leukemia in all adults worldwide and American adults. Air pollution played a role in the increased polymorphisms of MTHFR 677 genotypes in childhood leukemia. PMID:27966457

Polymorphic DNA microsatellite markers for forensic individual identification and parentage analyses of seven threatened species of parrots (family Psittacidae)

PubMed Central

Jan, Catherine

2016-01-01

The parrot family represents one of the bird group with the largest number of endangered species, as a result of habitat destruction and illegal trade. This illicit traffic involves the smuggling of eggs and animals, and the laundering through captive breeding facilities of wild-caught animals. Despite the huge potential of wildlife DNA forensics to determine with conclusive evidence illegal trade, current usage of DNA profiling approaches in parrots has been limited by the lack of suitable molecular markers specifically developed for the focal species and by low cross-species polymorphism. In this study, we isolated DNA microsatellite markers in seven parrot species threatened with extinction (Amazona brasiliensis, A. oratrix, A. pretrei, A. rhodocorytha, Anodorhynchus leari, Ara rubrogenys and Primolius couloni). From an enriched genomic library followed by 454 pyrosequencing, we characterized a total of 106 polymorphic microsatellite markers (mostly tetranucleotides) in the seven species and tested them across an average number of 19 individuals per species. The mean number of alleles per species and across loci varied from 6.4 to 8.3, with the mean observed heterozygosities ranging from 0.65 to 0.84. Identity and parentage exclusion probabilities were highly discriminatory. The high variability displayed by these microsatellite loci demonstrates their potential utility to perform individual genotyping and parentage analyses, in order to develop a DNA testing framework to determine illegal traffic in these threatened species. PMID:27688959

Polymorphic DNA microsatellite markers for forensic individual identification and parentage analyses of seven threatened species of parrots (family Psittacidae).

PubMed

Jan, Catherine; Fumagalli, Luca

2016-01-01

The parrot family represents one of the bird group with the largest number of endangered species, as a result of habitat destruction and illegal trade. This illicit traffic involves the smuggling of eggs and animals, and the laundering through captive breeding facilities of wild-caught animals. Despite the huge potential of wildlife DNA forensics to determine with conclusive evidence illegal trade, current usage of DNA profiling approaches in parrots has been limited by the lack of suitable molecular markers specifically developed for the focal species and by low cross-species polymorphism. In this study, we isolated DNA microsatellite markers in seven parrot species threatened with extinction (Amazona brasiliensis, A. oratrix, A. pretrei, A. rhodocorytha, Anodorhynchus leari, Ara rubrogenys and Primolius couloni). From an enriched genomic library followed by 454 pyrosequencing, we characterized a total of 106 polymorphic microsatellite markers (mostly tetranucleotides) in the seven species and tested them across an average number of 19 individuals per species. The mean number of alleles per species and across loci varied from 6.4 to 8.3, with the mean observed heterozygosities ranging from 0.65 to 0.84. Identity and parentage exclusion probabilities were highly discriminatory. The high variability displayed by these microsatellite loci demonstrates their potential utility to perform individual genotyping and parentage analyses, in order to develop a DNA testing framework to determine illegal traffic in these threatened species.

Transforming growth factor beta-3 and environmental factors and cleft lip with/without cleft palate.

PubMed

Guo, Zeqiang; Huang, Chengle; Ding, Kaihong; Lin, Jianyan; Gong, Binzhong

2010-07-01

To identify the interactions among two loci (C641A and G15572-) of transforming growth factor beta 3 (TGFbeta3), and exposures in pregnancy with cleft lip with/without cleft palate (CL/P), a hospital-based case-control study was conducted. Associations among offspring polymorphisms of TGFbeta3 C641A and G15572-, paternal smoking, paternal high-risk drinking, maternal passive smoking, and maternal multivitamin supplement with CL/P were analyzed by logistic regression analysis, and the results showed that maternal passive smoking exposures and maternal multivitamin use were associated with the risk of CL/P but offspring polymorphisms of TGFbeta3 C641A and G15572-, paternal smoking, and paternal high-risk drinking were not. Interactions among these variables were analyzed using the multifactor dimensionality reduction method, and the results showed that the two-factor model, including maternal passive smoking and TGFbeta3 C641A, among all models evaluated had the best ability to predict CL/P risk with a maximum cross-validation consistency (9/10) and a maximum average testing accuracy (0.5892; p = 0.0010). These findings suggested that maternal passive smoking exposure is a risk factor for CL/P, whereas maternal multivitamin supplement is a protective factor. The polymorphism of TGFbeta3 C641A participates in interaction effect for CL/P with environmental exposures, although the polymorphism was not associated with CL/P in single-locus analysis, and synergistic effect of TGFbeta3 C641A and maternal passive smoking could provide a new tool for identifying high-risk individuals of CL/P and also an additional evidence that CL/P is determined by both genetic and environmental factors.

ABCB1 C3435T polymorphism is associated with tetrahydrocannabinol blood levels in heavy cannabis users.

PubMed

Kebir, Oussama; Lafaye, Genevieve; Blecha, Lisa; Chaumette, Boris; Mouaffak, Fayçal; Laqueille, Xavier; Benyamina, Amine

2018-04-01

ABCB1 polymorphisms are known to modify drug pharmacokinetics but have yet to be studied for their role in generating and maintaining cannabis dependence. The objective of this study is to determine if ABCB1 C3435T (rs1045642) polymorphism may modulate Δ9-Tetrahydrocannabinol (THC) blood levels in a sample of heavy cannabis users. The study sample includes 39 Caucasian individuals, recruited in two French addictology centres, with isolated cannabis dependence and heavy use (defined as ≥ 7 joints per week). Each underwent clinical evaluation, cannabis blood metabolite dosage (THC, 11-OH-THC, and THC-COOH) and genotyping of ABCB1 C3435T polymorphism. In this population (males: 74.4%, average age 29.5 +/- 9), average cannabis use was 21 joints per week (median 12; range 7 - 80). T carriers (TT/CT) had significantly lower plasma THC levels (ng/ml) versus non T carriers (8 vs 15.70, significant), controlling for level of weekly use, 11-OH-THC and THC-COOH levels. Our results show that ABCB1 C3435T polymorphism may modulate serum THC levels in chronic heavy cannabis users. The exact mechanisms and roles that this may play in cannabis dependence genesis and evolution remain to be elucidated. These results should be controlled in a replication study using a larger population. Copyright © 2017 Elsevier B.V. All rights reserved.

Duffy blood group phenotype-genotype correlations using high-resolution melting analysis PCR and microarray reveal complex cases including a new null FY*A allele: the role for sequencing in genotyping algorithms.

PubMed

Lopez, G H; Morrison, J; Condon, J A; Wilson, B; Martin, J R; Liew, Y-W; Flower, R L; Hyland, C A

2015-10-01

Duffy blood group phenotypes can be predicted by genotyping for single nucleotide polymorphisms (SNPs) responsible for the Fy(a) /Fy(b) polymorphism, for weak Fy(b) antigen, and for the red cell null Fy(a-b-) phenotype. This study correlates Duffy phenotype predictions with serotyping to assess the most reliable procedure for typing. Samples, n = 155 (135 donors and 20 patients), were genotyped by high-resolution melt PCR and by microarray. Samples were in three serology groups: 1) Duffy patterns expected n = 79, 2) weak and equivocal Fy(b) patterns n = 29 and 3) Fy(a-b-) n = 47 (one with anti-Fy3 antibody). Discrepancies were observed for five samples. For two, SNP genotyping predicted weak Fy(b) expression discrepant with Fy(b-) (Group 1 and 3). For three, SNP genotyping predicted Fy(a) , discrepant with Fy(a-b-) (Group 3). DNA sequencing identified silencing mutations in these FY*A alleles. One was a novel FY*A 719delG. One, the sample with the anti-Fy3, was homozygous for a 14-bp deletion (FY*01N.02); a true null. Both the high-resolution melting analysis and SNP microarray assays were concordant and showed genotyping, as well as phenotyping, is essential to ensure 100% accuracy for Duffy blood group assignments. Sequencing is important to resolve phenotype/genotype conflicts which here identified alleles, one novel, that carry silencing mutations. The risk of alloimmunisation may be dependent on this zygosity status. © 2015 International Society of Blood Transfusion.

A supergene determines highly divergent male reproductive morphs in the ruff

PubMed Central

dos Remedios, Natalie; Farrell, Lindsay L.; McRae, Susan B.; Morgan, Tawna C.; Karlionova, Natalia; Pinchuk, Pavel; Verkuil, Yvonne I.; Kitaysky, Alexander S.; Wingfield, John C.; Piersma, Theunis; Zeng, Kai; Slate, Jon; Blaxter, Mark; Lank, David B.; Burke, Terry

2015-01-01

Three strikingly different alternative male mating morphs (aggressive “Independents”, semi-cooperative “Satellites” and female mimic “Faeders”) coexist as a balanced polymorphism in the ruff, Philomachus pugnax, a lek-breeding wading bird1,2,3. Major differences in body size, ornamentation, and aggressive and mating behaviour are inherited as an autosomal polymorphism4,5. We show that development into Satellites and Faeders is determined by a supergene6,7,8 consisting of divergent alternative, dominant, non-recombining haplotypes of an inversion on chromosome 11, which contains 125 predicted genes. Independents are homozygous for the ancestral sequence. One breakpoint of the inversion disrupts the essential Centromere protein N (CENP-N) gene, and pedigree analysis confirms lethality of inversion homozygotes. We describe novel behavioural, testes size, and steroid metabolic differences among morphs, and identify polymorphic genes within the inversion that are likely to contribute to the differences among morphs in reproductive traits. PMID:26569125

DNA variants in DHFR gene and response to treatment in children with childhood B ALL: revisited in AIEOP-BFM protocol.

PubMed

Ceppi, Francesco; Gagné, Vincent; Douyon, Laurance; Quintin, Camille J; Colombini, Antonella; Parasole, Rosanna; Buldini, Barbara; Basso, Giuseppe; Conter, Valentino; Cazzaniga, Giovanni; Krajinovic, Maja

2018-01-01

We have previously reported an association of dihydrofolate reductase promoter polymorphisms with reduced event-free survival in childhood acute lymphoblastic leukemia (ALL) patients treated with Dana Farber Cancer Institute protocol. Here, we assessed whether these associations are applicable to other protocol, based on different methotrexate doses. Genotypes for six tag polymorphisms and resulting haplotypes were analyzed for an association with ALL outcome. The association was found with the polymorphisms A-680C, A-317G and C-35T in high-risk group patients. Carriers of haplotype *1 had a remarkably higher risk of events compared with noncarriers and a lower probability of event-free survival (21.4 vs 81.3%). The role of DHFR variants in predicting the outcome of childhood ALL extends beyond single-treatment protocol and can be useful biomarker in personalizing treatment.

Distinguishing functional polymorphism from random variation in the sequences of >10,000 HLA-A, -B and -C alleles.

PubMed

Robinson, James; Guethlein, Lisbeth A; Cereb, Nezih; Yang, Soo Young; Norman, Paul J; Marsh, Steven G E; Parham, Peter

2017-06-01

HLA class I glycoproteins contain the functional sites that bind peptide antigens and engage lymphocyte receptors. Recently, clinical application of sequence-based HLA typing has uncovered an unprecedented number of novel HLA class I alleles. Here we define the nature and extent of the variation in 3,489 HLA-A, 4,356 HLA-B and 3,111 HLA-C alleles. This analysis required development of suites of methods, having general applicability, for comparing and analyzing large numbers of homologous sequences. At least three amino-acid substitutions are present at every position in the polymorphic α1 and α2 domains of HLA-A, -B and -C. A minority of positions have an incidence >1% for the 'second' most frequent nucleotide, comprising 70 positions in HLA-A, 85 in HLA-B and 54 in HLA-C. The majority of these positions have three or four alternative nucleotides. These positions were subject to positive selection and correspond to binding sites for peptides and receptors. Most alleles of HLA class I (>80%) are very rare, often identified in one person or family, and they differ by point mutation from older, more common alleles. These alleles with single nucleotide polymorphisms reflect the germ-line mutation rate. Their frequency predicts the human population harbors 8-9 million HLA class I variants. The common alleles of human populations comprise 42 core alleles, which represent all selected polymorphism, and recombinants that have assorted this polymorphism.

Distinguishing functional polymorphism from random variation in the sequences of >10,000 HLA-A, -B and -C alleles

PubMed Central

Cereb, Nezih; Yang, Soo Young; Marsh, Steven G. E.; Parham, Peter

2017-01-01

HLA class I glycoproteins contain the functional sites that bind peptide antigens and engage lymphocyte receptors. Recently, clinical application of sequence-based HLA typing has uncovered an unprecedented number of novel HLA class I alleles. Here we define the nature and extent of the variation in 3,489 HLA-A, 4,356 HLA-B and 3,111 HLA-C alleles. This analysis required development of suites of methods, having general applicability, for comparing and analyzing large numbers of homologous sequences. At least three amino-acid substitutions are present at every position in the polymorphic α1 and α2 domains of HLA-A, -B and -C. A minority of positions have an incidence >1% for the ‘second’ most frequent nucleotide, comprising 70 positions in HLA-A, 85 in HLA-B and 54 in HLA-C. The majority of these positions have three or four alternative nucleotides. These positions were subject to positive selection and correspond to binding sites for peptides and receptors. Most alleles of HLA class I (>80%) are very rare, often identified in one person or family, and they differ by point mutation from older, more common alleles. These alleles with single nucleotide polymorphisms reflect the germ-line mutation rate. Their frequency predicts the human population harbors 8–9 million HLA class I variants. The common alleles of human populations comprise 42 core alleles, which represent all selected polymorphism, and recombinants that have assorted this polymorphism. PMID:28650991

Genetic diversity in longleaf pine (Pinus palustris): influence of historical and prehistorical events

Treesearch

Ronald C. Schmidtling; V. Hipkins

1998-01-01

Genetic diversity of allozymes at 24 loci was studied in 23 populations of longleaf pine (Pinus palustris Mill.), including three seed orchard populations and an old-growth stand. Overall, the mean number of alleles per polymorphic locus was 2.9, the percentage of polymorphic loci was 92 percent, and the mean expected heterozygosity was 0.105. These...

Effect of Gamma Rays on Sophora davidii and Detection of DNA Polymorphism through ISSR Marker

PubMed Central

Wang, Puchang; Mo, Bentian; Luo, Tianqiong

2017-01-01

Sophora davidii (Franch.) Kom. ex Pavol is an important medicinal plant and a feeding scrub with ecological value. The effects of different gamma irradiation doses (20–140 Kr) on seed germination and seedling morphology were investigated in S. davidii, and intersimple sequence repeat (ISSR) markers were used to identify the DNA polymorphism among mutants. Significant variations were observed for seed germination, stem diameter, and number of branches per plant. The improved agronomic traits, such as stem diameter and number of branches per plant, were recorded at 80 Kr dose and 20 Kr dose for seed germination. ISSR analysis generated in total 183 scorable fragments, of which 94 (51.37%) were polymorphic. The percentage of polymorphism ranged from 14.29 to 93.33 with an average of 45.69%. Jaccard's coefficients of dissimilarity varied from 0.6885 to 1.000, indicative of the level of genetic variation among the mutants. The constructed dendrogram grouped the entities into five clusters. Consequently, it was concluded that gamma rays irradiation of seeds generates a sufficient number of induced mutations and that ISSR analysis offered a useful molecular marker for the identification of mutants. PMID:28612030

Personalized tacrolimus doses determined by CYP3A5 genotype for induction and maintenance phases of kidney transplantation.

PubMed

Vannaprasaht, Suda; Reungjui, Sirirat; Supanya, Darika; Sirivongs, Dhavee; Pongskul, Cholatip; Avihingsanon, Yingyos; Tassaneeyakul, Wichittra

2013-11-01

Cytochrome P450 (CYP) 3A4 and 3A5 are major isoforms involved in the metabolism of tacrolimus, with the CYP3A5 gene being more polymorphic. It is hypothesized that individual variation in the metabolism of tacrolimus drug may result from genetic polymorphism of CYP3A5. It has been reported that the clearance of tacrolimus in patients with the CYP3A5*1 allele was ~2.5-fold greater than that in those with the CYP3A5*3/*3 genotype. Recent data have also shown that polymorphism in exon 26 (C3435T) of the multidrug resistance gene (MDR1) was correlated with the expression level and function of P-glycoprotein in the lower duodenum, making the relationship between polymorphism of MDR1 and the effective dose of tacrolimus a source of controversy. This study investigated the influence of genetic polymorphisms of CYP3A5 and MDR1 on the dose requirements for the induction and maintenance phases of tacrolimus therapy in kidney transplant recipients. Sixty-eight kidney transplant recipients were enrolled, and their clinical and laboratory data were retrospectively reviewed after 6 months of tacrolimus administration. Genotypes of CYP3A5*1 and CYP3A5*3 and exon 26 of MDR1 (C3435T) were determined by the single-nucleotide polymorphism genotyping method. The frequencies of CYP3A5*3/*3, CYP3A5*1/*3, and CYP3A5*1/*1 were 44.1%, 35.3%, and 20.6%, respectively. The mean dose of tacrolimus required for the induction phase was significantly greater in the CYP3A5*1/*1 group (0.142 [0.050] mg/kg/d) than that required in the CYP3A5*1/*3 group (0.097 [0.040] mg/kg/d; P = 0.072) and in the CYP3A5*3/*3 group (0.077 [0.020] mg/kg/d; P = 0.005). The maintenance dose of tacrolimus required in the CYP3A5*1/*1 group (0.12 [0.03] mg/kg/d) was 1.3-fold higher than that in the CYP3A5*1/*3 group (0.09 [0.03] mg/kg/d; P = 0.018) and 2.4-fold higher than in the CYP3A5*3/*3 group (0.05 [0.02] mg/kg/d; P < 0.0001). No statistically significant relationship was observed between the doses of tacrolimus required for the induction and maintenance phases and MDR1 polymorphism. Determination of the CYP3A5 genotype would be helpful in the design of adequate immunosuppressive treatment and in lowering toxicity by predicting the doses of tacrolimus required for the induction and maintenance phases in individual kidney transplant recipients. © 2013 Elsevier HS Journals, Inc. All rights reserved.

CYP2D6 polymorphisms as predictors of outcome in breast cancer patients treated with tamoxifen: expanded polymorphism coverage improves risk stratification.

PubMed

Schroth, Werner; Hamann, Ute; Fasching, Peter A; Dauser, Silke; Winter, Stefan; Eichelbaum, Michel; Schwab, Matthias; Brauch, Hiltrud

2010-09-01

This study aimed to validate matrix-assisted laser desorption/ionization-time-of-flight mass spectrometry (MALDI-TOF MS)/Taqman copy number assay (CNA) CYP2D6 genotyping by AmpliChip CYP450 Test for the prediction of tamoxifen metabolizer phenotypes in breast cancer, and to investigate the influence of CYP2D6 variant coverage on genotype-phenotype relationships and tamoxifen outcome. Hormone receptor-positive postmenopausal breast cancer patients (n = 492) treated with adjuvant tamoxifen, previously analyzed by MALDI-TOF MS/CNA, were reanalyzed by AmpliChip CYP450 Test and validated by independent methods. Cox proportional hazard ratios (HR) were calculated for recurrence of poor (PM) relative to extensive metabolizer (EM) phenotypes with increasing numbers of CYP2D6 variants. Kaplan-Meier distributions were calculated for different phenotype classifications. Concordance was 99.2% to 99.5% for CNA and 99.8% to 100% per CYP2D6 allele (*3, *4, *5, *9, *10, and *41). The prevalence of predicted phenotypes was 1.2% for ultrarapid metabolizer (UM), 37.2% for EM without variant, 43.5% for heterozygous EM, 9.7% for intermediate metabolizer (IM), and 8.3% for PM. Approximately, one third of patients were misclassified based on a *4 analysis only, but inclusion of all reduced-function alleles increased the PM-associated HR from 1.33 (P = 0.58) to 2.87 (P = 0.006). Kaplan-Meier analyses showed highest and lowest clinical benefit for UM and PM with respect to both the AmpliChip-based and a redefined phenotype assignment. The latter revealed significant allele-dose-dependent associations (P = 0.011) and largest effect size (HR(PM_EM) = 2.77; 95% confidence interval, 1.31-5.89). MALDI-TOF MS/CNA is suitable for accurate CYP2D6 genotyping. For tamoxifen pharmacogenetics, broad CYP2D6 allele coverage is recommended to reduce phenotype misclassification. Classification based on refined EM and reduced-function metabolizers is advisable. AACR.

The 3R polymorph of CaSi{sub 2}

DOE Office of Scientific and Technical Information (OSTI.GOV)

Nedumkandathil, Reji; Benson, Daryn E.; Grins, Jekabs

The Zintl phase CaSi{sub 2} commonly occurs in the 6R structure where puckered hexagon layers of Si atoms are stacked in an AA′BB′CC′ fashion. In this study we show that sintering of CaSi{sub 2} in a hydrogen atmosphere (30 bar) at temperatures between 200 and 700 °C transforms 6R-CaSi{sub 2} quantitatively into 3R-CaSi{sub 2}. In the 3R polymorph (space group R-3m (no. 166), a=3.8284(1), c=15.8966(4), Z=3) puckered hexagon layers are stacked in an ABC fashion. The volume per formula unit is about 3% larger compared to 6R-CaSi{sub 2}. First principles density functional calculations reveal that 6R and 3R-CaSi{sub 2} aremore » energetically degenerate at zero Kelvin. With increasing temperature 6R-CaSi{sub 2} stabilizes over 3R because of its higher entropy. This suggests that 3R-CaSi{sub 2} should revert to 6R at elevated temperatures, which however is not observed up to 800 °C. 3R-CaSi{sub 2} may be stabilized by small amounts of incorporated hydrogen and/or defects. - Graphical abstract: The common 6R form of CaSi{sub 2} can be transformed quantitatively into 3R-CaSi{sub 2} upon sintering in a hydrogen atmosphere. - Highlights: • Quantitative and reproducible bulk synthesis of the rare 3R polymorph of CaSi{sub 2}. • Clarification of the energetic relation between 3R and conventional 6R form. • 3R-CaSi{sub 2} is presumably stabilized by small amounts of incorporated hydrogen and/or defects.« less

The presence of IL-8 +781 T/C polymorphism is associated with the parameters of severe Clostridium difficile infection.

PubMed

Czepiel, Jacek; Biesiada, Grażyna; Dróżdż, Mirosław; Gdula-Argasińska, Joanna; Żurańska, Justyna; Marchewka, Jakub; Perucki, William; Wołkow, Paweł; Garlicki, Aleksander

2018-01-01

There is large variation in the clinical manifestations of Clostridium difficile infection (CDI). We also still can not predict which patients are more susceptible to reinfection with CDI. The aim of our study was to evaluate the effect of gene single nucleotide polymorphisms (SNP) of proinflammatory cytokines, specifically IL-1β, IL-8 on the development, clinical course and recurrence of CDI. We performed a prospective study of adults (130 people ≥ 18 years) including 65 patients with CDI treated in tertiary hospital and 65 healthy persons. The following 3 variants were analyzed for the occurrence of gene polymorphisms in patients with CDI versus the control group: IL-1β +3953 A/G (rs1143634), IL-1β -31 A/G (rs1143627), and IL-8 +781 T/C (rs2227306). Then, we assessed the correlation between these genetic polymorphisms and biochemical parameters important in CDI course, CDI severity as well as CDI recurrence. The presence of genetic polymorphisms of IL-1β +3953 A/G, -31 A/G and IL-8 +781 T/C did not have an effect on the development or recurrence of CDI. The presence of IL-8 +781 T/C polymorphism is associated with the severe CDI. Copyright © 2017 Elsevier Ltd. All rights reserved.

Characterization of clinical and genetic risk factors associated with dyslipidemia after kidney transplantation.

PubMed

Numakura, Kazuyuki; Kagaya, Hideaki; Yamamoto, Ryohei; Komine, Naoki; Saito, Mitsuru; Hiroshi, Tsuruta; Akihama, Susumu; Inoue, Takamitsu; Narita, Shintaro; Tsuchiya, Norihiko; Habuchi, Tomonori; Niioka, Takenori; Miura, Masatomo; Satoh, Shigeru

2015-01-01

We determined the prevalence of dyslipidemia in a Japanese cohort of renal allograft recipients and investigated clinical and genetic characteristics associated with having the disease. In total, 126 patients that received renal allograft transplants between February 2002 and August 2011 were studied, of which 44 recipients (34.9%) were diagnosed with dyslipidemia at 1 year after transplantation. Three clinical factors were associated with a risk of having dyslipidemia: a higher prevalence of disease observed among female than male patients (P = 0.021) and treatment with high mycophenolate mofetil (P = 0.012) and prednisolone (P = 0.023) doses per body weight at 28 days after transplantation. The genetic association between dyslipidemia and 60 previously described genetic polymorphisms in 38 putative disease-associated genes was analyzed. The frequency of dyslipidemia was significantly higher in patients with the glucocorticoid receptor (NR3C1) Bcl1 G allele than in those with the CC genotype (P = 0.001). A multivariate analysis revealed that the NR3C1 Bcl1 G allele was a significant risk factor for the prevalence of dyslipidemia (odds ratio = 4.6; 95% confidence interval = 1.8-12.2). These findings may aid in predicting a patient's risk of developing dyslipidemia.

A Common Polymorphism in SCN2A Predicts General Cognitive Ability through Effects on PFC Physiology.

PubMed

Scult, Matthew A; Trampush, Joey W; Zheng, Fengyu; Conley, Emily Drabant; Lencz, Todd; Malhotra, Anil K; Dickinson, Dwight; Weinberger, Daniel R; Hariri, Ahmad R

2015-09-01

Here we provide novel convergent evidence across three independent cohorts of healthy adults (n = 531), demonstrating that a common polymorphism in the gene encoding the α2 subunit of neuronal voltage-gated type II sodium channels (SCN2A) predicts human general cognitive ability or "g." Using meta-analysis, we demonstrate that the minor T allele of a common polymorphism (rs10174400) in SCN2A is associated with significantly higher "g" independent of gender and age. We further demonstrate using resting-state fMRI data from our discovery cohort (n = 236) that this genetic advantage may be mediated by increased capacity for information processing between the dorsolateral PFC and dorsal ACC, which support higher cognitive functions. Collectively, these findings fill a gap in our understanding of the genetics of general cognitive ability and highlight a specific neural mechanism through which a common polymorphism shapes interindividual variation in "g."

Polymorphic microsatellite loci for two Atlantic oyster species: Crassostrea rhizophorae and C. gasar.

PubMed

Cavaleiro, Nathalia P; Solé-Cava, Antonio M; Lazoski, Cristiano; Cunha, Haydée A

2013-12-01

Using a CA/CAA enriched library screening procedure, we isolated and characterised a total of seventeen polymorphic microsatellite loci for two species of Crassostrea with recognised economic importance. Eleven microsatellite loci were developed for C. rhizophorae, a Western Atlantic species for which no microsatellites were previously known. Another six loci were developed for C. gasar, a species that occurs on both sides of the South Atlantic, adding to the ten loci previously described for the species. The levels of polymorphism were estimated using 24 C. rhizophorae from Southeast Brazil (São Paulo) and 23 C. gasar individuals from North Brazil (Maranhão). The number of alleles per polymorphic locus varied from 3 to 27, and the observed and expected heterozygosities ranged between 0.174 and 0.958 and between 0.237 and 0.972 in C. rhizophorae and C. gasar, respectively. No linkage disequilibrium was found between any locus pair, and four of them exhibited deviations from Hardy-Weinberg expectations. Of the 17 loci developed, 8 cross-amplified in C. gigas and 13 in C. virginica. These markers are useful for evolution and population genetics studies of Crassostrea species and may provide fundamental data for the future cultivation of native oysters in Western Atlantic.

Identification of a psoriasis susceptibility candidate gene by linkage disequilibrium mapping with a localized single nucleotide polymorphism map.

PubMed

Hewett, Duncan; Samuelsson, Lena; Polding, Joanne; Enlund, Fredrik; Smart, Devi; Cantone, Kathryn; See, Chee Gee; Chadha, Sapna; Inerot, Annica; Enerback, Charlotta; Montgomery, Doug; Christodolou, Chris; Robinson, Phil; Matthews, Paul; Plumpton, Mary; Wahlstrom, Jan; Swanbeck, Gunnar; Martinsson, Tommy; Roses, Allen; Riley, John; Purvis, Ian

2002-03-01

Psoriasis is a chronic inflammatory disease of the skin with both genetic and environmental risk factors. Here we describe the creation of a single-nucleotide polymorphism (SNP) map spanning 900-1200 kb of chromosome 3q21, which had been previously recognized as containing a psoriasis susceptibility locus, PSORS5. We genotyped 644 individuals, from 195 Swedish psoriatic families, for 19 polymorphisms. Linkage disequilibrium (LD) between marker and disease was assessed using the transmission/disequilibrium test (TDT). In the TDT analysis, alleles of three of these SNPs showed significant association with disease (P<0.05). A 160-kb interval encompassing these three SNPs was sequenced, and a coding sequence consisting of 13 exons was identified. The predicted protein shares 30-40% homology with the family of cation/chloride cotransporters. A five-marker haplotype spanning the 3' half of this gene is associated with psoriasis to a P value of 3.8<10(-5). We have called this gene SLC12A8, coding for a member of the solute carrier family 12 proteins. It belongs to a class of genes that were previously unrecognized as playing a role in psoriasis pathogenesis.

Vasopressin V1a receptor polymorphism and interval walking training effects in middle-aged and older people.

PubMed

Masuki, Shizue; Mori, Masayuki; Tabara, Yasuharu; Miki, Tetsuro; Sakurai, Akihiro; Morikawa, Mayuko; Miyagawa, Ken; Higuchi, Keiichi; Nose, Hiroshi

2010-03-01

We assessed whether single nucleotide polymorphism rs1042615 of the vasopressin V1a receptor altered the indices of lifestyle-related diseases in middle-aged and older people (mean+/-SD: 64+/-7 years), and, if so, whether it also altered the effects of interval walking training (IWT). CC, CT, and TT carriers of rs1042615 (42, 118, and 64 men, respectively; 113, 263, and 154 women, respectively) performed IWT. We included 5 sets of 3-minute fast walking at > or =70% peak aerobic capacity for walking and 3-minute slow walking at 40% peak aerobic capacity per day for > or =4 days per week for 5 months. Before IWT, the body mass index and diastolic blood pressure (DBP) for men were 25.1+/-0.3 kg/m(2) (mean+/-SE) and 84+/-1 mm Hg in TT, higher than the 23.6+/-0.4 kg/m(2) and 78+/-1 mm Hg in CC, respectively (P<0.01), differences that disappeared after IWT despite similar training achievement between groups (P>0.6). After IWT, body mass index and DBP decreased in TT (-0.9+/-0.1 kg/m(2) and -5+/-1 mm Hg, respectively), more than in CC (-0.5+/-0.1 kg/m(2) and 1+/-1 mm Hg, respectively; P<0.05), with a greater decrease in low-density lipoprotein cholesterol in TT than CC carriers (P<0.01). The decreases in DBP and low-density lipoprotein cholesterol were still greater in TT carriers even after adjustment for their pretraining values. On the other hand, for women, these parameters before IWT and their changes after IWT were similar among CC, CT, and TT carriers. Thus, polymorphism rs1042615 of the V1a receptor altered body mass index and DBP in middle-aged and older men and the training-induced responses of DBP and low-density lipoprotein cholesterol, whereas women did not show any of these responses.

Gene polymorphisms of epidermal growth factor receptor and its downstream effector, interleukin-8, predict oxaliplatin efficacy in patients with advanced colorectal cancer.

PubMed

Zhang, Wu; Stoehlmacher, Jan; Park, David J; Yang, Dongyun; Borchard, Erin; Gil, Ji; Tsao-Wei, Denice D; Yun, Jim; Gordon, Michael; Press, Oliver A; Rhodes, Katrin; Groshen, Susan; Lenz, Heinz-Josef

2005-07-01

Researchers have recently reported an association between the epidermal growth factor receptor (EGFR) pathway and platinum-chemotherapy sensitivity in cancer patients. The (CA)(n) repeat polymorphism in intron 1 of the EGFR gene has been identified and found to alter EGFR expression in vitro as well as in vivo. A higher number of these CA repeats is associated with lower EGFR levels, whereas a low number of repeats is associated with higher EGFR levels. A second key polymorphism within the EGFR pathway (HER1 R497K) is a single nucleotide change (G-A) in codon 497 of the EGFR gene, which leads to an arginine-lysine substitution in the extracellular domain of subdomain IV. Furthermore, interleukin-8 (IL-8), recently identified as an EGFR downstream effector, plays a vital role in tumor angiogenesis and progression. Three other polymorphisms, each related to the IL-8 gene, have also been identified as playing a pivotal role in the EGFR pathway: T-251A in the promoter region of the IL-8 gene, G+2607C in exon 2 of the IL-8 receptor CXCR1 gene, and C+785T in exon 11 of the IL-8 receptor CXCR2 gene. In this study, we employed a 5'-end 33P-gATP-labeled polymerase chain reaction (PCR) protocol as well as the PCR-restriction fragment length polymorphism method in order to determine the genotypes for the previously mentioned polymorphisms in 105 patients with metastatic colorectal cancer. Tests were conducted to establish whether these polymorphisms could predict clinical outcome to 5-flourouracil/oxaliplatin chemotherapy. Among all patients assessed, those possessing < 20 EGFR CA repeats were more likely to show disease progression than were patients with >or= 20 CA repeats (P = 0.019; log-rank test). Also, patients with the CXCR1 GC genotype were found to have an increased relative risk of time to tumor progression that was 1.55 (95% CI, 0.8-3.0) times that of patients with the homozygous GG genotype (P = 0.17; log-rank test). Overall, our data suggest that gene polymorphisms active in the EGFR pathway may be associated with the sensitivity of colorectal cancer patients to platinum-based chemotherapy.

Validation and Interrogation of Differentially Expressed and Alternatively Spliced Genes in African American Prostate Cancer

DTIC Science & Technology

2016-10-01

These analyses have led to two submitted manuscripts. The first manuscript, “Variants of stemness -related genes predicted to regulate RNA splicing...and Table 1-3 at the end of this progress report. The second manuscript, “Single nucleotide polymorphisms of stemness pathway genes predicted to...cancer and support a contribution of the stemness pathway to prostate cancer patient outcome. Please see Figure 5-7 and Table 4-6 at the end of this

Predictive impact of polymorphism of PNPLA3 on HCC development after interferon therapy in Japanese patients with chronic hepatitis C.

PubMed

Moritou, Yuki; Ikeda, Fusao; Iwasaki, Yoshiaki; Baba, Nobuyuki; Takaguchi, Kouichi; Senoh, Tomonori; Nagano, Takuya; Takeuchi, Yasuto; Yasunaka, Tetsuya; Ohnishi, Hideki; Miyake, Yasuhiro; Takaki, Akinobu; Nouso, Kazuhiro; Yamamoto, Kazuhide

2013-12-01

The impact of single-nucleotide polymorphisms (SNP) of patatin-like phospholipase domain-containing protein 3 (PNPLA3) on development of hepatocellular carcinoma (HCC) is not clarified for Japanese patients with chronic hepatitis C. The present study investigated the associations of rs738409 PNPLA3 with HCC development after the antiviral therapy with peg-interferon and ribavirin for Japanese patients with hepatitis C virus serotype 1 and high viral load. Of the 271 patients enrolled in the study, 20 patients developed HCC, during a median follow-up period of 4.6 years. Multivariate analysis in the proportional hazards models revealed that sex, body mass index, platelet counts, and alpha feroprotein (AFP) had significant associations with HCC development (p = 0.011, 0.029, 0.0002, and 0.046, respectively). Multivariate regression analysis revealed that PNPLA3 148 M was significantly associated with serum AFP level (p = 0.032), other than body mass index, platelet count, and alanine aminotransferase (p = 0.0006, 0.0002, and 0.037, respectively), and that serum AFP level was significantly associated with PNPLA3 148 M (p = 0.017). Serum AFP level is an important factor in predicting HCC development after the antiviral therapy for Japanese patients with chronic hepatitis C, the mechanism of which might involve its significant associations with the SNP genotype of PNPLA3.

Preproghrelin Leu72Met polymorphism predicts a lower rate of developing renal dysfunction in type 2 diabetic nephropathy.

PubMed

Lee, Dae-Yeol; Kim, Sun-Young; Jo, Dae-Sun; Hwang, Pyoung Han; Kang, Kyung Pyo; Lee, Sik; Kim, Won; Park, Sung Kwang

2006-07-01

Ghrelin is a novel peptide hormone, which exerts somatotropic, orexigenic and adipogenic effects. Recent studies have shown that the preproghrelin Leu72Met polymorphism is associated with serum creatinine (Scr) concentration in type 2 diabetes; 72Met carriers exhibited lower Scr levels as compared with the 72Met non-carriers. We hypothesized that the preproghrelin Leu72Met polymorphism is associated with a lower rate of developing renal dysfunction in patients with type 2 diabetic nephropathy. The preproghrelin Leu72Met polymorphism was investigated using PCR techniques in 138 patients with diabetic nephropathy divided into two groups, one with normal renal function and the other with renal dysfunction. Determination of the frequency of the preproghrelin Leu72Met polymorphism was the main outcome measure. The frequency of the Leu72Met polymorphism in diabetic nephropathy was significantly lower in patients with renal dysfunction (15.9%, P < 0.01) than in patients with normal renal function (42.0%) or in the diabetes control group (40.6%). The Leu72Met polymorphism was also associated with serum total cholesterol levels in diabetic nephropathy patients with renal dysfunction; the 72Met carriers had lower total cholesterol levels than the 72Met non-carriers (P < 0.05). These data suggest that 72Met carrier status may be used as a marker predicting a lower chance of developing renal dysfunction in diabetic nephropathy.

TS gene polymorphisms are not good markers of response to 5-FU therapy in stage III colon cancer patients.

PubMed

Fariña-Sarasqueta, A; Gosens, M J E M; Moerland, E; van Lijnschoten, I; Lemmens, V E P P; Slooter, G D; Rutten, H J T; van den Brule, Adriaan J C

2011-08-01

Although the predictive and prognostic value of thymidylate synthase (TS) expression and gene polymorphism in colon cancer has been widely studied, the results are inconclusive probably because of methodological differences. With this study, we aimed to elucidate the role of TS gene polymorphisms genotyping in therapy response in stage III colon carcinoma patients treated with 5-FU adjuvant chemotherapy. 251 patients diagnosed with stage III colon carcinoma treated with surgery followed by 5-FU based adjuvant therapy were selected. The variable number of tandem repeats (VNTR) and the single nucleotide polymorphism (SNP) in the 5'untranslated region of the TS gene were genotyped. There was a positive association between tumor T stage and the VNTR genotypes (p = 0.05). In both univariate and multivariate survival analysis no effects of the studied polymorphisms on survival were found. However, there was an association between both polymorphisms and age. Among patients younger than 60 years, the patients homozygous for 2R seemed to have a better overall survival, whereas among the patients older than 67 this longer survival was seen by the carriers of other genotypes. We conclude that the TS VNTR and SNP do not predict response to 5-FU therapy in patients with stage III colon carcinoma. However, age appears to modify the effects of TS polymorphisms on survival.

TS gene polymorphisms are not good markers of response to 5-FU therapy in stage III colon cancer patients.

PubMed

Fariña-Sarasqueta, A; Gosens, M J E M; Moerland, E; van Lijnschoten, I; Lemmens, V E P P; Slooter, G D; Rutten, H J T; van den Brule, A J C

2010-01-01

Although the predictive and prognostic value of thymidylate synthase (TS) expression and gene polymorphism in colon cancer has been widely studied, the results are inconclusive probably because of methodological differences. With this study, we aimed to elucidate the role of TS gene polymorphisms genotyping in therapy response in stage III colon carcinoma patients treated with 5-FU adjuvant chemotherapy. 251 patients diagnosed with stage III colon carcinoma treated with surgery followed by 5-FU based adjuvant therapy were selected. The variable number of tandem repeats (VNTR) and the single nucleotide polymorphism (SNP) in the 5'-untranslated region of the TS gene were genotyped. There was a positive association between tumor T stage and the VNTR genotypes (p=0.05).In both univariate and multivariate survival analysis no effects of the studied polymorphisms on survival were found. However, there was an association between both polymorphisms and age. Among patients younger than 60 years, the patients homozygous for 2R seemed to have a better overall survival, whereas among the patients older than 67 this longer survival was seen by the carriers of other genotypes. We conclude that the TS VNTR and SNP do not predict response to 5-FU therapy in patients with stage III colon carcinoma. However, age appears to modify the effects of TS polymorphisms on survival.

TS Gene Polymorphisms Are Not Good Markers of Response to 5-FU Therapy in Stage III Colon Cancer Patients

PubMed Central

Fariña-Sarasqueta, A.; Gosens, M. J. E. M.; Moerland, E.; van Lijnschoten, I.; Lemmens, V. E. P. P.; Slooter, G. D.; Rutten, H. J. T.; van den Brule, A. J. C.

2010-01-01

Aim: Although the predictive and prognostic value of thymidylate synthase (TS) expression and gene polymorphism in colon cancer has been widely studied, the results are inconclusive probably because of methodological differences. With this study, we aimed to elucidate the role of TS gene polymorphisms genotyping in therapy response in stage III colon carcinoma patients treated with 5-FU adjuvant chemotherapy. Patients and Methods: 251 patients diagnosed with stage III colon carcinoma treated with surgery followed by 5-FU based adjuvant therapy were selected. The variable number of tandem repeats (VNTR) and the single nucleotide polymorphism (SNP) in the 5′-untranslated region of the TS gene were genotyped. Results: There was a positive association between tumor T stage and the VNTR genotypes (p=0.05). In both univariate and multivariate survival analysis no effects of the studied polymorphisms on survival were found. However, there was an association between both polymorphisms and age. Among patients younger than 60 years, the patients homozygous for 2R seemed to have a better overall survival, whereas among the patients older than 67 this longer survival was seen by the carriers of other genotypes. Conclusion: We conclude that the TS VNTR and SNP do not predict response to 5-FU therapy in patients with stage III colon carcinoma. However, age appears to modify the effects of TS polymorphisms on survival. PMID:20966539

Cytochrome P450 and ABCB1 genetics: association with quetiapine and norquetiapine plasma and cerebrospinal fluid concentrations and with clinical response in patients suffering from schizophrenia. A pilot study.

PubMed

Nikisch, Georg; Baumann, Pierre; Oneda, Beatrice; Kiessling, Bernhard; Weisser, Heike; Mathé, Aleksander A; Yoshitake, Takashi; Kehr, Jan; Wiedemann, Georg; Eap, Chin B

2011-07-01

Variability in response to atypical antipsychotic drugs is due to genetic and environmental factors. Cytochrome P450 (CYP) isoforms are implicated in the metabolism of drugs, while the P-glycoprotein transporter (P-gp), encoded by the ABCB1 gene, may influence both the blood and brain drug concentrations. This study aimed to identify the possible associations of CYP and ABCB1 genetic polymorphisms with quetiapine and norquetiapine plasma and cerebrospinal fluid (CSF) concentrations and with response to treatment. Twenty-two patients with schizophrenia receiving 600 mg of quetiapine daily were genotyped for four CYP isoforms and ABCB1 polymorphisms. Quetiapine and norquetiapine peak plasma and CSF concentrations were measured after 4 weeks of treatment. Stepwise multiple regression analysis revealed that ABCB1 3435C > T (rs1045642), 2677G > T (rs2032582) and 1236C > T (rs1128503) polymorphisms predicted plasma quetiapine concentrations, explaining 41% of the variability (p = 0.001). Furthermore, the ABCB1 polymorphisms predicted 48% (p = 0.024) of the variability of the Δ PANSS total score, with the non-carriers of the 3435TT showing higher changes in the score. These results suggest that ABCB1 genetic polymorphisms may be a predictive marker of quetiapine treatment in schizophrenia.

Polymorphisms A387P in thrombospondin-4 and N700S in thrombospondin-1 perturb calcium binding sites.

PubMed

Stenina, Olga I; Ustinov, Valentin; Krukovets, Irene; Marinic, Tina; Topol, Eric J; Plow, Edward F

2005-11-01

Recent genetic studies have associated members of the thrombospondin (TSP) gene family with premature cardiovascular disease. The disease-associated polymorphisms lead to single amino acid changes in TSP-4 (A387P) and TSP-1 (N700S). These substitutions reside in adjacent domains of these highly homologous proteins. Secondary structural predictive programs and the homology of the domains harboring these amino acid substitutions to those in other proteins pointed to potential alterations of putative Ca2+ binding sites that reside in close proximity to the polymorphic amino acids. Since Ca2+ binding is critical for the structure and function of TSP family members, direct evidence for differences in Ca2+ binding by the polymorphic forms was sought. Using synthetic peptides and purified recombinant variant fragments bearing the amino acid substitutions, we measured differences in Tb3+ luminescence as an index of Ca2+ binding. The Tb3+ binding constants placed the TSP-1 region affected by N700S polymorphism among other high-affinity Ca2+ binding sites. The affinity of Ca2+ binding was lower for peptides (3.5-fold) and recombinant fragments (10-fold) containing the S700 vs. the N700 form. In TSP-4, the P387 form acquired an additional Ca2+ binding site absent in the A387 form. The results of our study suggest that both substitutions (A387P in TSP-4 and N700S in TSP-1) alter Ca2+ binding properties. Since these substitutions exert the opposite effects on Ca2+ binding, a decrease in TSP-1 and an increase in TSP-4, the two TSP variants are likely to influence cardiovascular functions in distinct but yet pathogenic ways.

C-reactive protein gene C1444T polymorphism and risk of recurrent ischemic events in patients with symptomatic intracranial atherostenoses.

PubMed

Arenillas, Juan F; Massot, Andreu; Alvarez-Sabín, Jose; Fernandez-Cadenas, Israel; del Rio-Espinola, Albert; Chacon, Pilar; Quintana, Manuel; Molina, Carlos A; Rovira, Alex; Montaner, Joan

2009-01-01

High levels of C-reactive protein (CRP) are associated with an increased risk of further ischemic events in patients with symptomatic intracranial atherosclerotic disease (ICAD). It remains unknown to which extent this increased risk might be genetically predetermined. We aimed to investigate the relationship between a common genetic polymorphism of the CRP gene and the risk of recurrent ischemic events in symptomatic ICAD patients. We studied 75 consecutive patients with a first-ever cerebral ischemic event attributable to symptomatic ICAD. Blood samples were drawn 3 months after the qualifying event. Genomic DNA was isolated and the C1444T single nucleotide polymorphism (SNP) of the CRP gene was determined. The blood concentration of CRP was also measured. Patients underwent long-term clinical follow-up to detect the occurrence of further major ischemic events. During a median follow-up time of 23 months, 18 patients (24%) suffered a major ischemic event (10 ischemic strokes, 3 transient ischemic attacks and 5 myocardial infarctions). Raised CRP levels at baseline (p = 0.02) and the presence of the T allele within the CRP C1444T SNP were associated with a higher risk of recurrent ischemic events (p = 0.02). Kaplan-Meier and multivariable Cox regression analyses adjusted for age, sex, vascular risk factors and CRP level identified that the presence of the T allele in the studied polymorphism predicted the occurrence of further ischemic events (hazard ratio 3.6, 95% confidence interval 1.2-11.1; p = 0.025). The presence of the T allele within the CRP gene C1444T polymorphism may be associated with a higher risk of further ischemic events in symptomatic ICAD patients. (c) 2009 S. Karger AG, Basel.

Predictive potential of IL-28B genetic testing for interferon based hepatitis C virus therapy in Pakistan: Current scenario and future perspective.

PubMed

Afzal, Muhammad Sohail

2016-09-18

In Pakistan which ranked second in terms of hepatitis C virus (HCV) infection, it is highly needed to have an established diagnostic test for antiviral therapy response prediction. Interleukin 28B (IL-28B) genetic testing is widely used throughout the world for interferon based therapy prediction for HCV patients and is quite helpful not only for health care workers but also for the patients. There is a strong relationship between single nucleotide polymorphisms at or near the IL-28B gene and the sustained virological response with pegylated interferon plus ribavirin treatment for chronic hepatitis C. Pakistan is a resource limited country, with very low per capita income and there is no proper social security (health insurance) system. The allocated health budget by the government is very low and is used on other health emergencies like polio virus and dengue virus infection. Therefore it is proposed that there should be a well established diagnostic test on the basis of IL-28B which can predict the antiviral therapy response to strengthen health care set-up of Pakistan. This test once established will help in better management of HCV infected patients.

ACE I/D sequence variants but not MTHFR C677T, is strongly linked to malignant glioma risk and its variant DD genotype may act as a promising predictive biomarker for overall survival of glioma patients.

PubMed

Pandith, Arshad A; Qasim, Iqbal; Zahoor, Wani; Shah, Parveen; Bhat, Abdul R

2018-01-10

ACE I/D and MTHFR C677T gene polymorphisms can be seen as candidate genes for glioma on the basis of their biological functions and their involvement in different cancers. The aim of this study was to analyze potential association and overall survival between MTHFR C677T and ACE I/D polymorphism in glioma patients in our population. We tested genotype distribution of 112 glioma patients against 141 cancer-free controls from the same region. Kaplan-Meier survival analysis was performed to evaluate overall survival of patients for both genes. No significant differences were found among MTHFR C677T wild type C and variant genotypes CT/TT with glioma patients. In ACE, the distribution of variant ID and DD was found to be significantly higher in glioma cases as compared to controls (p<0.0001). ACE DD genotypes were highly presented in glioma cases 26.8% versus 10.6% in controls (p<0.0001) and conferred 5-fold risk for predisposition in glioma cases. Per copy D allele frequency was found higher in cases than in controls (0.54 versus 0.25: p<0.0001). Interestingly we found a significant overall survival (with log rank p<0.01) in patients who presented with ACE DD genotypes had the least estimated overall survival of 13.4months in comparison to 21. 7 and 17.6months for ACE II and I/D genotypes respectively. We conclude ACE I/D polymorphism plays a vital role in predisposition of higher risk for glioma. We also suggest that ACE DD genotypes may act as an important predictive biomarker for overall survival of glioma patients. Copyright © 2017. Published by Elsevier B.V.

R353Q polymorphism in the factor VII gene and cardiovascular risk in Heterozygous Familial Hypercholesterolemia: a case-control study.

PubMed

Criado-García, Juan; Fuentes, Francisco; Cruz-Teno, Cristina; García-Rios, Antonio; Jiménez-Morales, Anabel; Delgado-Lista, Javier; Mata, Pedro; Alonso, Rodrigo; López-Miranda, José; Pérez-Jiménez, Francisco

2011-04-09

Heterozygous Familial Hypercholesterolemia (FH) is a genetic disorder characterized by a high risk of cardiovascular disease. Certain polymorphisms of the factor VII gene have been associated with the development of coronary artery disease and there is a known association between factor VII levels and polymorphic variants in this gene. To date, no study has evaluated the association between factor VII and coronary artery disease in patients with FH. This case-control study comprised 720 patients (546 with FH and 174 controls). We determined the prevalence and allele frequencies of the R353Q polymorphism of factor VII, the plasma levels of factor VII antigen (FVII Ag) and whether they could be predictive factors for cardiovascular risk. 75% (410) of the patients with FH were RR, 23% (127) RQ and 1.6% (9) QQ; in the control group 75.3% (131) were RR, 21.3% (37) RQ and 3.4% (6) QQ (p = 0.32). No statistically significant associations were observed in the distribution of genotypes and allele frequencies between case (FH) and control groups. Nor did we find differences when we evaluated the relationship between the R353Q polymorphism and cardiovascular risk (including coronary disease, ischemic stroke and peripheral arterial disease), either in the univariate analysis or after adjustment for sex, age, arterial hypertension, body mass index, xanthomas, diabetes, smoking, HDLc and LDLc and lipid-lowering treatment. The FVII Ag concentrations behaved in a similar fashion, with no differences for the interaction between controls and those with FH (RR vs. RQ/QQ; p = 0.96). In the subgroup of patients with FH no association was found among cardiovascular disease, genotype and FVII Ag levels (RR vs. RQ/QQ; p = 0.97). Our study did not find a direct relationship between cardiovascular risk in patients with Heterozygous Familial Hypercholesterolemia, the R353Q polymorphism of factor VII and FVII Ag levels.

R353Q polymorphism in the factor VII gene and cardiovascular risk in Heterozygous Familial Hypercholesterolemia: a case-control study

PubMed Central

2011-01-01

Background Heterozygous Familial Hypercholesterolemia (FH) is a genetic disorder characterized by a high risk of cardiovascular disease. Certain polymorphisms of the factor VII gene have been associated with the development of coronary artery disease and there is a known association between factor VII levels and polymorphic variants in this gene. To date, no study has evaluated the association between factor VII and coronary artery disease in patients with FH. Results This case-control study comprised 720 patients (546 with FH and 174 controls). We determined the prevalence and allele frequencies of the R353Q polymorphism of factor VII, the plasma levels of factor VII antigen (FVII Ag) and whether they could be predictive factors for cardiovascular risk. 75% (410) of the patients with FH were RR, 23% (127) RQ and 1.6% (9) QQ; in the control group 75.3% (131) were RR, 21.3% (37) RQ and 3.4% (6) QQ (p = 0.32). No statistically significant associations were observed in the distribution of genotypes and allele frequencies between case (FH) and control groups. Nor did we find differences when we evaluated the relationship between the R353Q polymorphism and cardiovascular risk (including coronary disease, ischemic stroke and peripheral arterial disease), either in the univariate analysis or after adjustment for sex, age, arterial hypertension, body mass index, xanthomas, diabetes, smoking, HDLc and LDLc and lipid-lowering treatment. The FVII Ag concentrations behaved in a similar fashion, with no differences for the interaction between controls and those with FH (RR vs. RQ/QQ; p = 0.96). In the subgroup of patients with FH no association was found among cardiovascular disease, genotype and FVII Ag levels (RR vs. RQ/QQ; p = 0.97). Conclusions Our study did not find a direct relationship between cardiovascular risk in patients with Heterozygous Familial Hypercholesterolemia, the R353Q polymorphism of factor VII and FVII Ag levels. PMID:21477332

DOE Office of Scientific and Technical Information (OSTI.GOV)

Alam, Asim; Mukhopadhyay, Nitai D.; Ning, Yi

Purpose: This study tested whether racial differences in genetic polymorphisms of 4 genes involved in wound repair and response to radiation can be used to predict the occurrence of normal tissue late effects of radiation therapy and indicate potential therapeutic targets. Methods and Materials: This prospective study examined genetic polymorphisms that modulate the expression of 4 genes involved in inflammation and fibrosis and response to radiation (HMOX1, NFE2L2, NOS3, and TGFβ1). DNA from blood samples of 179 patients (∼80% breast and head and neck) collected at the time of diagnosis by their radiation oncologist as exhibiting late normal tissue toxicitymore » was used for the analysis. Patient demographics were as follows: 56% white, 43% African American, 1% other. Allelic frequencies of the different polymorphisms of the participants were compared with those of the general American population stratified by race. Twenty-six additional patients treated with radiation, but without toxicity at 3 months or later after therapy, were also analyzed. Results: Increased frequency of a long GT repeat in the HMOX1 promoter was associated with late effects in both African American and white populations. The single nucleotide polymorphisms (SNP) rs1800469 in the TGFβ1 promoter and the rs6721961 SNP in the NFE2L2 promoter were also found to significantly associate with late effects in African Americans but not whites. A combined analysis of these polymorphisms revealed that >90% of African American patients with late effects had at least 1 of these minor alleles, and 58% had 2 or more. No statistical significance was found relating the studied NOS3 polymorphisms and normal tissue toxicity. Conclusions: These results support a strong association between wound repair and late toxicities of radiation. The presence of these genetic risk factors can vary significantly among different ethnic groups, as demonstrated for some of the SNPs. Future studies should account for the possibility of such ethnic heterogeneity in the late toxicities of radiation.« less

Naturally selected hepatitis C virus polymorphisms confer broad neutralizing antibody resistance.

PubMed

Bailey, Justin R; Wasilewski, Lisa N; Snider, Anna E; El-Diwany, Ramy; Osburn, William O; Keck, Zhenyong; Foung, Steven K H; Ray, Stuart C

2015-01-01

For hepatitis C virus (HCV) and other highly variable viruses, broadly neutralizing mAbs are an important guide for vaccine development. The development of resistance to anti-HCV mAbs is poorly understood, in part due to a lack of neutralization testing against diverse, representative panels of HCV variants. Here, we developed a neutralization panel expressing diverse, naturally occurring HCV envelopes (E1E2s) and used this panel to characterize neutralizing breadth and resistance mechanisms of 18 previously described broadly neutralizing anti-HCV human mAbs. The observed mAb resistance could not be attributed to polymorphisms in E1E2 at known mAb-binding residues. Additionally, hierarchical clustering analysis of neutralization resistance patterns revealed relationships between mAbs that were not predicted by prior epitope mapping, identifying 3 distinct neutralization clusters. Using this clustering analysis and envelope sequence data, we identified polymorphisms in E2 that confer resistance to multiple broadly neutralizing mAbs. These polymorphisms, which are not at mAb contact residues, also conferred resistance to neutralization by plasma from HCV-infected subjects. Together, our method of neutralization clustering with sequence analysis reveals that polymorphisms at noncontact residues may be a major immune evasion mechanism for HCV, facilitating viral persistence and presenting a challenge for HCV vaccine development.

GWAS for plant growth stages and yield components in spring wheat (Triticum aestivum L.) harvested in three regions of Kazakhstan.

PubMed

Turuspekov, Yerlan; Baibulatova, Aida; Yermekbayev, Kanat; Tokhetova, Laura; Chudinov, Vladimir; Sereda, Grigoriy; Ganal, Martin; Griffiths, Simon; Abugalieva, Saule

2017-11-14

Spring wheat is the largest agricultural crop grown in Kazakhstan with an annual sowing area of 12 million hectares in 2016. Annually, the country harvests around 15 million tons of high quality grain. Despite environmental stress factors it is predicted that the use of new technologies may lead to increases in productivity from current levels of 1.5 to up to 3 tons per hectare. One way of improving wheat productivity is by the application of new genomic oriented approaches in plant breeding projects. Genome wide association studies (GWAS) are emerging as powerful tools for the understanding of the inheritance of complex traits via utilization of high throughput genotyping technologies and phenotypic assessments of plant collections. In this study, phenotyping and genotyping data on 194 spring wheat accessions from Kazakhstan, Russia, Europe, and CIMMYT were assessed for the identification of marker-trait associations (MTA) of agronomic traits by using GWAS. Field trials in Northern, Central and Southern regions of Kazakhstan using 194 spring wheat accessions revealed strong correlations of yield with booting date, plant height, biomass, number of spikes per plant, and number of kernels per spike. The accessions from Europe and CIMMYT showed high breeding potential for Southern and Central regions of the country in comparison with the performance of the local varieties. The GGE biplot method, using average yield per plant, suggested a clear separation of accessions into their three breeding origins in relationship to the three environments in which they were evaluated. The genetic variation in the three groups of accessions was further studied using 3245 polymorphic SNP (single nucleotide polymorphism) markers. The application of Principal Coordinate analysis clearly grouped the 194 accessions into three clades according to their breeding origins. GWAS on data from nine field trials allowed the identification of 114 MTAs for 12 different agronomic traits. Field evaluation of foreign germplasm revealed its poor yield performance in Northern Kazakhstan, which is the main wheat growing region in the country. However, it was found that EU and CIMMYT germplasm has high breeding potential to improve yield performance in Central and Southern regions. The use of Principal Coordinate analysis clearly separated the panel into three distinct groups according to their breeding origin. GWAS based on use of the TASSEL 5.0 package allowed the identification of 114 MTAs for twelve agronomic traits. The study identifies a network of key genes for improvement of yield productivity in wheat growing regions of Kazakhstan.

Conformational flexibility and packing plausibility of repaglinide polymorphs

NASA Astrophysics Data System (ADS)

Rani, Dimpy; Goyal, Parnika; Chadha, Renu

2018-04-01

The present manuscript highlights the structural insight into the repaglinide polymorphs. The experimental screening for the possible crystal forms were carried out using various solvents, which generated three forms. The crystal structure of Form II and III was determined using PXRD pattern whereas structural analysis of Form I has already been reported. Form I, II and II was found to exist in P212121, PNA21 and P21/c space groups respectively. Conformational analysis was performed to account the conformational flexibility of RPG. The obtained conformers were further utilized to obtain the information about the crystal packing pattern of RPG polymorphs by polymorph prediction module. The lattice energy landscape, depicting the relationship between lattice energy and density of the polymorphs has been obtained for various possible polymorphs. The experimentally isolated polymorphs were successfully fitted into lattice energy landscape.

Effects of the BDNF Val66Met Polymorphism on Anxiety-Like Behavior Following Nicotine Withdrawal in Mice

PubMed Central

Lee, Bridgin G.; Anastasia, Agustin; Hempstead, Barbara L.; Lee, Francis S.

2015-01-01

Introduction: Nicotine withdrawal is characterized by both affective and cognitive symptoms. Identifying genetic polymorphisms that could affect the symptoms associated with nicotine withdrawal are important in predicting withdrawal sensitivity and identifying personalized cessation therapies. In the current study we used a mouse model of a non-synonymous single nucleotide polymorphism in the translated region of the brain-derived neurotrophic factor (BDNF) gene that substitutes a valine (Val) for a methionine (Met) amino acid (Val66Met) to examine the relationship between the Val66Met single nucleotide polymorphism and nicotine dependence. Methods: This study measured proBDNF and the BDNF prodomain levels following nicotine and nicotine withdrawal and examined a mouse model of a common polymorphism in this protein (BDNFMet/Met) in three behavioral paradigms: novelty-induced hypophagia, marble burying, and the open-field test. Results: Using the BDNF knock-in mouse containing the BDNF Val66Met polymorphism we found: (1) blunted anxiety-like behavior in BDNFMet/Met mice following withdrawal in three behavioral paradigms: novelty-induced hypophagia, marble burying, and the open-field test; (2) the anxiolytic effects of chronic nicotine are absent in BDNFMet/Met mice; and (3) an increase in BDNF prodomain in BDNFMet/Met mice following nicotine withdrawal. Conclusions: Our study is the first to examine the effect of the BDNF Val66Met polymorphism on the affective symptoms of withdrawal from nicotine in mice. In these mice, a single-nucleotide polymorphism in the translated region of the BDNF gene can result in a blunted withdrawal, as measured by decreased anxiety-like behavior. The significant increase in the BDNF prodomain in BDNFMet/Met mice following nicotine cessation suggests a possible role of this ligand in the circuitry remodeling after withdrawal. PMID:25744957

[Mathematic Model for Prediction of Liver Fibrosis Progression Rate in Patients with Chronic Hepatitis C Based on Combination of Genomic Markers].

PubMed

Samokhodskaia, L M; Starostina, E E; Yarovaya, E B; Krasnova, T N; Mukhin, N A; Tkachuk, V A; Sadovnichy, V A

2015-01-01

To evaluate clinical significance of different combinations of gene polymorphisms IL-1b, IL-6, IL-10, TNF, HFE, TGF-b, ATR1, N0S3894, CYBA, AGT, MTHFR, FII, FV, FVII, FXIII, ITGA2, ITGB3, FBG, PAI and their prognostic value for prediction of liver fibrosis progression rate in patients with chronic hepatitis C (CHC). 118 patients with CHC were divided into "fast" and "slow" (fibrosis rate progression ≥ 0.13 and < 0.13 fibrosis units/yr; n = 64 and n = 54) fibrosis groups. Gene polymorphisms were determined. Statistical analysis was performed using Statistica 10. A allele (p = 0.012) and genotype AA (p = 0.024) of AGT G-6T gene, as well as T allele (p = 0.013) and MT+TT genotypes (p = 0.005) of AGT 235 M/T gene were significantly more common in "fast fibrosers" than in "slow fibrosers". Patients with genotype TT of CYBA 242 C/T had a higher fibrosis progression rate than patients with CC+CT genotype (p = 0.02). Our analysis showed a protective effect of TTgenotype of ITGA2 807 C/T on fibrosis progression rate (p = 0.03). There was a trend (p < 0.15) to higher fibrosis progression rate in patients with mutant alleles and genotypes of TGFb +915 G/C, FXIII 103 G/T, PAI-675 5G/4G genes. Other gene polymorphisms were not associated with enhanced liver fibrosis. To build a mathematical modelfor prediction of liverfibrosis progression rate we performed coding with scores for genotypes and virus genotype. Total score correlated with the fibrosis progression rate (R = 0.39, p = 0.000). Determination of genetic profile of the patient and virus genotype allows to predict the course of CHC.

Development of microsatellite markers for Dimorphandra mollis (Leguminosae), a widespread tree from the Brazilian cerrado.

PubMed

Souza, Helena A V; Collevatti, Rosane G; Lemos-Filho, José P; Santos, Fabrício R; Lovato, Maria Bernadete

2012-03-01

Microsatellite markers were developed for Dimorphandra mollis (Leguminosae), a widespread tree in the Brazilian cerrado (a savanna-like vegetation). Microsatellite markers were developed from an enriched library. The analyses of polymorphism were based on 56 individuals from three populations. Nine microsatellite loci were polymorphic, with the number of alleles per locus ranging from three to 10 across populations. The observed and expected heterozygosities per locus and population ranged from 0.062 to 0.850 and from 0.062 to 0.832, respectively. These microsatellites provide an efficient tool for population genetics studies and will be used to assess the genetic diversity and spatial genetic structure of D. mollis.

Adrenoceptor Polymorphisms in Hypertension and Diabetes with obesity-update in 2014.

PubMed

Masuo, K

2014-08-12

Hypertension, diabetes mellitus (especially type 2 diabetes mellitus) and metabolic syndrome associated with obesity are rapidly growing public health problems. Sympathetic nerve activation is well documented in hypertension, diabetes mellitus, and obesity, hypertension and diabetes are determined by genetic background and environmental factors. Reduced energy expenditure and resting metabolic rate are predictive of weight gain, and the sympathetic nervous system participates in regulating energy balance through thermogenesis. The thermogenic effects of sympathetic nervous system in obesity have been mainly mediated via the β2 and β3-adrenergic receptors in humans. Further, β2-adrenoceptors importantly influence vascular reactivity and may regulate blood pressure. Genetic polymorphisms of the -adrenoceptor gene have been shown to alter the function of several adrenoceptor subtype and thus to modify the response to catecholamine. Among β2-adrenoceptor polymorphisms, Arg16Gly, Gln27Glu, and Thr164Ile are considered the most functionally important. β2-adrenoceptor genes have been studied in relation to hypertension. Genetic variations in the β3-adrenoceptor, such as the Try64Arg variant, are also associated with both obesity and hypertension. This review is an update of several versions published of the relationships between adrenoceptor polymorphisms and hypertension, diabetes and obesiy based on the my own review on the relationship with obesity in 2011 in "Journal of Obesity" [1], and another of my own reviews on the relationships with hypertension in 2010 in "International journal of Hypertension" [2], with 37 articles provided by the "PubMed" with the keywords of "adrenoceptor polymorphisms, obesity, hypertension and diabetes" searched on December 2013. However, the relationships of the polymorphisms of β2- and β3-adrenoceptor genes with sympathetic nervous system activity, hypertension and metabolic syndrome have been still discordant, it might be related to the ethnicity, gender, severeity of obesity, duration of hypertension or obesity, etc (refer the "Possible confounding variable affecting the relationships" section and Table 4). Therefore, this review may not be so much different from the previous ones, but, of importance, currently most investigations have shown that the β-adrenoceptor polymorphisms accompanying sympathetic nervous activity contribute to the onset and maintenance of hypertension, diabetes and obesity.

In silico epitope prediction, expression and functional analysis of Per a 10 allergen from the American cockroach

PubMed Central

Tong, Xunliang; Guo, Miao; Jin, Min; Chen, Hao; Li, Yanming; Wei, Ji-Fu

2016-01-01

Cockroach (CR) allergies caused by the American cockroach hyave been recognized to be repsonsible for IgE-mediated type I hypersensitivity worldwide. Per a 10 is one of the recognized main allergens of the American CR. In a previous study, we examined another American CR allergen, Per a 9 in patients with CR allergies and examined epitope sequences in this allergen. In the present study, we aimed to examine epitope sequences in the Per a 10 allergen. for this purpose, the Per a 10 gene was cloned and expressed in Escherichia coli (E. coli) systems. Our results revealed that 9 out of 16 (56.3%) sera from patients with American CR allergies reacted to Per a10, as assessed by ELISA, confirming that Per a 10 is a major allergen of the American CR. Our results also revealed that the expression of CD63 and CCR3 on passively sensitized basophils (obtained sera of patients with American CR allergies) was increased by approximately 2.3-fold, indicating that recombinant Per a 10 is functionally active. In addition, 3 immunoinformatics tools, namely the DNAStar Protean system, the Bioinformatics Predicted Antigenic Peptides (BPAP) system and the BepiPred 1.0 server were used to predict the peptides and the results revealed 8 peptides (2–12, 55–67, 98–120, 125–133, 149–160, 170–182, 201–208 and 223–227) as potential B cell epitopes of the Per a 10 allergen. Moreover, Per a 10 was predicted to have 3 T cell epitope sequences, namely 83–92, 139–147 and 162–170. The findings of our study on the CR allergen may prove to be useful in the development of peptide-based vaccine for the prevention and/or treatment of CR allergies. PMID:27840898

In silico epitope prediction, expression and functional analysis of Per a 10 allergen from the American cockroach.

PubMed

Tong, Xunliang; Guo, Miao; Jin, Min; Chen, Hao; Li, Yanming; Wei, Ji-Fu

2016-12-01

Cockroach (CR) allergies caused by the American cockroach hyave been recognized to be repsonsible for IgE-mediated type I hypersensitivity worldwide. Per a 10 is one of the recognized main allergens of the American CR. In a previous study, we examined another American CR allergen, Per a 9 in patients with CR allergies and examined epitope sequences in this allergen. In the present study, we aimed to examine epitope sequences in the Per a 10 allergen. for this purpose, the Per a 10 gene was cloned and expressed in Escherichia coli (E. coli) systems. Our results revealed that 9 out of 16 (56.3%) sera from patients with American CR allergies reacted to Per a10, as assessed by ELISA, confirming that Per a 10 is a major allergen of the American CR. Our results also revealed that the expression of CD63 and CCR3 on passively sensitized basophils (obtained sera of patients with American CR allergies) was increased by approximately 2.3-fold, indicating that recombinant Per a 10 is functionally active. In addition, 3 immunoinformatics tools, namely the DNAStar Protean system, the Bioinformatics Predicted Antigenic Peptides (BPAP) system and the BepiPred 1.0 server were used to predict the peptides and the results revealed 8 peptides (2-12, 55-67, 98-120, 125-133, 149-160, 170-182, 201-208 and 223-227) as potential B cell epitopes of the Per a 10 allergen. Moreover, Per a 10 was predicted to have 3 T cell epitope sequences, namely 83-92, 139-147 and 162-170. The findings of our study on the CR allergen may prove to be useful in the development of peptide-based vaccine for the prevention and/or treatment of CR allergies.

Effect of genetic polymorphisms involved in folate metabolism on the concentration of serum folate and plasma total homocysteine (p-tHcy) in healthy subjects after short-term folic acid supplementation: a randomized, double blind, crossover study.

PubMed

Cabo, Rona; Hernes, Sigrunn; Slettan, Audun; Haugen, Margaretha; Ye, Shu; Blomhoff, Rune; Mansoor, M Azam

2015-05-01

Data on the effect of combined genetic polymorphisms, involved in folate metabolism, on the concentration of serum folate after folic acid supplementation are scarce. Therefore, we investigated the impact of seven gene polymorphisms on the concentration of serum folate and p-tHcy in healthy subjects after short-term folic acid supplementation. In a randomized, double blind, crossover study, apparently healthy subjects were given either 0.8 mg folic acid per day (n = 46) or placebo (n = 45) for 14 days. The washout period was 14 days. Fasting blood samples were collected on day 1, 15, 30 and 45. Data on subjects on folic acid supplementation (n = 91) and on placebo (n = 45) were used for the statistical analysis. The concentration of serum folate increased higher in subjects with higher age (53.5 ± 7.0 years) than in subjects with lower age (24.3 ± 3.2 years) after folic acid supplementation (p = 0.006). The baseline concentration of serum folate in subjects with polymorphism combination, reduced folate carrier protein, RFC1-80 GA and methylenetetrahydrofolate reductase, MTHFR677 CT+TT, was lower than RFC1-80 AA and MTHFR677 CT+TT (p = 0.002). After folic acid supplementation, a higher increase in the concentration of serum folate was detected in subjects with polymorphism combination RFC1-80 GA and MTHFR677 CC than RFC1-80 GG and MTHFR CT+TT combination (p < 0.0001). The baseline concentration of plasma total homocysteine (p-tHcy) was altered by combined polymorphisms in genes associated with folate metabolism. After folic acid supplementation, in subjects with combined polymorphisms in methylenetetrahydrofolate dehydrogenase, MTHFD1-1958 and MTHFR-677 genes, the concentration of p-tHcy was changed (p = 0.002). The combination of RFC1-80 and MTHFR-677 polymorphisms had a profound affect on the concentration of serum folate in healthy subjects before and after folic acid supplementation.

Analysis of BIM (BCL-2 like 11 gene) deletion polymorphism in Chinese non-small cell lung cancer patients

PubMed Central

Zhong, Jia; Li, Zheng-Xiang; Zhao, Jun; Duan, Jian-Chun; Bai, Hua; An, Tong-Tong; Yang, Xiao-Dan; Wang, Jie

2014-01-01

Background Drug resistance significantly weakens the efficacy of cancer treatment, and the BIM (also known as the BCL2L11 gene) deletion polymorphism has been identified as a potential biomarker for drug resistance. In this retrospective study, we included a total of 290 patients with advanced non-small cell lung cancer (NSCLC) who received treatment with epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) and chemotherapy. Methods The BIM deletion polymorphism of each patient was detected by polymerase chain reaction. EGFR mutations were detected by denaturing high-performance liquid chromatography methods and the amplification refractory mutation system. Results The BIM deletion polymorphism was detected in 45/290 (15.5%) Chinese NSCLC patients. No associations were observed between the BIM deletion and clinic-pathologic characteristics of patients. The BIM deletion polymorphism was predictive of shorter progression-free survival in Chinese patients with EGFR-mutant adenocarcinoma and who were treated with EGFR-TKIs (7.30 vs. 9.53 months, P = 0.034). Additionally, we found that the BIM deletion polymorphism was an effective predictor of short progression-free survival in individuals with EGFR-mutant NSCLC and treated with chemotherapy containing pemetrexed (3.32 vs. 5.30, P = 0.012) or second-/beyond-line chemotherapy containing taxanes (1.53 vs. 2.61 months, P = 0.025). The BIM deletion was not correlated with overall survival. Conclusion The BIM deletion polymorphism occurs in 15.5% of Chinese NSCLC patients, and is a biomarker for resistance to TKIs and chemotherapy. However, BIM deletion was not a decisive factor in overall survival. PMID:26767045

Analysis of BIM (BCL-2 like 11 gene) deletion polymorphism in Chinese non-small cell lung cancer patients.

PubMed

Zhong, Jia; Li, Zheng-Xiang; Zhao, Jun; Duan, Jian-Chun; Bai, Hua; An, Tong-Tong; Yang, Xiao-Dan; Wang, Jie

2014-11-01

Drug resistance significantly weakens the efficacy of cancer treatment, and the BIM (also known as the BCL2L11 gene) deletion polymorphism has been identified as a potential biomarker for drug resistance. In this retrospective study, we included a total of 290 patients with advanced non-small cell lung cancer (NSCLC) who received treatment with epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) and chemotherapy. The BIM deletion polymorphism of each patient was detected by polymerase chain reaction. EGFR mutations were detected by denaturing high-performance liquid chromatography methods and the amplification refractory mutation system. The BIM deletion polymorphism was detected in 45/290 (15.5%) Chinese NSCLC patients. No associations were observed between the BIM deletion and clinic-pathologic characteristics of patients. The BIM deletion polymorphism was predictive of shorter progression-free survival in Chinese patients with EGFR-mutant adenocarcinoma and who were treated with EGFR-TKIs (7.30 vs. 9.53 months, P = 0.034). Additionally, we found that the BIM deletion polymorphism was an effective predictor of short progression-free survival in individuals with EGFR-mutant NSCLC and treated with chemotherapy containing pemetrexed (3.32 vs. 5.30, P = 0.012) or second-/beyond-line chemotherapy containing taxanes (1.53 vs. 2.61 months, P = 0.025). The BIM deletion was not correlated with overall survival. The BIM deletion polymorphism occurs in 15.5% of Chinese NSCLC patients, and is a biomarker for resistance to TKIs and chemotherapy. However, BIM deletion was not a decisive factor in overall survival.

An improved in silico selection of phenotype affecting polymorphisms in SLC6A4, HTR1A and HTR2A genes.

PubMed

Piva, Francesco; Giulietti, Matteo; Nardi, Bernardo; Bellantuono, Cesario; Principato, Giovanni

2010-03-01

Among the experimentally assessed DNA variations in serotonin related genes, some influence physiological expression of personality and mental disorders, others alter the responses to pharmacological and/or psychotherapeutic treatments. Because of the huge number of polymorphisms lying in genes and of the great length of time necessary to perform association studies, a selection of the variations being studied is a necessary and crucial step. In this work we used the most updated and assessed bioinformatic tools to predict the phenotype affecting polymorphisms of the human HTR1A, HTR2A and SLC6A4 serotonin related genes. Moreover, we carried out a literature search to collect information about the recent association studies to compare it versus our prediction data. Gene polymorphism analysis indicated the variations that are worth considering in the association studies in the field of psychiatry, psychology and pharmacogenomics. The literature revision allowed to show both the few well and the most not enough investigated polymorphisms. Our data can be useful to select polymorphisms for new association studies, especially those not yet investigated that can be related to behaviour, mental disorders and individual treatment response. Copyright 2010 John Wiley & Sons, Ltd.

Bitterness of the Non-nutritive Sweetener Acesulfame Potassium Varies With Polymorphisms in TAS2R9 and TAS2R31

PubMed Central

2013-01-01

Demand for nonnutritive sweeteners continues to increase due to their ability to provide desirable sweetness with minimal calories. Acesulfame potassium and saccharin are well-studied nonnutritive sweeteners commonly found in food products. Some individuals report aversive sensations from these sweeteners, such as bitter and metallic side tastes. Recent advances in molecular genetics have provided insight into the cause of perceptual differences across people. For example, common alleles for the genes TAS2R9 and TAS2R38 explain variable response to the bitter drugs ofloxacin in vitro and propylthiouracil in vivo. Here, we wanted to determine whether differences in the bitterness of acesulfame potassium could be predicted by common polymorphisms (genetic variants) in bitter taste receptor genes (TAS2Rs). We genotyped participants (n = 108) for putatively functional single nucleotide polymorphisms in 5 TAS2Rs and asked them to rate the bitterness of 25 mM acesulfame potassium on a general labeled magnitude scale. Consistent with prior reports, we found 2 single nucleotide polymorphisms in TAS2R31 were associated with acesulfame potassium bitterness. However, TAS2R9 alleles also predicted additional variation in acesulfame potassium bitterness. Conversely, single nucleotide polymorphisms in TAS2R4, TAS2R38, and near TAS2R16 were not significant predictors. Using 1 single nucleotide polymorphism each from TAS2R9 and TAS2R31, we modeled the simultaneous influence of these single nucleotide polymorphisms on acesulfame potassium bitterness; together, these 2 single nucleotide polymorphisms explained 13.4% of the variance in perceived bitterness. These data suggest multiple polymorphisms within TAS2Rs contribute to the ability to perceive the bitterness from acesulfame potassium. PMID:23599216

Genetic Diversity in Nothofagus alessandrii (Fagaceae), an Endangered Endemic Tree Species of the Coastal Maulino Forest of Central Chile

PubMed Central

Torres-Díaz, Cristian; Ruiz, Eduardo; González, Fidelina; Fuentes, Glenda; Cavieres, Lohengrin A.

2007-01-01

Background and Aims The endemic tree Nothofagus alessandrii (Fagaceae) has been historically restricted to the coastal range of Region VII of central Chile, and its forests have been increasingly destroyed and fragmented since the end of the 19th century. In this study, the patterns of within- and among-population genetic diversity in seven fragments of this endangered narrowly endemic tree were examined. Methods Allozyme electrophoresis of seven loci of N. alessandrii was used to estimate genetic diversity, genetic structure and gene flow. Key Results High levels of genetic diversity were found as shown by mean expected heterozygosity (He = 0·182 ± 0·034), percentage of polymorphic loci (Pp = 61·2 %), mean number of alleles per locus (A = 1·8) and mean number of alleles per polymorphic locus (Ap = 2·3). Genetic differentiation was also high (GST = 0·257 and Nm = 0·7). These values are high compared with more widespread congeneric species. Conclusions Despite its endemic status and restricted geographical range N. alessandrii showed high levels of genetic diversity. The observed patterns of diversity are explained in part by historical processes and more recent human fragmentation. PMID:17513870

Evaluation of warfarin management with international normalized ratio self-testing and online remote monitoring and management plus low-dose vitamin k with genomic considerations: a pilot study.

PubMed

Bussey, Henry I; Bussey, Marie; Bussey-Smith, Kristin L; Frei, Christopher R

2013-11-01

As better international normalized ratio (INR) control and self-testing reduce events in warfarin-treated patients, and vitamin K supplementation may improve INR control, our primary objective was to evaluate the effect of a system combining frequent INR self-testing with online remote monitoring and management (STORM₂) and low-dose vitamin K supplementation on INR control; our secondary objectives were to assess the impact of STORM₂ on clinician time and to evaluate the influence of pharmacogenomics on INR stability and warfarin dose after vitamin K supplementation. Prospective pre- and postintervention study. Freestanding clinical research center. Fifty-five patients treated with long-term warfarin therapy who were referred from four anticoagulation clinics and seven medical practices. All patients performed weekly INR self-testing and received vitamin K 100 µg/day and online anticoagulation management for 1 year. INR control and time required for anticoagulation management were assessed, and an analysis of warfarin dosing and INR stability by genetic polymorphism subgroup (vitamin K epoxide reductase complex 1 [VKORC1] and cytochrome P450 2C9 isoenzyme) was performed; vitamin K product content was also analyzed. The percentage of time that the INR is within the time in therapeutic range (TTR) improved from 56% before the intervention to 81% after the intervention (p<0.0001), and time spent at extreme INR values of lower than 1.5 or higher than 5 was reduced from 3.1% to 0.4% (p=0.01). Clinician time was less than 10 minutes per four patient visits per month. Genetic polymorphisms did not correlate with INR stability or the increase in warfarin dose after vitamin K supplementation. The content of the vitamin K product, however, was only 34-76% of the labeled amount. Patients with the GG VKORC1 genotype required a higher warfarin dose than predicted by the genomic-based dosing chart in the warfarin package insert. The 25% point improvement in TTR with STORM₂ is a greater improvement than reported previously with other efforts to improve TTR. STORM₂ required a minimum amount of clinician time. Pharmacogenomics were not predictive of improved INR control or the magnitude of the warfarin dose after vitamin K supplementation, although the content of the product was unreliable. Patients with the GG VKORC1 genotype required a higher warfarin dose than predicted by the product information. The potential clinical impact of improved INR control with this method warrants comparisons with conventionally managed warfarin and with the new oral anticoagulants. © 2013 Pharmacotherapy Publications, Inc.

Adsorption of magnetic transition metals on borophene: an ab initio study

NASA Astrophysics Data System (ADS)

Tomar, Shalini; Rastogi, Priyank; Bhadoria, Bhagirath Singh; Bhowmick, Somnath; Chauhan, Yogesh Singh; Agarwal, Amit

2018-03-01

We explore the doping strategy for adsorbing different metallic 3d transition-metal atoms (Fe, Co and Ni) on two different polymorphs of borophene monolayer: 2-Pmmn and 8-Pmmn borophene. Both have energy dispersion, with 2-Pmmn borophene being metallic in nature, and 8-Pmmn borophene being semi-metallic with a tilted Dirac cone like dispersion. Using density functional theory based calculations, we find the most suitable adsorption site for each adatom, and calculate the binding energy, binding energy per atom, charge transfer, density of states and magnetic moment of the resulting borophene-adatom system. We show that Ni is the most effective for electron doping for both the polymorphs. Additionally Fe is the most suitable to magnetically dope 8-Pmmn borophene, while Co is the best for magnetically doping 2-Pmmn borophene.

Predicting change in symptoms of depression during the transition to university: the roles of BDNF and working memory capacity.

PubMed

LeMoult, Joelle; Carver, Charles S; Johnson, Sheri L; Joormann, Jutta

2015-03-01

Studies on depression risk emphasize the importance of both cognitive and genetic vulnerability factors. The present study has provided the first examination of whether working memory capacity, the BDNF Val66Met polymorphism, and their interaction predict changes in symptoms of depression during the transition to university. Early in the semester, students completed a self-report measure of depressive symptoms and a modified version of the reading span task to assess working memory capacity in the presence of both neutral and negative distractors. Whole blood was genotyped for the BDNF Val66Met polymorphism. Students returned at the end of the semester to complete additional self-report questionnaires. Neither working memory capacity nor the BDNF Val66Met polymorphism predicted change in depressive symptoms either independently or in interaction with self-reported semester difficulty. The BDNF Val66Met polymorphism, however, moderated the association between working memory capacity and symptom change. Among met carriers, lower working memory capacity in the presence of negative-but not neutral-distractors was associated with increased symptoms of depression over the semester. For the val/val group, working memory capacity did not predict symptom change. These findings contribute directly to biological and cognitive models of depression and highlight the importance of examining Gene × Cognition interactions when investigating risk for depression.

Polymorphism in the major histocompatibility complex (MHC class II B) genes of the Rufous-backed Bunting (Emberiza jankowskii)

PubMed Central

Li, Dan; Zhao, Yunjiao; Lin, Aiqing; Li, Shi; Feng, Jiang

2017-01-01

Genetic diversity is one of the pillars of conservation biology research. High genetic diversity and abundant genetic variation in an organism may be suggestive of capacity to adapt to various environmental changes. The major histocompatibility complex (MHC) is known to be highly polymorphic and plays an important role in immune function. It is also considered an ideal model system to investigate genetic diversity in wildlife populations. The Rufous-backed Bunting (Emberiza jankowskii) is an endangered species that has experienced a sharp decline in both population and habitat size. Many historically significant populations are no longer present in previously populated regions, with only three breeding populations present in Inner Mongolia (i.e., the Aolunhua, Gahaitu and Lubei557 populations). Efforts focused on facilitating the conservation of the Rufous-backed Bunting (Emberiza jankowskii) are becoming increasingly important. However, the genetic diversity of E. jankowskii has not been investigated. In the present study, polymorphism in exon 2 of the MHCIIB of E. jankowskii was investigated. This polymorphism was subsequently compared with a related species, the Meadow Bunting (Emberiza cioides). A total of 1.59 alleles/individual were detected in E. jankowskii and 1.73 alleles/individual were identified in E. cioides. The maximum number of alleles per individual from the three E. jankowskii populations suggest the existence of at least three functional loci, while the maximum number of alleles per individual from the three E. cioides populations suggest the presence of at least four functional loci. Two of the alleles were shared between the E. jankowskii and E. cioides. Among the 12 unique alleles identified in E. jankowskii, 10.17 segregating sites per allele were detected, and the nucleotide diversity was 0.1865. Among the 17 unique alleles identified in E. cioides, eight segregating sites per allele were detected, and the nucleotide diversity was 0.1667. Overall, compared to other passerine birds, a relatively low level of MHC polymorphism was revealed in E. jankowskii, which was similar to that in E. cioides. Positive selection was detected by PAML/SLAC/FEL analyses in the region encoding the peptide-binding region in both species, and no recombination was detected. Phylogenetic analysis showed that the alleles from E. jankowskii and E. cioides belong to the same clade and the two species shared similar alleles, suggesting the occurrence of a trans-species polymorphism between the two Emberiza species. PMID:28149689

GRECOS Project (Genotyping Recurrence Risk of Stroke): The Use of Genetics to Predict the Vascular Recurrence After Stroke.

PubMed

Fernández-Cadenas, Israel; Mendióroz, Maite; Giralt, Dolors; Nafria, Cristina; Garcia, Elena; Carrera, Caty; Gallego-Fabrega, Cristina; Domingues-Montanari, Sophie; Delgado, Pilar; Ribó, Marc; Castellanos, Mar; Martínez, Sergi; Freijo, Marimar; Jiménez-Conde, Jordi; Rubiera, Marta; Alvarez-Sabín, José; Molina, Carlos A; Font, Maria Angels; Grau Olivares, Marta; Palomeras, Ernest; Perez de la Ossa, Natalia; Martinez-Zabaleta, Maite; Masjuan, Jaime; Moniche, Francisco; Canovas, David; Piñana, Carlos; Purroy, Francisco; Cocho, Dolores; Navas, Inma; Tejero, Carlos; Aymerich, Nuria; Cullell, Natalia; Muiño, Elena; Serena, Joaquín; Rubio, Francisco; Davalos, Antoni; Roquer, Jaume; Arenillas, Juan Francisco; Martí-Fábregas, Joan; Keene, Keith; Chen, Wei-Min; Worrall, Bradford; Sale, Michele; Arboix, Adrià; Krupinski, Jerzy; Montaner, Joan

2017-05-01

Vascular recurrence occurs in 11% of patients during the first year after ischemic stroke (IS) or transient ischemic attack. Clinical scores do not predict the whole vascular recurrence risk; therefore, we aimed to find genetic variants associated with recurrence that might improve the clinical predictive models in IS. We analyzed 256 polymorphisms from 115 candidate genes in 3 patient cohorts comprising 4482 IS or transient ischemic attack patients. The discovery cohort was prospectively recruited and included 1494 patients, 6.2% of them developed a new IS during the first year of follow-up. Replication analysis was performed in 2988 patients using SNPlex or HumanOmni1-Quad technology. We generated a predictive model using Cox regression (GRECOS score [Genotyping Reurrence Risk of Stroke]) and generated risk groups using a classification tree method. The analyses revealed that rs1800801 in the MGP gene (hazard ratio, 1.33; P =9×10 - 03 ), a gene related to artery calcification, was associated with new IS during the first year of follow-up. This polymorphism was replicated in a Spanish cohort (n=1.305); however, it was not significantly associated in a North American cohort (n=1.683). The GRECOS score predicted new IS ( P =3.2×10 - 09 ) and could classify patients, from low risk of stroke recurrence (1.9%) to high risk (12.6%). Moreover, the addition of genetic risk factors to the GRECOS score improves the prediction compared with previous Stroke Prognosis Instrument-II score ( P =0.03). The use of genetics could be useful to estimate vascular recurrence risk after IS. Genetic variability in the MGP gene was associated with vascular recurrence in the Spanish population. © 2017 American Heart Association, Inc.

Molecular genetics of the platelet serotonin system in first-degree relatives of patients with autism.

PubMed

Cross, Sarah; Kim, Soo-Jeong; Weiss, Lauren A; Delahanty, Ryan J; Sutcliffe, James S; Leventhal, Bennett L; Cook, Edwin H; Veenstra-Vanderweele, Jeremy

2008-01-01

Elevated platelet serotonin (5-hydroxytryptamine, 5-HT) is found in a subset of children with autism and in some of their first-degree relatives. Indices of the platelet serotonin system, including whole blood 5-HT, 5-HT binding affinity for the serotonin transporter (K(m)), 5-HT uptake (V(max)), and lysergic acid diethylamide (LSD) receptor binding, were previously studied in 24 first-degree relatives of probands with autism, half of whom were selected for elevated whole blood 5-HT levels. All subjects were then genotyped for selected polymorphisms at the SLC6A4, HTR7, HTR2A, ITGB3, and TPH1 loci. Previous studies allowed an a priori prediction of SLC6A4 haplotypes that separated the subjects into three groups that showed significantly different 5-HT binding affinity (K(m), p=0.005) and 5-HT uptake rate (V(max), p=0.046). Genotypes at four individual polymorphisms in SLC6A4 were not associated with platelet 5-HT indices. Haplotypes at SLC6A4 and individual genotypes of polymorphisms at SLC6A4, HTR7, HTR2A, ITGB3, and TPH1 showed no significant association with whole blood 5-HT. Haplotype analysis of two polymorphisms in TPH1 revealed a nominally significant association with whole blood 5-HT (p=0.046). These initial studies of indices of the 5-HT system with several single-nucleotide polymorphisms at loci in this system generate hypotheses for testing in other samples.

Body mass index and C-174G interleukin-6 promoter polymorphism interact in predicting type 2 diabetes.

PubMed

Möhlig, Matthias; Boeing, Heiner; Spranger, Joachim; Osterhoff, Martin; Kroke, Anja; Fisher, Eva; Bergmann, Manuela M; Ristow, Michael; Hoffmann, Kurt; Pfeiffer, Andreas F H

2004-04-01

Increased levels of IL-6 add further risk to the impact of obesity in respect to the development of type 2 diabetes mellitus (T2DM). A C-174G polymorphism within the IL-6 promoter region was shown to influence transcription rate of IL-6. We made use of a nested case-control study within the European Prospective Investigation into Cancer and Nutrition-Potsdam cohort of 27,548 individuals, selecting 188 T2DM cases and 376 controls to investigate this polymorphism in respect to development of T2DM. This polymorphism was found to modify the correlation between body mass index (BMI) and IL-6 by showing a much stronger increase of IL-6 at increased BMI for CC genotypes compared with GG genotypes. Interestingly, C-174G polymorphism was found to be an effect modifier for the impact of BMI regarding T2DM. Whereas BMI greater than or equal to 28 kg/m(2) increased the risk of T2DM 3.44-fold [95% confidence interval (CI), 1.34- to 8.24-fold] for GG genotypes and 2.94-fold (95% CI, 1.56- to 5.56-fold) for GC genotypes, we found a 17.68-fold (95% CI, 3.57- to 87.66-fold) increase in risk for CC genotypes. In conclusion, obese individuals with BMI greater than or equal to 28 kg/m(2) carrying the CC genotype showed a more than 5-fold increased risk of developing T2DM compared with the remaining genotypes and, hence, might profit most from weight reduction.

Characterization of Capsicum annuum Genetic Diversity and Population Structure Based on Parallel Polymorphism Discovery with a 30K Unigene Pepper GeneChip

PubMed Central

Hill, Theresa A.; Ashrafi, Hamid; Reyes-Chin-Wo, Sebastian; Yao, JiQiang; Stoffel, Kevin; Truco, Maria-Jose; Kozik, Alexander; Michelmore, Richard W.; Van Deynze, Allen

2013-01-01

The widely cultivated pepper, Capsicum spp., important as a vegetable and spice crop world-wide, is one of the most diverse crops. To enhance breeding programs, a detailed characterization of Capsicum diversity including morphological, geographical and molecular data is required. Currently, molecular data characterizing Capsicum genetic diversity is limited. The development and application of high-throughput genome-wide markers in Capsicum will facilitate more detailed molecular characterization of germplasm collections, genetic relationships, and the generation of ultra-high density maps. We have developed the Pepper GeneChip® array from Affymetrix for polymorphism detection and expression analysis in Capsicum. Probes on the array were designed from 30,815 unigenes assembled from expressed sequence tags (ESTs). Our array design provides a maximum redundancy of 13 probes per base pair position allowing integration of multiple hybridization values per position to detect single position polymorphism (SPP). Hybridization of genomic DNA from 40 diverse C. annuum lines, used in breeding and research programs, and a representative from three additional cultivated species (C. frutescens, C. chinense and C. pubescens) detected 33,401 SPP markers within 13,323 unigenes. Among the C. annuum lines, 6,426 SPPs covering 3,818 unigenes were identified. An estimated three-fold reduction in diversity was detected in non-pungent compared with pungent lines, however, we were able to detect 251 highly informative markers across these C. annuum lines. In addition, an 8.7 cM region without polymorphism was detected around Pun1 in non-pungent C. annuum. An analysis of genetic relatedness and diversity using the software Structure revealed clustering of the germplasm which was confirmed with statistical support by principle components analysis (PCA) and phylogenetic analysis. This research demonstrates the effectiveness of parallel high-throughput discovery and application of genome-wide transcript-based markers to assess genetic and genomic features among Capsicum annuum. PMID:23409153

Characterization of Capsicum annuum genetic diversity and population structure based on parallel polymorphism discovery with a 30K unigene Pepper GeneChip.

PubMed

Hill, Theresa A; Ashrafi, Hamid; Reyes-Chin-Wo, Sebastian; Yao, JiQiang; Stoffel, Kevin; Truco, Maria-Jose; Kozik, Alexander; Michelmore, Richard W; Van Deynze, Allen

2013-01-01

The widely cultivated pepper, Capsicum spp., important as a vegetable and spice crop world-wide, is one of the most diverse crops. To enhance breeding programs, a detailed characterization of Capsicum diversity including morphological, geographical and molecular data is required. Currently, molecular data characterizing Capsicum genetic diversity is limited. The development and application of high-throughput genome-wide markers in Capsicum will facilitate more detailed molecular characterization of germplasm collections, genetic relationships, and the generation of ultra-high density maps. We have developed the Pepper GeneChip® array from Affymetrix for polymorphism detection and expression analysis in Capsicum. Probes on the array were designed from 30,815 unigenes assembled from expressed sequence tags (ESTs). Our array design provides a maximum redundancy of 13 probes per base pair position allowing integration of multiple hybridization values per position to detect single position polymorphism (SPP). Hybridization of genomic DNA from 40 diverse C. annuum lines, used in breeding and research programs, and a representative from three additional cultivated species (C. frutescens, C. chinense and C. pubescens) detected 33,401 SPP markers within 13,323 unigenes. Among the C. annuum lines, 6,426 SPPs covering 3,818 unigenes were identified. An estimated three-fold reduction in diversity was detected in non-pungent compared with pungent lines, however, we were able to detect 251 highly informative markers across these C. annuum lines. In addition, an 8.7 cM region without polymorphism was detected around Pun1 in non-pungent C. annuum. An analysis of genetic relatedness and diversity using the software Structure revealed clustering of the germplasm which was confirmed with statistical support by principle components analysis (PCA) and phylogenetic analysis. This research demonstrates the effectiveness of parallel high-throughput discovery and application of genome-wide transcript-based markers to assess genetic and genomic features among Capsicum annuum.

Polygenic hazard score to guide screening for aggressive prostate cancer: development and validation in large scale cohorts.

PubMed

Seibert, Tyler M; Fan, Chun Chieh; Wang, Yunpeng; Zuber, Verena; Karunamuni, Roshan; Parsons, J Kellogg; Eeles, Rosalind A; Easton, Douglas F; Kote-Jarai, ZSofia; Al Olama, Ali Amin; Garcia, Sara Benlloch; Muir, Kenneth; Grönberg, Henrik; Wiklund, Fredrik; Aly, Markus; Schleutker, Johanna; Sipeky, Csilla; Tammela, Teuvo Lj; Nordestgaard, Børge G; Nielsen, Sune F; Weischer, Maren; Bisbjerg, Rasmus; Røder, M Andreas; Iversen, Peter; Key, Tim J; Travis, Ruth C; Neal, David E; Donovan, Jenny L; Hamdy, Freddie C; Pharoah, Paul; Pashayan, Nora; Khaw, Kay-Tee; Maier, Christiane; Vogel, Walther; Luedeke, Manuel; Herkommer, Kathleen; Kibel, Adam S; Cybulski, Cezary; Wokolorczyk, Dominika; Kluzniak, Wojciech; Cannon-Albright, Lisa; Brenner, Hermann; Cuk, Katarina; Saum, Kai-Uwe; Park, Jong Y; Sellers, Thomas A; Slavov, Chavdar; Kaneva, Radka; Mitev, Vanio; Batra, Jyotsna; Clements, Judith A; Spurdle, Amanda; Teixeira, Manuel R; Paulo, Paula; Maia, Sofia; Pandha, Hardev; Michael, Agnieszka; Kierzek, Andrzej; Karow, David S; Mills, Ian G; Andreassen, Ole A; Dale, Anders M

2018-01-10

To develop and validate a genetic tool to predict age of onset of aggressive prostate cancer (PCa) and to guide decisions of who to screen and at what age. Analysis of genotype, PCa status, and age to select single nucleotide polymorphisms (SNPs) associated with diagnosis. These polymorphisms were incorporated into a survival analysis to estimate their effects on age at diagnosis of aggressive PCa (that is, not eligible for surveillance according to National Comprehensive Cancer Network guidelines; any of Gleason score ≥7, stage T3-T4, PSA (prostate specific antigen) concentration ≥10 ng/L, nodal metastasis, distant metastasis). The resulting polygenic hazard score is an assessment of individual genetic risk. The final model was applied to an independent dataset containing genotype and PSA screening data. The hazard score was calculated for these men to test prediction of survival free from PCa. Multiple institutions that were members of international PRACTICAL consortium. All consortium participants of European ancestry with known age, PCa status, and quality assured custom (iCOGS) array genotype data. The development dataset comprised 31 747 men; the validation dataset comprised 6411 men. Prediction with hazard score of age of onset of aggressive cancer in validation set. In the independent validation set, the hazard score calculated from 54 single nucleotide polymorphisms was a highly significant predictor of age at diagnosis of aggressive cancer (z=11.2, P<10 -16 ). When men in the validation set with high scores (>98th centile) were compared with those with average scores (30th-70th centile), the hazard ratio for aggressive cancer was 2.9 (95% confidence interval 2.4 to 3.4). Inclusion of family history in a combined model did not improve prediction of onset of aggressive PCa (P=0.59), and polygenic hazard score performance remained high when family history was accounted for. Additionally, the positive predictive value of PSA screening for aggressive PCa was increased with increasing polygenic hazard score. Polygenic hazard scores can be used for personalised genetic risk estimates that can predict for age at onset of aggressive PCa. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.

SLCO1B1 polymorphism is not associated with risk of statin-induced myalgia/myopathy in a Czech population.

PubMed

Hubáček, Jaroslav A; Dlouhá, Dana; Adámková, Vera; Zlatohlavek, Lukáš; Viklický, Ondřej; Hrubá, Petra; Češka, Richard; Vrablík, Michal

2015-05-20

Gene SLCO1B1, encoding solute organic anionic transport polypeptide OATP1B1, belongs to the group of candidates potentially influencing statin treatment safety. OATP1B1 regulates (not only) the hepatic uptake of statins. Its genetic variation was described as an important predictor of statin-associated myopathy in a cohort of patients treated with a maximum dose of simvastatin. However, the impact of SLCO1B1 gene polymorphism on this risk in patients treated with other statins or lower doses of simvastatin needs to be assessed. Therefore, we performed the present study. SLCO1B1 tagging rs4363657 polymorphism was analyzed in 2 groups of patients with dyslipidemia (treated with simvastatin or atorvastatin, 10 or 20 mg per day), subgroup with statin-induced myalgia (N=286), and subgroup (N=707) without myalgia/myopathy, and in 2301 population controls without lipid-lowering treatment. Frequency of the individual genotypes in patients with myalgia/myopathy (TT=62.3%, CT=34.5%, CC=2.8%) did not significantly differ (both P values over 0.19) from that in patients without muscle symptoms (TT=61.4%, CT=32.9%, CC=5.7%) or from the population controls (TT=63.9%, CT=32.5%, CC=3.6%). Null results were also obtained for the dominant and recessive models of the analysis. In Czech patients treated with low statin doses, there is no association between SLCO1B1 gene polymorphism and risk of myalgia/myopathy.

SLCO1B1 Polymorphism is not associated with Risk of Statin-Induced Myalgia/Myopathy in a Czech Population

PubMed Central

Hubáček, Jaroslav A.; Dlouhá, Dana; Adámková, Vera; Zlatohlávek, Lukáš; Viklický, Ondřej; Hrubá, Petra; Češka, Richard; Vrablík, Michal

2015-01-01

Background Gene SLCO1B1, encoding solute organic anionic transport polypeptide OATP1B1, belongs to the group of candidates potentially influencing statin treatment safety. OATP1B1 regulates (not only) the hepatic uptake of statins. Its genetic variation was described as an important predictor of statin-associated myopathy in a cohort of patients treated with a maximum dose of simvastatin. However, the impact of SLCO1B1 gene polymorphism on this risk in patients treated with other statins or lower doses of simvastatin needs to be assessed. Therefore, we performed the present study. Material/Methods SLCO1B1 tagging rs4363657 polymorphism was analyzed in 2 groups of patients with dyslipidemia (treated with simvastatin or atorvastatin, 10 or 20 mg per day), subgroup with statin-induced myalgia (N=286), and subgroup (N=707) without myalgia/myopathy, and in 2301 population controls without lipid-lowering treatment. Results Frequency of the individual genotypes in patients with myalgia/myopathy (TT=62.3%, CT=34.5%, CC=2.8%) did not significantly differ (both P values over 0.19) from that in patients without muscle symptoms (TT=61.4%, CT=32.9%, CC=5.7%) or from the population controls (TT=63.9%, CT=32.5%, CC=3.6%). Null results were also obtained for the dominant and recessive models of the analysis. Conclusions In Czech patients treated with low statin doses, there is no association between SLCO1B1 gene polymorphism and risk of myalgia/myopathy. PMID:25992810

Genomic Variation in Natural Populations of Drosophila melanogaster

PubMed Central

Langley, Charles H.; Stevens, Kristian; Cardeno, Charis; Lee, Yuh Chwen G.; Schrider, Daniel R.; Pool, John E.; Langley, Sasha A.; Suarez, Charlyn; Corbett-Detig, Russell B.; Kolaczkowski, Bryan; Fang, Shu; Nista, Phillip M.; Holloway, Alisha K.; Kern, Andrew D.; Dewey, Colin N.; Song, Yun S.; Hahn, Matthew W.; Begun, David J.

2012-01-01

This report of independent genome sequences of two natural populations of Drosophila melanogaster (37 from North America and 6 from Africa) provides unique insight into forces shaping genomic polymorphism and divergence. Evidence of interactions between natural selection and genetic linkage is abundant not only in centromere- and telomere-proximal regions, but also throughout the euchromatic arms. Linkage disequilibrium, which decays within 1 kbp, exhibits a strong bias toward coupling of the more frequent alleles and provides a high-resolution map of recombination rate. The juxtaposition of population genetics statistics in small genomic windows with gene structures and chromatin states yields a rich, high-resolution annotation, including the following: (1) 5′- and 3′-UTRs are enriched for regions of reduced polymorphism relative to lineage-specific divergence; (2) exons overlap with windows of excess relative polymorphism; (3) epigenetic marks associated with active transcription initiation sites overlap with regions of reduced relative polymorphism and relatively reduced estimates of the rate of recombination; (4) the rate of adaptive nonsynonymous fixation increases with the rate of crossing over per base pair; and (5) both duplications and deletions are enriched near origins of replication and their density correlates negatively with the rate of crossing over. Available demographic models of X and autosome descent cannot account for the increased divergence on the X and loss of diversity associated with the out-of-Africa migration. Comparison of the variation among these genomes to variation among genomes from D. simulans suggests that many targets of directional selection are shared between these species. PMID:22673804

Effect of rs6923761 gene variant of glucagon-like peptide 1 receptor on metabolic response and weight loss after a 3-month intervention with a hypocaloric diet.

PubMed

de Luis, Daniel Antonio; Aller, Rocío; Izaola, Olatz; Lopez, J J; Gomez, E; Torres, B; Soto, G Diaz

2014-10-01

Studies of the GLP-1 receptor (GLP-1 R) have been directed at identifying polymorphisms in the GLP-1 R gene that may be a contributing factor in the pathogenesis of obesity and cardiovascular risk factors. Nevertheless, the role of GLP-1 R variants on body weight response after dietary intervention has not been evaluated. We decided to analyze the effects of the rs6923761 GLP-1 R polymorphism on body weight changes and metabolic parameters after 3 months of a hypocaloric diet. A sample of 91 obese subjects was analyzed in a prospective way. The hypocaloric diet had 1,520 calories per day; 52 % of carbohydrates, 25 % of lipids and 23 % of proteins. Distribution of fats was: 50.7 % of monounsaturated fats, 38.5 % of saturated fats and 11.8 % of polyunsaturated fats. In both genotype groups (GG vs. GA + AA), weight, body mass index, fat mass, waist circumference, systolic blood pressure, total cholesterol, LDL cholesterol, leptin, insulin and HOMA levels decreased. No statistical differences were detected in these changes between genotypes. In wild group (GG genotype) (pretreatment and posttreatment), BMI, weight, fat mass, waist circumference and triglyceride levels were higher than (GA + AA) group. Our data showed better anthropometric parameters and triglyceride levels in obese subjects with the mutant allele (A) of rs6923761 GLP-1R polymorphism. A lack of association of this polymorphism with weight loss or biochemical changes after a hypocaloric diet was observed.

Computational Analysis of Single Nucleotide Polymorphisms Associated with Altered Drug Responsiveness in Type 2 Diabetes

PubMed Central

Costa, Valerio; Federico, Antonio; Pollastro, Carla; Ziviello, Carmela; Cataldi, Simona; Formisano, Pietro; Ciccodicola, Alfredo

2016-01-01

Type 2 diabetes (T2D) is one of the most frequent mortality causes in western countries, with rapidly increasing prevalence. Anti-diabetic drugs are the first therapeutic approach, although many patients develop drug resistance. Most drug responsiveness variability can be explained by genetic causes. Inter-individual variability is principally due to single nucleotide polymorphisms, and differential drug responsiveness has been correlated to alteration in genes involved in drug metabolism (CYP2C9) or insulin signaling (IRS1, ABCC8, KCNJ11 and PPARG). However, most genome-wide association studies did not provide clues about the contribution of DNA variations to impaired drug responsiveness. Thus, characterizing T2D drug responsiveness variants is needed to guide clinicians toward tailored therapeutic approaches. Here, we extensively investigated polymorphisms associated with altered drug response in T2D, predicting their effects in silico. Combining different computational approaches, we focused on the expression pattern of genes correlated to drug resistance and inferred evolutionary conservation of polymorphic residues, computationally predicting the biochemical properties of polymorphic proteins. Using RNA-Sequencing followed by targeted validation, we identified and experimentally confirmed that two nucleotide variations in the CAPN10 gene—currently annotated as intronic—fall within two new transcripts in this locus. Additionally, we found that a Single Nucleotide Polymorphism (SNP), currently reported as intergenic, maps to the intron of a new transcript, harboring CAPN10 and GPR35 genes, which undergoes non-sense mediated decay. Finally, we analyzed variants that fall into non-coding regulatory regions of yet underestimated functional significance, predicting that some of them can potentially affect gene expression and/or post-transcriptional regulation of mRNAs affecting the splicing. PMID:27347941

Multiple Novel Prostate Cancer Predisposition Loci Confirmed by an International Study: The PRACTICAL Consortium

PubMed Central

Kote-Jarai, Zsofia; Easton, Douglas F.; Stanford, Janet L.; Ostrander, Elaine A.; Schleutker, Johanna; Ingles, Sue A.; Schaid, Daniel; Thibodeau, Stephen; Dörk, Thilo; Neal, David; Cox, Angela; Maier, Christiane; Vogel, Walter; Guy, Michelle; Muir, Kenneth; Lophatananon, Artitaya; Kedda, Mary-Anne; Spurdle, Amanda; Steginga, Suzanne; John, Esther M.; Giles, Graham; Hopper, John; Chappuis, Pierre O.; Hutter, Pierre; Foulkes, William D.; Hamel, Nancy; Salinas, Claudia A.; Koopmeiners, Joseph S.; Karyadi, Danielle M.; Johanneson, Bo; Wahlfors, Tiina; Tammela, Teuvo L.; Stern, Mariana C.; Corral, Roman; McDonnell, Shannon K.; Schürmann, Peter; Meyer, Andreas; Kuefer, Rainer; Leongamornlert, Daniel A.; Tymrakiewicz, Malgorzata; Liu, Jo-fen; O'Mara, Tracy; Gardiner, R.A. (Frank); Aitken, Joanne; Joshi, Amit D.; Severi, Gianluca; English, Dallas R.; Southey, Melissa; Edwards, Stephen M.; Amin Al Olama, Ali; Eeles, Rosalind A.

2009-01-01

A recent genome-wide association study found that genetic variants on chromosomes 3, 6, 7, 10, 11, 19 and X were associated with prostate cancer risk. We evaluated the most significant single-nucleotide polymorphisms (SNP) in these loci using a worldwide consortium of 13 groups (PRACTICAL). Blood DNA from 7,370 prostate cancer cases and 5,742 male controls was analyzed by genotyping assays. Odds ratios (OR) associated with each genotype were estimated using unconditional logistic regression. Six of the seven SNPs showed clear evidence of association with prostate cancer (P = 0.0007-P = 10−17). For each of these six SNPs, the estimated per-allele OR was similar to those previously reported and ranged from 1.12 to 1.29. One SNP on 3p12 (rs2660753) showed a weaker association than previously reported [per-allele OR, 1.08 (95% confidence interval, 1.00-1.16; P = 0.06) versus 1.18 (95% confidence interval, 1.06-1.31)]. The combined risks associated with each pair of SNPs were consistent with a multiplicative risk model. Under this model, and in combination with previously reported SNPs on 8q and 17q, these loci explain 16% of the familial risk of the disease, and men in the top 10% of the risk distribution have a 2.1-fold increased risk relative to general population rates. This study provides strong confirmation of these susceptibility loci in multiple populations and shows that they make an important contribution to prostate cancer risk prediction. PMID:18708398

Interactions between genetic variants associated with adiposity traits and soft drinks in relation to longitudinal changes in body weight and waist circumference.

PubMed

Olsen, Nanna J; Ängquist, Lars; Larsen, Sofus C; Linneberg, Allan; Skaaby, Tea; Husemoen, Lise Lotte N; Toft, Ulla; Tjønneland, Anne; Halkjær, Jytte; Hansen, Torben; Pedersen, Oluf; Overvad, Kim; Ahluwalia, Tarunveer S; Sørensen, Thorkild Ia; Heitmann, Berit L

2016-09-01

Intake of sugar-sweetened beverages is associated with obesity, and this association may be modified by a genetic predisposition to obesity. We examined the interactions between a molecular genetic predisposition to various aspects of obesity and the consumption of soft drinks, which are a major part of sugar-sweetened beverages, in relation to changes in adiposity measures. A total of 4765 individuals were included in the study. On the basis of 50 obesity-associated single nucleotide polymorphisms that are associated with body mass index (BMI), waist circumference (WC), or the waist-to-hip ratio adjusted for BMI (WHRBMI), the following 4 genetic predisposition scores (GRSs) were constructed: a complete genetic predisposition score including all 50 single nucleotide polymorphisms (GRSComplete), a genetic predisposition score including BMI-associated single nucleotide polymorphisms (GRSBMI), a genetic predisposition score including waist circumference-associated single nucleotide polymorphisms (GRSWC), and a genetic predisposition score including the waist-to-hip ratio adjusted for BMI-associated single nucleotide polymorphisms (GRSWHR). Associations between soft drink intake and the annual change (Δ) in body weight (BW), WC, or waist circumference adjusted for BMI (WCBMI) and possible interactions with the GRSs were examined with the use of linear regression analyses and meta-analyses. For each soft drink serving per day, soft drink consumption was significantly associated with a higher ΔBW of 0.07 kg/y (95% CI: 0.01, 0.13 kg/y; P = 0.020) but not with the ΔWC or ΔWCBMI In analyses of the ΔBW, we showed an interaction only with the GRSWC (per risk allele for each soft drink serving per day: -0.06 kg/y; 95% CI: -0.10, -0.02 kg/y; P = 0.006). In analyses of the ΔWC, we showed interactions only with the GRSBMI and GRSComplete [per risk allele for each soft drink serving per day: 0.05 cm/y (95% CI: 0.02, 0.09 cm/y; P = 0.001) and 0.05 cm/y (95% CI: 0.02, 0.07 cm/y; P = 0.001), respectively]. Nearly identical results were observed in analyses of the ΔWCBMI CONCLUSIONS: A genetic predisposition to a high WC may attenuate the association between soft drink intake and BW gain. A genetic predisposition to high BMI as well as a genetic predisposition to high BMI, WC, and WHRBMI combined may strengthen the association between soft drink intake and WC gain. However, the public health impact may be limited. © 2016 American Society for Nutrition.

First principles crystal engineering of nonlinear optical materials. I. Prototypical case of urea

NASA Astrophysics Data System (ADS)

Masunov, Artëm E.; Tannu, Arman; Dyakov, Alexander A.; Matveeva, Anastasia D.; Freidzon, Alexandra Ya.; Odinokov, Alexey V.; Bagaturyants, Alexander A.

2017-06-01

The crystalline materials with nonlinear optical (NLO) properties are critically important for several technological applications, including nanophotonic and second harmonic generation devices. Urea is often considered to be a standard NLO material, due to the combination of non-centrosymmetric crystal packing and capacity for intramolecular charge transfer. Various approaches to crystal engineering of non-centrosymmetric molecular materials were reported in the literature. Here we propose using global lattice energy minimization to predict the crystal packing from the first principles. We developed a methodology that includes the following: (1) parameter derivation for polarizable force field AMOEBA; (2) local minimizations of crystal structures with these parameters, combined with the evolutionary algorithm for a global minimum search, implemented in program USPEX; (3) filtering out duplicate polymorphs produced; (4) reoptimization and final ranking based on density functional theory (DFT) with many-body dispersion (MBD) correction; and (5) prediction of the second-order susceptibility tensor by finite field approach. This methodology was applied to predict virtual urea polymorphs. After filtering based on packing similarity, only two distinct packing modes were predicted: one experimental and one hypothetical. DFT + MBD ranking established non-centrosymmetric crystal packing as the global minimum, in agreement with the experiment. Finite field approach was used to predict nonlinear susceptibility, and H-bonding was found to account for a 2.5-fold increase in molecular hyperpolarizability to the bulk value.

Acute Normal Tissue Reactions in Head-and-Neck Cancer Patients Treated With IMRT: Influence of Dose and Association With Genetic Polymorphisms in DNA DSB Repair Genes

DOE Office of Scientific and Technical Information (OSTI.GOV)

Werbrouck, Joke; Ruyck, Kim de; Duprez, Frederic

2009-03-15

Purpose: To investigate the association between dose-related parameters and polymorphisms in DNA DSB repair genes XRCC3 (c.-1843A>G, c.562-14A>G, c.722C>T), Rad51 (c.-3429G>C, c.-3392G>T), Lig4 (c.26C>T, c.1704T>C), Ku70 (c.-1310C>G), and Ku80 (c.2110-2408G>A) and the occurrence of acute reactions after radiotherapy. Materials and Methods: The study population consisted of 88 intensity-modulated radiation therapy (IMRT)-treated head-and-neck cancer patients. Mucositis, dermatitis, and dysphagia were scored using the Common Terminology Criteria (CTC) for Adverse Events v.3.0 scale. The population was divided into a CTC0-2 and CTC3+ group for the analysis of each acute effect. The influence of the dose on critical structures was analyzed using dose-volumemore » histograms. Genotypes were determined by polymerase chain reaction (PCR) combined with restriction fragment length polymorphism or PCR-single base extension assays. Results: The mean dose (D{sub mean}) to the oral cavity and constrictor pharyngeus (PC) muscles was significantly associated with the development of mucositis and dysphagia, respectively. These parameters were considered confounding factors in the radiogenomics analyses. The XRCC3c.722CT/TT and Ku70c.-1310CG/GG genotypes were significantly associated with the development of severe dysphagia (CTC3+). No association was found between the investigated polymorphisms and the development of mucositis or dermatitis. A risk analysis model for severe dysphagia, which was developed based on the XRCC3c.722CT/TT and Ku70c.-1310CG/GG genotypes and the PC dose, showed a sensitivity of 78.6% and a specificity of 77.6%. Conclusions: The XRCC3c.722C>T and Ku70c.-1310C>G polymorphisms as well as the D{sub mean} to the PC muscles were highly associated with the development of severe dysphagia after IMRT. The prediction model developed using these parameters showed a high sensitivity and specificity.« less

Crystal structures of CaSiO3 polymorphs control growth and osteogenic differentiation of human mesenchymal stem cells on bioceramic surfaces.

PubMed

Zhang, Nianli; Molenda, James A; Mankoci, Steven; Zhou, Xianfeng; Murphy, William L; Sahai, Nita

2013-10-01

The repair and replacement of damaged or diseased human bone tissue requires a stable interface between the orthopedic implant and living tissue. The ideal material should be both osteoconductive (promote bonding to bone) and osteoinductive (induce osteogenic differentiation of cells and generate new bone). Partially resorbable bioceramic materials with both properties are developed by expensive trial-and-error methods. Structure-reactivity relationships for predicting the osteoinductive properties of ceramics would significantly increase the efficiency of developing materials for bone tissue engineering. Here we propose the novel hypothesis that the crystal structure of a bioceramic controls the release rates, subsequent surface modifications due to precipitation of new phases, and thus, the concentrations of soluble factors, and ultimately, the attachment, viability and osteogenic differentiation of human Mesenchymal Stem Cells (hMSCs). To illustrate our hypothesis, we used two CaSiO 3 polymorphs, pseudo-wollastonite (psw, β-CaSiO 3 ) and wollastonite (wol, α-CaSiO 3 ) as scaffolds for hMSC culture. Polymorphs are materials which have identical chemical composition and stoichiometry, but different crystal structures. We combined the results of detailed surface characterizations, including environmental Scanning Electron Microscopy (SEM) back-scattered imaging, and spot-analysis and 2D elemental mapping by SEM-Energy Dispersive X-ray (SEM-EDX), High Resolution Transmission Electron Microscopy (HRTEM) and surface roughness analysis; culture medium solution analyses; and molecular/genetic assays from cell culture. Our results confirmed the hypothesis that the psw polymorph, which has a strained silicate ring structure, is more osteoinductive than the wol polymorph, which has a more stable, open silicate chain structure. The observations could be attributed to easier dissolution (resorption) of psw compared to wol, which resulted in concentration profiles that were more osteoinductive for the former. Thus, we showed that crystal structure is a fundamental parameter to be considered in the intelligent design of pro-osteogenic, partially resorbable bioceramics.

A Common Polymorphism in SCN2A Predicts General Cognitive Ability Through Effects on Prefrontal Cortex Physiology

PubMed Central

Scult, Matthew A.; Trampush, Joey W.; Zheng, Fengyu; Conley, Emily Drabant; Lencz, Todd; Malhotra, Anil K.; Dickinson, Dwight; Weinberger, Daniel R.; Hariri, Ahmad R.

2015-01-01

Here we provide novel convergent evidence across three independent cohorts of healthy adults (n=531) demonstrating that a common polymorphism in the gene encoding the α2 subunit of neuronal voltage-gated type II sodium channels (SCN2A) predicts human general cognitive ability or “g.” Using meta-analysis, we demonstrate that the minor T allele of a common polymorphism (rs10174400) in SCN2A is associated with significantly higher “g” independent of gender and age. We further demonstrate using resting-state fMRI data from our discovery cohort (n=236) that this genetic advantage may be mediated by increased capacity for information processing between the dorsolateral prefrontal cortex and dorsal anterior cingulate cortex, which support higher cognitive functions. Collectively, these findings fill a gap in our understanding of the genetics of general cognitive ability and highlight a specific neural mechanism through which a common polymorphism shapes inter-individual variation in “g.” PMID:25961639

The impact of HIV-1 reverse transcriptase polymorphisms on responses to first-line nonnucleoside reverse transcriptase inhibitor-based therapy in HIV-1-infected adults.

PubMed

Mackie, Nicola E; Dunn, David T; Dolling, David; Garvey, Lucy; Harrison, Linda; Fearnhill, Esther; Tilston, Peter; Sabin, Caroline; Geretti, Anna M

2013-09-10

HIV-1 genetic variability may influence antiretroviral therapy (ART) outcomes. The study aim was to determine the impact of polymorphisms in regions known to harbor major nonnucleoside reverse transcriptase inhibitor (NNRTI) resistance mutations (codons 90-108, 135-138, 179-190, 225-348) on virologic responses to first-line NNRTI-based ART. Reverse transcriptase sequences from ART-naive individuals who commenced efavirenz (EFV) or nevirapine (NVP) with at least two nucleos(t)ide reverse transcriptase inhibitors (NRTIs) without major drug resistance mutations were analyzed. The impact of polymorphisms on week 4 viral load decrease and time to virologic failure was measured over a median 97 weeks. Among 4528 patients, most were infected with HIV-1 subtype B (67%) and commenced EFV-based ART (84%). Overall, 2598 (57%) had at least one polymorphism, most frequently at codons 90, 98, 101, 103, 106, 135, 138, 179, and 238. Virologic failure rates were increased in patients with two (n = 597) or more than two (n = 72) polymorphisms [adjusted hazard ratio 1.43; 95% confidence interval (CI) 1.07-1.92; P = 0.016]. Polymorphisms associated with virologic failure occurred at codons 90 (mostly V90I), 98 (mostly A98S), and 103 (mostly K103R), with adjusted hazard ratios of 1.78 (1.15-2.73; P = 0.009), 1.55 (1.16-2.08; P = 0.003), and 1.75 (1.00-3.05: P = 0.049), respectively. Polymorphisms at codon 179, especially V179D/E/T, predicted reduced week 4 responses (P = 0.001) but not virologic failure. The occurrence of multiple polymorphisms, though uncommon, was associated with a small increase in the risk of NNRTI treatment failure; significant effects were seen with polymorphisms at codon 90, 98, and 103. The mechanisms underlying the slower suppression seen with V179D/E/T deserve further investigation.

Polymorphic microsatellite loci for the sand pocket mouse Chaetodipus arenarius, an endemic from the Baja California Peninsula

USGS Publications Warehouse

Munguia-Vega, A.; Rodriguez-Estrella, R.; Nachman, M.; Culver, M.

2009-01-01

Fifteen polymorphic microsatellite loci were isolated from an enriched genomic library of the sand pocket mouse Chaetodipus arenarius. The mean number of alleles per locus was 11.53 (range five to 19) and the average observed heterozygosity was 0.764 (range 0.121 to 1.0). The markers will be used for detecting the impact of human-induced habitat fragmentation on patterns of gene flow, genetic structure, and extinction risk. In addition, these markers will be useful across the genus because most of the loci cross-amplified and were polymorphic in three other species of Chaetodipus. ?? 2008 The Authors.

Estimating the probability of elevated nitrate (NO2+NO3-N) concentrations in ground water in the Columbia Basin Ground Water Management Area, Washington

USGS Publications Warehouse

Frans, Lonna M.

2000-01-01

Logistic regression was used to relate anthropogenic (man-made) and natural factors to the occurrence of elevated concentrations of nitrite plus nitrate as nitrogen in ground water in the Columbia Basin Ground Water Management Area, eastern Washington. Variables that were analyzed included well depth, depth of well casing, ground-water recharge rates, presence of canals, fertilizer application amounts, soils, surficial geology, and land-use types. The variables that best explain the occurrence of nitrate concentrations above 3 milligrams per liter in wells were the amount of fertilizer applied annually within a 2-kilometer radius of a well and the depth of the well casing; the variables that best explain the occurrence of nitrate above 10 milligrams per liter included the amount of fertilizer applied annually within a 3-kilometer radius of a well, the depth of the well casing, and the mean soil hydrologic group, which is a measure of soil infiltration rate. Based on the relations between these variables and elevated nitrate concentrations, models were developed using logistic regression that predict the probability that ground water will exceed a nitrate concentration of either 3 milligrams per liter or 10 milligrams per liter. Maps were produced that illustrate the predicted probability that ground-water nitrate concentrations will exceed 3 milligrams per liter or 10 milligrams per liter for wells cased to 78 feet below land surface (median casing depth) and the predicted depth to which wells would need to be cased in order to have an 80-percent probability of drawing water with a nitrate concentration below either 3 milligrams per liter or 10 milligrams per liter. Maps showing the predicted probability for the occurrence of elevated nitrate concentrations indicate that the irrigated agricultural regions are most at risk. The predicted depths to which wells need to be cased in order to have an 80-percent chance of obtaining low nitrate ground water exceed 600 feet in the irrigated agricultural regions, whereas wells in dryland agricultural areas generally need a casing in excess of 400 feet. The predicted depth to which wells need to be cased to have at least an 80-percent chance to draw water with a nitrate concentration less than 10 milligrams per liter generally did not exceed 800 feet, with a 200-foot casing depth typical of the majority of the area.

Bioinformatics analysis reveals biophysical and evolutionary insights into the 3-nitrotyrosine post-translational modification in the human proteome

PubMed Central

Ng, John Y.; Boelen, Lies; Wong, Jason W. H.

2013-01-01

Protein 3-nitrotyrosine is a post-translational modification that commonly arises from the nitration of tyrosine residues. This modification has been detected under a wide range of pathological conditions and has been shown to alter protein function. Whether 3-nitrotyrosine is important in normal cellular processes or is likely to affect specific biological pathways remains unclear. Using GPS-YNO2, a recently described 3-nitrotyrosine prediction algorithm, a set of predictions for nitrated residues in the human proteome was generated. In total, 9.27 per cent of the proteome was predicted to be nitratable (27 922/301 091). By matching the predictions against a set of curated and experimentally validated 3-nitrotyrosine sites in human proteins, it was found that GPS-YNO2 is able to predict 73.1 per cent (404/553) of these sites. Furthermore, of these sites, 42 have been shown to be nitrated endogenously, with 85.7 per cent (36/42) of these predicted to be nitrated. This demonstrates the feasibility of using the predicted dataset for a whole proteome analysis. A comprehensive bioinformatics analysis was subsequently performed on predicted and all experimentally validated nitrated tyrosine. This found mild but specific biophysical constraints that affect the susceptibility of tyrosine to nitration, and these may play a role in increasing the likelihood of 3-nitrotyrosine to affect processes, including phosphorylation and DNA binding. Furthermore, examining the evolutionary conservation of predicted 3-nitrotyrosine showed that, relative to non-nitrated tyrosine residues, 3-nitrotyrosine residues are generally less conserved. This suggests that, at least in the majority of cases, 3-nitrotyrosine is likely to have a deleterious effect on protein function and less likely to be important in normal cellular function. PMID:23389939

SNP discovery and development of genetic markers for mapping innate immune response genes in common carp (Cyprinus carpio).

PubMed

Kongchum, Pawapol; Palti, Yniv; Hallerman, Eric M; Hulata, Gideon; David, Lior

2010-08-01

Single nucleotide polymorphisms (SNPs) in immune response genes have been reported as markers for susceptibility to infectious diseases in human and livestock. A disease caused by cyprinid herpesvirus 3 (CyHV-3) is highly contagious and virulent in common carp (Cyprinus carpio). With the aim to develop molecular tools for breeding CyHV-3-resistant carp, we have amplified and sequenced 11 candidate genes for viral disease resistance including TLR2, TLR3, TLR4ba, TLR7, TLR9, TLR21, TLR22, MyD88, TRAF6, type I IFN and IL-1beta. For each gene, we initially cloned and sequenced PCR amplicons from 8 to 12 fish (2-3 fish per strain) from the SNP discovery panel. We then identified and evaluated putative SNPs for their polymorphisms in the SNP discovery panel and validated their usefulness for linkage analysis in a full-sib family using the SNaPshot method. Our sequencing results and phylogenetic analyses suggested that TLR3, TLR7 and MyD88 genes are duplicated in the common carp genome. We, therefore, developed locus-specific PCR primers and SNP genotyping assays for the duplicated loci. A total of 48 SNP markers were developed from PCR fragments of the 13 loci (7 single-locus and 3 duplicated genes). Thirty-nine markers were polymorphic with estimated minor allele frequencies of more than 0.1. The utility of the SNP markers was evaluated in one full-sib family and revealed that 20 markers from 9 loci segregated in a disomic and Mendelian pattern and would be useful for linkage analysis. Published by Elsevier Ltd.

High-Throughput Development of SSR Markers from Pea (Pisum sativum L.) Based on Next Generation Sequencing of a Purified Chinese Commercial Variety

PubMed Central

Zhang, Xiaoyan; Hu, Jinguo; Bao, Shiying; Hao, Junjie; Li, Ling; He, Yuhua; Jiang, Junye; Wang, Fang; Tian, Shufang; Zong, Xuxiao

2015-01-01

Pea (Pisum sativum L.) is an important food legume globally, and is the plant species that J.G. Mendel used to lay the foundation of modern genetics. However, genomics resources of pea are limited comparing to other crop species. Application of marker assisted selection (MAS) in pea breeding has lagged behind many other crops. Development of a large number of novel and reliable SSR (simple sequence repeat) or microsatellite markers will help both basic and applied genomics research of this crop. The Illumina HiSeq 2500 System was used to uncover 8,899 putative SSR containing sequences, and 3,275 non-redundant primers were designed to amplify these SSRs. Among the 1,644 SSRs that were randomly selected for primer validation, 841 yielded reliable amplifications of detectable polymorphisms among 24 genotypes of cultivated pea (Pisum sativum L.) and wild relatives (P. fulvum Sm.) originated from diverse geographical locations. The dataset indicated that the allele number per locus ranged from 2 to 10, and that the polymorphism information content (PIC) ranged from 0.08 to 0.82 with an average of 0.38. These 1,644 novel SSR markers were also tested for polymorphism between genotypes G0003973 and G0005527. Finally, 33 polymorphic SSR markers were anchored on the genetic linkage map of G0003973 × G0005527 F2 population. PMID:26440522

Associations of CYP3A4, NR1I2, CYP2C19 and P2RY12 polymorphisms with clopidogrel resistance in Chinese patients with ischemic stroke

PubMed Central

Liu, Rui; Zhou, Zi-yi; Chen, Yi-bei; Li, Jia-li; Yu, Wei-bang; Chen, Xin-meng; Zhao, Min; Zhao, Yuan-qi; Cai, Ye-feng; Jin, Jing; Huang, Min

2016-01-01

Aim: There is a high incidence of the antiplatelet drug clopidogrel resistance (CR) in Asian populations. Because clopidogrel is a prodrug, polymorphisms of genes encoding the enzymes involved in its biotransformation may be the primary influential factors. The goal of this study was to investigate the associations of polymorphisms of CYP3A4, NR1I2, CYP2C19 and P2RY12 genes with CR in Chinese patients with ischemic stroke. Methods: A total of 191 patients with ischemic stroke were enrolled. The patients were treated with clopidogrel for at least 5 days. Platelet function was measured by light transmission aggregometry. The SNPs NR1I2 (rs13059232), CYP3A4*1G (rs2242480), CYP2C19*2 (rs4244285) and P2RY12 (rs2046934) were genotyped. Results: The CR rate in this population was 36%. The CYP2C19*2 variant was a risk factor for CR (*2/*2+wt/*2 vs wt/wt, OR: 2.366, 95% CI: 1.180–4.741, P=0.014), whereas the CYP3A4*1G variant had a protective effect on CR (*1/*1 vs *1G/*1G+*1/*1G, OR: 2.360, 95% CI: 1.247–4.468, P=0.008). The NR1I2 (rs13059232) polymorphism was moderately associated with CR (CC vs TT+TC, OR: 0.533, 95% CI: 0.286–0.991, P=0.046). The C allele in P2RY12 (rs2046934) was predicted to be a protective factor for CR (CC+TC vs TT, OR: 0.407, 95% CI: 0.191–0.867, P=0.018). In addition, an association was found between hypertension and CR (P=0.022). Conclusion: The individuals with both the CYP2C19*2 allele and hypertension are at high risk of CR during anti-thrombosis therapy. The CYP3A4*1G allele, P2RY12 (rs2046934) C allele and NR1I2 (rs13059232) CC genotype may be protective factors for CR. The associated SNPs studied may be useful to predict clopidogrel resistance in Chinese patients with ischemic stroke. PMID:27133299

Significant SNPs have limited prediction ability for thyroid cancer

PubMed Central

Guo, Shicheng; Wang, Yu-Long; Li, Yi; Jin, Li; Xiong, Momiao; Ji, Qing-Hai; Wang, Jiucun

2014-01-01

Recently, five thyroid cancer significantly associated genetic variants (rs965513, rs944289, rs116909374, rs966423, and rs2439302) have been discovered and validated in two independent GWAS and numerous case–control studies, which were conducted in different populations. We genotyped the above five single nucleotide polymorphisms (SNPs) in Han Chinese populations and performed thyroid cancer-risk predictions with nine machine learning methods. We found that four SNPs were significantly associated with thyroid cancer in Han Chinese population, while no polymorphism was observed for rs116909374. Small familial relative risks (1.02–1.05) and limited power to predict thyroid cancer (AUCs: 0.54–0.60) indicate limited clinical potential. Four significant SNPs have limited prediction ability for thyroid cancer. PMID:24591304

Mechanical properties of zirconium alloys and zirconium hydrides predicted from density functional perturbation theory

DOE PAGES

Weck, Philippe F.; Kim, Eunja; Tikare, Veena; ...

2015-10-13

Here, the elastic properties and mechanical stability of zirconium alloys and zirconium hydrides have been investigated within the framework of density functional perturbation theory. Results show that the lowest-energy cubic Pn-3m with combining macron]m polymorph of δ-ZrH 1.5 does not satisfy all the Born requirements for mechanical stability, unlike its nearly degenerate tetragonal P4 2/ mcm polymorph. Elastic moduli predicted with the Voigt–Reuss–Hill approximations suggest that mechanical stability of α-Zr, Zr-alloy and Zr-hydride polycrystalline aggregates is limited by the shear modulus. According to both Pugh's and Poisson's ratios, α-Zr, Zr-alloy and Zr-hydride polycrystalline aggregates can be considered ductile. The Debyemore » temperatures predicted for γ-ZrH, δ-ZrH 1.5 and ε-ZrH 2 are θ D = 299.7, 415.6 and 356.9 K, respectively, while θ D = 273.6, 284.2, 264.1 and 257.1 K for the α-Zr, Zry-4, ZIRLO and M5 matrices, i.e. suggesting that Zry-4 possesses the highest micro-hardness among Zr matrices.« less

Reserch of the gene polymorphism TOX3 / LOC643714 and the risk of breast cancer development in persons exposed to ionizing radiation after Chornobyl disaster.

PubMed

Polinyk, S I; Rybchenko, L A; Klimyk, B T

2017-12-01

The objective of this work was to identify and compare the polymorphism of the rs3803662 polymorphism of the TOX3/LOC643714 gene in breast cancer patients who have undergone ionizing radiation due to the Chornobyl accident and in patients without ionizing radiation (IR) in the history. The determination of the rs3803662 polymorphism of the TOX3/LOC643714 gene was per formed by polymerase chain reaction (PCR) in 83 patients with breast cancer: 42 subjects who were exposed to ion izing radiation due to the Chornobyl accident, 41 people without ionizing radiation in history and 17 controls in Ukraine without cancer pathology. In order to compare the obtained data on spontaneous and radiation associated breast cancer and to calculate the differences in the frequencies of alleles and the risk of oncopathology, data from literature on control groups of the populations of the Russian Federation, Sweden, and the United Kingdom were used. Comparing with the literature data and the group of exposed subjects, the homozygous carriers of the minor alleles of the TOX3/LOC643714 ТТ gene revealed an increased risk of developing breast cancer: OR = 2.89, p = 0.02 (CI 95% 1.17 7,16). In subjects without the influence of IR in history, the carrier of homozygous minor axis of the gene TOX3/LOC643714 ТТ is also associated with the risk of breast cancer: OR = 3.83, p = 0.0002 (CI 95% 0.82-14.14). In the homozygous carriers of the minor alleles of the TOX3 / LOC643714 gene exposed to IR, there was no increase in the risk of developing breast cancer (OR = 0.65, p = 0.46, CI 95% 0.21-2.04) compared with the con trol group of Ukrainian population. The carrier of homozygous minor alleles of the TOX3/LOC643714 gene is not a risk factor for the devel opment of breast cancer under conditions of exposure to ionizing radiation in the study group of the Ukrainian population. S. I. Polinyk, L. A. Rybchenko, B. T. Klimyk.

A Rapid and Accurate Method to Evaluate Helicobacter pylori Infection, Clarithromycin Resistance, and CYP2C19 Genotypes Simultaneously From Gastric Juice

PubMed Central

Kuo, Chao-Hung; Liu, Chung-Jung; Yang, Ching-Chia; Kuo, Fu-Chen; Hu, Huang-Ming; Shih, Hsiang-Yao; Wu, Meng-Chieh; Chen, Yen-Hsu; Wang, Hui-Min David; Ren, Jian-Lin; Wu, Deng-Chyang; Chang, Lin-Li

2016-01-01

Abstract Because Helicobacter pylori (H pylori) would cause carcinogenesis of the stomach, we need sufficient information for deciding on an appropriate strategy of eradication. Many factors affect the efficacy of eradication including antimicrobial resistance (especially clarithromycin resistance) and CYP2C19 polymorphism. This study was to survey the efficiency of gastric juice for detecting H pylori infection, clarithromycin resistance, and CYP2C19 polymorphism. The specimens of gastric juice were collected from all patients while receiving gastroscopy. DNA was extracted from gastric juice and then urease A and cag A were amplified by polymerase chain reaction (PCR) for detecting the existence of H pylori. By PCR-restriction fragment length polymorphism (PCR-RFLP), the 23S rRNA of H pylori and CYP2C19 genotypes of host were examined respectively. During endoscopy examination, biopsy-based specimens were also collected for rapid urease test, culture, and histology. The blood samples were also collected for analysis of CYP2C19 genotypes. We compared the results of gastric juice tests with the results of traditional clinical tests. When compared with the results from traditional clinical tests, our results from gastric juice showed that the sensitivity (SEN), specificity (SPE), positive predictive value (PPV), negative predictive value (NPV), and accuracy to detect H pylori infection were 92.1% (105/114), 92.9% (143/154), 90.5% (105/116), 94.1% (143/152), and 92.5% (248/268), respectively. The SEN, SPE, PPV, and NPV to detect clarithromycin resistance were 97.3% (36/37), 91.5% (43/47), 90.0% (36/40), and 97.7% (43/44), respectively. By using PCR-RFLP, the consistency of human CYP2C19 gene polymorphism from blood samples and gastric juice was as high as 94.9% (149/157). The manipulated gastric juice is actually an effective diagnostic sample for evaluation of H pylori existence, clarithromycin resistance, and host CYP2C19 polymorphism. PMID:27227911

Unlocking Diversity in Germplasm Collections via Genomic Selection: A Case Study Based on Quantitative Adult Plant Resistance to Stripe Rust in Spring Wheat.

PubMed

Muleta, Kebede T; Bulli, Peter; Zhang, Zhiwu; Chen, Xianming; Pumphrey, Michael

2017-11-01

Harnessing diversity from germplasm collections is more feasible today because of the development of lower-cost and higher-throughput genotyping methods. However, the cost of phenotyping is still generally high, so efficient methods of sampling and exploiting useful diversity are needed. Genomic selection (GS) has the potential to enhance the use of desirable genetic variation in germplasm collections through predicting the genomic estimated breeding values (GEBVs) for all traits that have been measured. Here, we evaluated the effects of various scenarios of population genetic properties and marker density on the accuracy of GEBVs in the context of applying GS for wheat ( L.) germplasm use. Empirical data for adult plant resistance to stripe rust ( f. sp. ) collected on 1163 spring wheat accessions and genotypic data based on the wheat 9K single nucleotide polymorphism (SNP) iSelect assay were used for various genomic prediction tests. Unsurprisingly, the results of the cross-validation tests demonstrated that prediction accuracy increased with an increase in training population size and marker density. It was evident that using all the available markers (5619) was unnecessary for capturing the trait variation in the germplasm collection, with no further gain in prediction accuracy beyond 1 SNP per 3.2 cM (∼1850 markers), which is close to the linkage disequilibrium decay rate in this population. Collectively, our results suggest that larger germplasm collections may be efficiently sampled via lower-density genotyping methods, whereas genetic relationships between the training and validation populations remain critical when exploiting GS to select from germplasm collections. Copyright © 2017 Crop Science Society of America.

DOE Office of Scientific and Technical Information (OSTI.GOV)

Gilchrist, Michael J.; Sobral, Daniel; Khoueiry, Pierre

Genome-wide resources, such as collections of cDNA clones encoding for complete proteins (full-ORF clones), are crucial tools for studying the evolution of gene function and genetic interactions. Non-model organisms, in particular marine organisms, provide a rich source of functional diversity. Marine organism genomes are, however, frequently highly polymorphic and encode proteins that diverge significantly from those of well-annotated model genomes. The construction of full-ORF clone collections from non-model organisms is hindered by the difficulty of predicting accurately the N-terminal ends of proteins, and distinguishing recent paralogs from highly polymorphic alleles. We also report a computational strategy that overcomes these difficulties,more » and allows for accurate gene level clustering of transcript data followed by the automated identification of full-ORFs with correct 5'- and 3'-ends. It is robust to polymorphism, includes paralog calling and does not require evolutionary proximity to well annotated model organisms. Here, we developed this pipeline for the ascidian Ciona intestinalis, a highly polymorphic member of the divergent sister group of the vertebrates, emerging as a powerful model organism to study chordate gene function, Gene Regulatory Networks and molecular mechanisms underlying human pathologies. Furthermore, using this pipeline we have generated the first full-ORF collection for a highly polymorphic marine invertebrate. It contains 19,163 full-ORF cDNA clones covering 60% of Ciona coding genes, and full-ORF orthologs for approximately half of curated human disease-associated genes.« less

Thermochemistry of paddle wheel MOFs: Cu-HKUST-1 and Zn-HKUST-1.

PubMed

Bhunia, Manas K; Hughes, James T; Fettinger, James C; Navrotsky, Alexandra

2013-06-25

Metal-organic framework (MOF) porosity relies upon robust metal-organic bonds to retain structural rigidity upon solvent removal. Both the as-synthesized and activated Cu and Zn polymorphs of HKUST-1 were studied by room temperature acid solution calorimetry. Their enthalpies of formation from dense assemblages (metal oxide (ZnO or CuO), trimesic acid (TMA), and N,N-dimethylformamide (DMF)) were calculated from the calorimetric data. The enthalpy of formation (ΔHf) of the as-synthesized Cu-HKUST-H2O ([Cu3TMA2·3H2O]·5DMF) is -52.70 ± 0.34 kJ per mole of Cu. The ΔHf for Zn-HKUST-DMF ([Zn3TMA2·3DMF]·2DMF) is -54.22 ± 0.57 kJ per mole of Zn. The desolvated Cu-HKUST-dg [Cu3TMA2] has a ΔHf of 16.66 ± 0.51 kJ/mol per mole Cu. The ΔHf for Zn-HKUST-amorph [Zn3TMA2·2DMF] is -3.57 ± 0.21 kJ per mole of Zn. Solvent stabilizes the Cu-HKUST-H2O by -69.4 kJ per mole of Cu and Zn-HKUST-DMF by at least -50.7 kJ per mole of Zn. Such strong chemisorption of solvent is similar in magnitude to the strongly exothermic binding at low coverage for chemisorbed H2O on transition metal oxide nanoparticle surfaces. The strongly exothermic solvent-framework interaction suggests that solvent can play a critical role in obtaining a specific secondary building unit (SBU) topology.

Development of microsatellite markers for Anadenanthera colubrina (Leguminosae), a neotropical tree species.

PubMed

Feres, Juliana Massimino; Monteiro, Mariza; Zucchi, Maria I; Pinheiro, José B; Mestriner, Moacyr A; Alzate-Marin, Ana Lilia

2012-04-01

We developed and characterized nuclear microsatellite markers for Anadenanthera colubrina, a tropical tree species widely distributed in South America. Leaf samples of mature A. colubrina trees, popularly called "angico," were collected from an area that is greatly impacted by agricultural practices in the region of Ribeirão Preto in São Paulo State in southeastern Brazil. Twenty simple sequence repeat (SSR) markers were developed, 14 of which had polymorphic loci. A total of 96 alleles were detected with an average of 6.86 alleles per polymorphic locus. The expected heterozygosity, calculated at polymorphic loci, ranged from 0.18 to 0.83. Finally, we demonstrated that 18 loci were cross-amplified in A. peregrina. A total of 14 polymorphic markers suggest a high potential for genetic diversity, gene flow, and mating system analyses in A. colubrina.

A Simple Sequence Repeat- and Single-Nucleotide Polymorphism-Based Genetic Linkage Map of the Brown Planthopper, Nilaparvata lugens

PubMed Central

Jairin, Jirapong; Kobayashi, Tetsuya; Yamagata, Yoshiyuki; Sanada-Morimura, Sachiyo; Mori, Kazuki; Tashiro, Kosuke; Kuhara, Satoru; Kuwazaki, Seigo; Urio, Masahiro; Suetsugu, Yoshitaka; Yamamoto, Kimiko; Matsumura, Masaya; Yasui, Hideshi

2013-01-01

In this study, we developed the first genetic linkage map for the major rice insect pest, the brown planthopper (BPH, Nilaparvata lugens). The linkage map was constructed by integrating linkage data from two backcross populations derived from three inbred BPH strains. The consensus map consists of 474 simple sequence repeats, 43 single-nucleotide polymorphisms, and 1 sequence-tagged site, for a total of 518 markers at 472 unique positions in 17 linkage groups. The linkage groups cover 1093.9 cM, with an average distance of 2.3 cM between loci. The average number of marker loci per linkage group was 27.8. The sex-linkage group was identified by exploiting X-linked and Y-specific markers. Our linkage map and the newly developed markers used to create it constitute an essential resource and a useful framework for future genetic analyses in BPH. PMID:23204257

Genetic diversity studies in pea (Pisum sativum L.) using simple sequence repeat markers.

PubMed

Kumari, P; Basal, N; Singh, A K; Rai, V P; Srivastava, C P; Singh, P K

2013-03-13

The genetic diversity among 28 pea (Pisum sativum L.) genotypes was analyzed using 32 simple sequence repeat markers. A total of 44 polymorphic bands, with an average of 2.1 bands per primer, were obtained. The polymorphism information content ranged from 0.657 to 0.309 with an average of 0.493. The variation in genetic diversity among these cultivars ranged from 0.11 to 0.73. Cluster analysis based on Jaccard's similarity coefficient using the unweighted pair-group method with arithmetic mean (UPGMA) revealed 2 distinct clusters, I and II, comprising 6 and 22 genotypes, respectively. Cluster II was further differentiated into 2 subclusters, IIA and IIB, with 12 and 10 genotypes, respectively. Principal component (PC) analysis revealed results similar to those of UPGMA. The first, second, and third PCs contributed 21.6, 16.1, and 14.0% of the variation, respectively; cumulative variation of the first 3 PCs was 51.7%.

Phylogenetic relationships of chrysanthemums in Korea based on novel SSR markers.

PubMed

Khaing, A A; Moe, K T; Hong, W J; Park, C S; Yeon, K H; Park, H S; Kim, D C; Choi, B J; Jung, J Y; Chae, S C; Lee, K M; Park, Y J

2013-11-07

Chrysanthemums are well known for their esthetic and medicinal values. Characterization of chrysanthemums is vital for their conservation and management as well as for understanding their genetic relationships. We found 12 simple sequence repeat markers (SSRs) of 100 designed primers to be polymorphic. These novel SSR markers were used to evaluate 95 accessions of chrysanthemums (3 indigenous and 92 cultivated accessions). Two hundred alleles were identified, with an average of 16.7 alleles per locus. KNUCRY-77 gave the highest polymorphic information content value (0.879), while KNUCRY-10 gave the lowest (0.218). Similar patterns of grouping were observed with a distance-based dendrogram developed using PowerMarker and model-based clustering with Structure. Three clusters with some admixtures were identified by model-based clustering. These newly developed SSR markers will be useful for further studies of chrysanthemums, such as taxonomy and marker-assisted selection breeding.

Sustained medically unexplained physical symptoms in euthymic patients with recurrent depression: predictive value for recurrence and associations with omega 3- and 6 fatty acids and 5-HTTLPR?

PubMed

Lok, Anja; Assies, Johanna; Koeter, Maarten W J; Bockting, Claudi L H; Wouters, Luuk F; Mocking, Roel J T; Schene, Aart H

2012-02-01

Identification of potentially modifiable risk factors for recurrence in recurrent depression could provide opportunities to improve preventive interventions. In this study we aimed to examine the predictive value of medically unexplained physical symptoms (MUPS) on time to recurrence in recurrent depression. Additionally, to elucidate pathophysiological mechanisms that could explain the relations between MUPS and depression, we investigate the association between a sustained high level of MUPS, and (I) omega (ω)-3 and -6 fatty acid (FA)-status and (II) functional polymorphisms in the promoter region of the serotonin transporter gene (5-HTTLPR). Based on three Physical Symptom Checklist (PCS) scores over 12 months, we defined two groups of remitted recurrently depressed patients: 41 patients with a sustained high number of MUPS and 34 patients with a sustained low number or no MUPS. Patients were followed-up for 3.5 years while recurrence of their depression was monitored. In addition, we analyzed patients' erythrocyte's FA-profiles and triallelically genotyped their 5-HTTLPR. A sustained high level of MUPS predicted consecutive depression recurrence over 3.5 years (adjusted relative risk 2.8). FA-status and distribution of 5-HTTLPR variant frequencies did not differ between patients with sustained high compared to low/absent MUPS-levels. Our sample was relatively small. Remitted recurrently depressed patients with sustained MUPS have a considerably increased risk of recurrence. Having sustained MUPS is not associated with either erythrocyte ω-3 or -6 FA-levels or 5-HTTLPR polymorphism. Recognition and reducing MUPS in an early state could prevent a (depressive) relapse. Copyright © 2011 Elsevier B.V. All rights reserved.

Interferon lambda 4 (IFNL4) gene polymorphism is associated with spontaneous clearance of HCV in HIV-1 positive patients.

PubMed

Alves, Camila Fernanda da Silveira; Grott, Camila Schultz; Lunge, Vagner Ricardo; Béria, Jorge Umberto; Tietzmann, Daniela Cardoso; Stein, Airton Tetelbom; Simon, Daniel

2016-01-01

Approximately one-third of the individuals infected with human immunodeficiency virus type 1 (HIV-1) are co-infected with hepatitis C virus (HCV). Co-infected patients have an increased risk for developing end-stage liver diseases. Variants upstream of the IFNL3 gene have been associated with spontaneous and treatment-induced clearance of HCV infection. Recently, a novel polymorphism was discovered, denoted IFNL4 ΔG > TT (rs368234815), which seems to be a better predictor of spontaneous clearance than the IFNL4 rs12979860 polymorphism. We aimed to determine the prevalence of the IFNL4 ΔG > TT variants and to evaluate the association with spontaneous clearance of HCV infection in Brazilian HIV-1 patients. The IFNL4 ΔG > TT genotypes were analyzed by polymerase chain reaction followed by restriction digestion in 138 HIV-1 positive patients who had an anti-HCV positive result. Spontaneous clearance of HCV was observed in 34 individuals (24.6%). IFNL4 genotype distribution was significantly different between individuals who had spontaneous clearance and chronic HCV patients (p=0.002). The probability of spontaneous clearance of HCV infection for patients with the IFNL4 TT/TT genotype was 3.6 times higher than for patients carrying the IFNL4 ΔG allele (OR=3.63, 95% CI:1.51-8.89, p=0.001). The IFNL4 ΔG > TT polymorphism seems to be better than IFNL4 rs12979860 to predict spontaneous clearance of the HCV in Brazilian HIV-1 positive patients.

Interferon lambda 4 (IFNL4) gene polymorphism is associated with spontaneous clearance of HCV in HIV-1 positive patients

PubMed Central

Alves, Camila Fernanda da Silveira; Grott, Camila Schultz; Lunge, Vagner Ricardo; Béria, Jorge Umberto; Tietzmann, Daniela Cardoso; Stein, Airton Tetelbom; Simon, Daniel

2016-01-01

Abstract Approximately one-third of the individuals infected with human immunodeficiency virus type 1 (HIV-1) are co-infected with hepatitis C virus (HCV). Co-infected patients have an increased risk for developing end-stage liver diseases. Variants upstream of the IFNL3 gene have been associated with spontaneous and treatment-induced clearance of HCV infection. Recently, a novel polymorphism was discovered, denoted IFNL4 ΔG > TT (rs368234815), which seems to be a better predictor of spontaneous clearance than the IFNL4 rs12979860 polymorphism. We aimed to determine the prevalence of the IFNL4 ΔG > TT variants and to evaluate the association with spontaneous clearance of HCV infection in Brazilian HIV-1 patients. The IFNL4 ΔG > TT genotypes were analyzed by polymerase chain reaction followed by restriction digestion in 138 HIV-1 positive patients who had an anti-HCV positive result. Spontaneous clearance of HCV was observed in 34 individuals (24.6%). IFNL4 genotype distribution was significantly different between individuals who had spontaneous clearance and chronic HCV patients (p=0.002). The probability of spontaneous clearance of HCV infection for patients with the IFNL4 TT/TT genotype was 3.6 times higher than for patients carrying the IFNL4 ΔG allele (OR=3.63, 95% CI:1.51-8.89, p=0.001). The IFNL4 ΔG > TT polymorphism seems to be better than IFNL4 rs12979860 to predict spontaneous clearance of the HCV in Brazilian HIV-1 positive patients. PMID:27560987

Drinking Water Disinfection By-products, Genetic Polymorphisms, and Birth Outcomes in a European Mother-Child Cohort Study.

PubMed

Kogevinas, Manolis; Bustamante, Mariona; Gracia-Lavedán, Esther; Ballester, Ferran; Cordier, Sylvaine; Costet, Nathalie; Espinosa, Ana; Grazuleviciene, Regina; Danileviciute, Asta; Ibarluzea, Jesus; Karadanelli, Maria; Krasner, Stuart; Patelarou, Evridiki; Stephanou, Euripides; Tardón, Adonina; Toledano, Mireille B; Wright, John; Villanueva, Cristina M; Nieuwenhuijsen, Mark

2016-11-01

We examined the association between exposure during pregnancy to trihalomethanes, the most common water disinfection by-products, and birth outcomes in a European cohort study (Health Impacts of Long-Term Exposure to Disinfection By-Products in Drinking Water). We took into account exposure through different water uses, measures of water toxicity, and genetic susceptibility. We enrolled 14,005 mothers (2002-2010) and their children from France, Greece, Lithuania, Spain, and the UK. Information on lifestyle- and water-related activities was recorded. We ascertained residential concentrations of trihalomethanes through regulatory records and ad hoc sampling campaigns and estimated route-specific trihalomethane uptake by trimester and for whole pregnancy. We examined single nucleotide polymorphisms and copy number variants in disinfection by-product metabolizing genes in nested case-control studies. Average levels of trihalomethanes ranged from around 10 μg/L to above the regulatory limits in the EU of 100 μg/L between centers. There was no association between birth weight and total trihalomethane exposure during pregnancy (β = 2.2 g in birth weight per 10 μg/L of trihalomethane, 95% confidence interval = 3.3, 7.6). Birth weight was not associated with exposure through different routes or with specific trihalomethane species. Exposure to trihalomethanes was not associated with low birth weight (odds ratio [OR] per 10 μg/L = 1.02, 95% confidence interval = 0.95, 1.10), small-for-gestational age (OR = 0.99, 0.94, 1.03) and preterm births (OR = 0.98, 0.9, 1.05). We found no gene-environment interactions for mother or child polymorphisms in relation to preterm birth or small-for-gestational age. In this large European study, we found no association between birth outcomes and trihalomethane exposures during pregnancy in the total population or in potentially genetically susceptible subgroups. (See video abstract at http://links.lww.com/EDE/B104.).

Genetic characterization of chayote [Sechium edule (Jacq.) Swartz.] landraces of North Eastern Hills of India and conservation measure.

PubMed

Verma, Veerendra Kumar; Pandey, Avinash; Jha, Anjani Kumar; Ngachan, S V

2017-10-01

Chayote or chow-chow is an underutilized cucurbit vegetable crop, widely cultivated by farmers in the backyards and Jhum lands for its tender leaves, fruits and tuberous root. In order to initiate crop improvement program in this crop, the present study was undertaken to assess the genetic variations in the 74 chow-chow landraces collected from the North Eastern Hill region of India. Wide variations for fruit colors, fruit length (6.5-21.5 cm), fruit width (4.2-10.7 cm), fruit weight (60-560 g), vitamin-C (2.6-13.8 mg/100 g), reducing sugar (0.18-2.77%), total sugar (1.09-2.94%) and phenol content (0.17-3.85 mg/100 g FW) were recorded among the landraces. All the landraces were also characterized using random amplified polymorphic DNA (RAPD) and inter simple sequence repeat (ISSR) markers. In RAPD analyses, out of 28 primers a total of 198 reproducible amplicons were formed at an average of 7.01 per primer and an overall polymorphism of 88.38%. Eight fragments were specific to landraces with light green fruits. Four fragments were observed to be specific to RCSC-22 (dark green fruits) and another four specific to a RCSC-30 (pale yellow fruits). Out of 30 ISSR, only 5 primers generated a total of 32 reproducible amplicons with an average of 6.4 per primer and overall polymorphism of 62.5%. The pair wise similarity coefficient values ranged from 0.55 to 0.96. The grouping of landraces in cluster analysis was found to be independent of their respective geographic locations. The cuttings of suckers and shoot top (2 months old) treated with indole-3-butyric acid (200 mg l -1 ) provide an alternative for the conservation of the diverse genetic materials to the researchers.

Population-Scale Sequencing Data Enable Precise Estimates of Y-STR Mutation Rates

PubMed Central

Willems, Thomas; Gymrek, Melissa; Poznik, G. David; Tyler-Smith, Chris; Erlich, Yaniv

2016-01-01

Short tandem repeats (STRs) are mutation-prone loci that span nearly 1% of the human genome. Previous studies have estimated the mutation rates of highly polymorphic STRs by using capillary electrophoresis and pedigree-based designs. Although this work has provided insights into the mutational dynamics of highly mutable STRs, the mutation rates of most others remain unknown. Here, we harnessed whole-genome sequencing data to estimate the mutation rates of Y chromosome STRs (Y-STRs) with 2–6 bp repeat units that are accessible to Illumina sequencing. We genotyped 4,500 Y-STRs by using data from the 1000 Genomes Project and the Simons Genome Diversity Project. Next, we developed MUTEA, an algorithm that infers STR mutation rates from population-scale data by using a high-resolution SNP-based phylogeny. After extensive intrinsic and extrinsic validations, we harnessed MUTEA to derive mutation-rate estimates for 702 polymorphic STRs by tracing each locus over 222,000 meioses, resulting in the largest collection of Y-STR mutation rates to date. Using our estimates, we identified determinants of STR mutation rates and built a model to predict rates for STRs across the genome. These predictions indicate that the load of de novo STR mutations is at least 75 mutations per generation, rivaling the load of all other known variant types. Finally, we identified Y-STRs with potential applications in forensics and genetic genealogy, assessed the ability to differentiate between the Y chromosomes of father-son pairs, and imputed Y-STR genotypes. PMID:27126583

Single-Nucleotide Polymorphisms Within the Thrombomodulin Gene (THBD) Predict Mortality in Patients With Graft-Versus-Host Disease.

PubMed

Rachakonda, Sivaramakrishna P; Penack, Olaf; Dietrich, Sascha; Blau, Olga; Blau, Igor Wolfgang; Radujkovic, Aleksandar; Isermann, Berend; Ho, Anthony D; Uharek, Lutz; Dreger, Peter; Kumar, Rajiv; Luft, Thomas

2014-10-20

Steroid-refractory graft-versus-host disease (GVHD) is a major and often fatal complication after allogeneic stem-cell transplantation (alloSCT). Although the pathophysiology of steroid refractoriness is not fully understood, evidence is accumulating that endothelial cell stress is involved, and endothelial thrombomodulin (THBD) plays a role in this process. Here we assess whether single-nucleotide polymorphisms (SNPs) within the THBD gene predict outcome after alloSCT. Seven SNPs within the THBD gene were studied (rs1962, rs1042579, rs1042580, rs3176123, rs3176124, rs3176126, and rs3176134) in a training cohort of 306 patients. The relevant genotypes were then validated in an independent cohort (n = 321). In the training cohort, an increased risk of nonrelapse mortality (NRM) was associated with three of seven SNPs tested: rs1962, rs1042579 (in linkage disequilibrium with rs3176123), and rs1042580. When patients were divided into risk groups (one v no high-risk SNP), a strong correlation with NRM was observed (hazard ratio [HR], 2.31; 95% CI, 1.36 to 3.95; P = .002). More specifically, NRM was predicted by THBD SNPs in patients who later developed GVHD (HR, 3.03; 95% CI, 1.61 to 5.68; P < .001) but not in patients without GVHD. In contrast, THBD SNPs did not predict incidence of acute GVHD. Multivariable analyses adjusting for clinical variables confirmed the independent effect of THBD SNPs on NRM. All findings could be reproduced in the validation cohort. THBD SNPs predict mortality of manifest GVHD but not the risk of acquiring GVHD, supporting the hypothesis that endothelial vulnerability contributes to GVHD refractoriness. © 2014 by American Society of Clinical Oncology.

Development of a Multicomponent Prediction Model for Acute Esophagitis in Lung Cancer Patients Receiving Chemoradiotherapy

DOE Office of Scientific and Technical Information (OSTI.GOV)

De Ruyck, Kim, E-mail: kim.deruyck@UGent.be; Sabbe, Nick; Oberije, Cary

2011-10-01

Purpose: To construct a model for the prediction of acute esophagitis in lung cancer patients receiving chemoradiotherapy by combining clinical data, treatment parameters, and genotyping profile. Patients and Methods: Data were available for 273 lung cancer patients treated with curative chemoradiotherapy. Clinical data included gender, age, World Health Organization performance score, nicotine use, diabetes, chronic disease, tumor type, tumor stage, lymph node stage, tumor location, and medical center. Treatment parameters included chemotherapy, surgery, radiotherapy technique, tumor dose, mean fractionation size, mean and maximal esophageal dose, and overall treatment time. A total of 332 genetic polymorphisms were considered in 112 candidatemore » genes. The predicting model was achieved by lasso logistic regression for predictor selection, followed by classic logistic regression for unbiased estimation of the coefficients. Performance of the model was expressed as the area under the curve of the receiver operating characteristic and as the false-negative rate in the optimal point on the receiver operating characteristic curve. Results: A total of 110 patients (40%) developed acute esophagitis Grade {>=}2 (Common Terminology Criteria for Adverse Events v3.0). The final model contained chemotherapy treatment, lymph node stage, mean esophageal dose, gender, overall treatment time, radiotherapy technique, rs2302535 (EGFR), rs16930129 (ENG), rs1131877 (TRAF3), and rs2230528 (ITGB2). The area under the curve was 0.87, and the false-negative rate was 16%. Conclusion: Prediction of acute esophagitis can be improved by combining clinical, treatment, and genetic factors. A multicomponent prediction model for acute esophagitis with a sensitivity of 84% was constructed with two clinical parameters, four treatment parameters, and four genetic polymorphisms.« less

Assessment of genetic diversity, population structure and relationships in Indian and non-Indian genotypes of finger millet (Eleusine coracana (L.) Gaertn) using genomic SSR markers.

PubMed

Ramakrishnan, M; Antony Ceasar, S; Duraipandiyan, V; Al-Dhabi, N A; Ignacimuthu, S

2016-01-01

We evaluated the genetic variation and population structure in Indian and non-Indian genotypes of finger millet using 87 genomic SSR primers. The 128 finger millet genotypes were collected and genomic DNA was isolated. Eighty-seven genomic SSR primers with 60-70 % GC contents were used for PCR analysis of 128 finger millet genotypes. The PCR products were separated and visualized on a 6 % polyacrylamide gel followed by silver staining. The data were used to estimate major allele frequency using Power Marker v3.0. Dendrograms were constructed based on the Jaccard's similarity coefficient. Statistical fitness and population structure analyses were performed to find the genetic diversity. The mean major allele frequency was 0.92; the means of polymorphic alleles were 2.13 per primer and 1.45 per genotype; the average polymorphism was 59.94 % per primer and average PIC value was 0.44 per primer. Indian genotypes produced an additional 0.21 allele than non-Indian genotypes. Gene diversity was in the range from 0.02 to 0.35. The average heterozygosity was 0.11, close to 100 % homozygosity. The highest inbreeding coefficient was observed with SSR marker UGEP67. The Jaccard's similarity coefficient value ranged from 0.011 to 0.836. The highest similarity value was 0.836 between genotypes DPI009-04 and GPU-45. Indian genotypes were placed in Eleusine coracana major cluster (EcMC) 1 along with 6 non-Indian genotypes. AMOVA showed that molecular variance in genotypes from various geographical regions was 4 %; among populations it was 3 % and within populations it was 93 %. PCA scatter plot analysis showed that GPU-28, GPU-45 and DPI009-04 were closely dispersed in first component axis. In structural analysis, the genotypes were divided into three subpopulations (SP1, SP2 and SP3). All the three subpopulations had an admixture of alleles and no pure line was observed. These analyses confirmed that all the genotypes were genetically diverse and had been grouped based on their geographic regions.

Influence of Donor and Recipient CYP3A4, CYP3A5, and ABCB1 Genotypes on Clinical Outcomes and Nephrotoxicity in Liver Transplant Recipients.

PubMed

Debette-Gratien, Marilyne; Woillard, Jean-Baptiste; Picard, Nicolas; Sebagh, Mylène; Loustaud-Ratti, Véronique; Sautereau, Denis; Samuel, Didier; Marquet, Pierre

2016-10-01

This study investigated the influence of the CYP3A4*22, CYP3A5*3, and ABCB1 exons 12, 21, and 26 polymorphisms in donors and recipients on clinical outcomes and renal function in 170 liver transplant patients on cyclosporin A (CsA) or tacrolimus (Tac). Allelic discrimination assays were used for genotyping. Multivariate time-dependent Cox proportional hazard models, multiple linear regression using the generalized estimating equation and linear mixed-effect models were used for statistical analysis. Expression of CYP3A5 by either or both the donor and the recipient was significantly associated with lower Tac, but not CsA, dose-normalized trough levels. In the whole population, graft loss was only significantly associated with longer exposure to high calcineurin inhibitor (CNI) concentrations (hazard ratio, 6.93; 95% confidence interval, 2.13-22.55), P = 0.00129), whereas in the Tac subgroup, the risk of graft loss was significantly higher in recipient CYP3A5*1 expressers (hazard ratio, 3.39; 95% confidence interval, 1.52-7.58; P = 0.0028). Renal function was significantly associated with: (1) baseline modification of diet in renal disease (β = 0.51 ± 0.05; P < 0.0001); (2) duration of patient follow-up (per visit, β = -0.98 ± 0.22; P < 0.0001); and (3) CNI exposure (per quantile increase, β = -2.42 ± 0.59; P < 0.0001). No genetic factor was associated with patient survival, acute rejection, liver function test results, recurrence of viral or other initial liver disease, or renal function. This study confirms the effect of CYP3A5*3 on tacrolimus dose requirement in liver transplantation and shows unexpected associations between the type of, and exposure to, CNI and either chronic rejection or graft loss. None of the genetic polymorphisms studied had a noticeable impact on renal function degradation at 10 years.

Population pharmacokinetic analysis of cilostazol in healthy subjects with genetic polymorphisms of CYP3A5, CYP2C19 and ABCB1

PubMed Central

Yoo, Hee-Doo; Cho, Hea-Young; Lee, Yong-Bok

2010-01-01

AIMS To investigate the influence of genetic polymorphisms in the CYP3A5, CYP2C19 and ABCB1 genes on the population pharmacokinetics of cilostazol in healthy subjects. METHODS Subjects who participated in four separate cilostazol bioequivalence studies with the same protocols were included in this retrospective analysis. One hundred and four healthy Korean volunteers were orally administered a single 50- or 100-mg dose of cilostazol. We estimated the population pharmacokinetics of cilostazol using a nonlinear mixed effects modelling (nonmem) method and explored the possible influence of genetic polymorphisms in CYP3A (CYP3A5*3), CYP2C19 (CYP2C19*2 and CYP2C19*3) and ABCB1 (C1236T, G2677T/A and C3435T) on the population pharmacokinetics of cilostazol. RESULTS A two-compartment model with a first-order absorption and lag time described the cilostazol serum concentrations well. The apparent oral clearance (CL/F) was estimated to be 12.8 l h−1. The volumes of the central and the peripheral compartment were characterized as 20.5 l and 73.1 l, respectively. Intercompartmental clearance was estimated at 5.6 l h−1. Absorption rate constant was estimated at 0.24 h−1 and lag time was predicted at 0.57 h. The genetic polymorphisms of CYP3A5 had a significant (P < 0.001) influence on the CL/F of cilostazol. When CYP2C19 was evaluated, a significant difference (P < 0.01) was observed among the three genotypes (extensive metabolizers, intermediate metabolizers and poor metabolizers) for the CL/F. In addition, a combination of CYP3A5 and CYP2C19 genotypes was found to be associated with a significant difference (P < 0.005) in the CL/F. When including these genotypes, the interindividual variability of the CL/F was reduced from 34.1% in the base model to 27.3% in the final model. However, no significant differences between the ABCB1 genotypes and cilostazol pharmacokinetic parameters were observed. CONCLUSIONS The results of the present study indicate that CYP3A5 and CYP2C19 polymorphisms explain the substantial interindividual variability that occurs in the metabolism of cilostazol. PMID:20078610

Predictors of variation in serum IGF1 and IGFBP3 levels in healthy African American and white men.

PubMed

Hoyo, Cathrine; Grubber, Janet; Demark-Wahnefried, Wendy; Lobaugh, Bruce; Jeffreys, Amy S; Grambow, Steven C; Marks, Jeffrey R; Keku, Temitope O; Walther, Phillip J; Schildkraut, Joellen M

2009-07-01

Individual variation in circulating insulinlike growth factor-1 (IGF1) and its major binding protein, insulinlike growth factor binding protein-3 (IGFBP3), have been etiologically linked to several chronic diseases, including some cancers. Factors associated with variation in circulating levels of these peptide hormones remain unclear. Multiple linear regression models were used to determine the extent to which sociodemographic characteristics, lifestyle factors, personal and family history of chronic disease, and common genetic variants, the (CA)n repeat polymorphism in the IGF1 promoter and the IGFBP3-202 A/C polymorphism (rs2854744) predict variation in IGF1 or IGFBP3 serum levels in 33 otherwise healthy African American and 37 white males recruited from Durham Veterans Administration Medical Center. Predictors of serum IGF1, IGFBP3, and the IGF1:IGFBP3 molar ratio varied by race. In African Americans, 17% and 28% of the variation in serum IGF1 and the IGF1:IGFBP3 molar ratio, were explained by cigarette smoking and carrying the IGF1 (CA)19 repeat allele, respectively. Not carrying at least 1 IGF1 (CA)19 repeat allele and a high body mass index explained 8% and 14%, respectively, of the variation IGFBP3 levels. These factors did not predict variation of these peptides in whites. If successfully replicated in larger studies, these findings would add to recent evidence, suggesting known genetic and lifestyle chronic disease risk factors influence IGF1 and IGFBP3 circulating levels differently in African Americans and whites.

Predictors of variation in serum IGFI and IGFBP3 levels in healthy African-American and white men

PubMed Central

Grubber, Janet; Demark-Wahnefried, Wendy; Lobaugh, Bruce; Jeffreys, Amy S.; Grambow, Steven C.; Marks, Jeffrey R.; Keku, Temitope O.; Walther, Phillip J.; Schildkraut, Joellen M.

2010-01-01

Background Individual variation in circulating insulin-like growth factor-I (IGF1) and its major binding protein, insulin-like growth factor binding protein-3 (IGFBP3) have been etiologically linked to several chronic diseases, including some cancers. Factors associated with variation in circulating levels of these peptide hormones remain unclear. Methods Multiple linear regression models were used to determine the extent to which socio-demographic characteristics, lifestyle factors, personal and family history of chronic disease, and common genetic variants, the (CA)n repeat polymorphism in the IGF1 promoter and the IGFBP3 -202 A/C polymorphism (rs2854744) predict variation in IGF1 or IGFBP3 serum levels in 33 otherwise healthy African American and 37 white males recruited from Durham Veterans Administration Medical Center. Results Predictors of serum IGF1, IGFBP3 and the IGF1:IGFBP3 molar ratio varied by race. In African Americans, 17% and 28% of the variation in serum IGF1 and the IGF1:IGFBP3 molar ratio, respectively, was explained by cigarette smoking and carrying the IGF1 (CA)19 repeat allele, respectively. Not carrying at least one IGF1 (CA)19 repeat allele and a high BMI explained 8% and 14%, respectively, of the variation IGFBP3 levels. These factors did not predict variation of these peptides in whites. Conclusion If successfully replicated in larger studies, these findings add to recent evidence suggesting known genetic and lifestyle chronic disease risk factors influence IGF1 and IGFBP3 circulating levels differently in African Americans and whites. PMID:19634593

Correlation between TS, MTHFR, and ERCC1 gene polymorphisms and the efficacy of platinum in combination with pemetrexed first-line chemotherapy in mesothelioma patients.

PubMed

Powrózek, Tomasz; Kowalski, Dariusz M; Krawczyk, Paweł; Ramlau, Rodryg; Kucharczyk, Tomasz; Kalinka-Warzocha, Ewa; Knetki-Wróblewska, Magdalena; Winiarczyk, Kinga; Dyszkiewicz, Wojciech; Krzakowski, Maciej; Milanowski, Janusz

2014-11-01

The combination of pemetrexed and platinum compound represents the standard regimen for first-line chemotherapy in malignant pleural mesothelioma patients. Pemetrexed is a multitarget antifolate agent that inhibits folate-dependent enzymes (eg, thymidylate synthase [TS]) and thus synthesis of nucleotides and DNA. Expression of TS and folate availability, regulated by gene polymorphisms, have implications for effectiveness of chemotherapy and the outcome of mesothelioma patients. The aim of this retrospective multicenter study was to assess the correlation between TS, 5,10-methylenetetrahydrofolate reductase (MTHFR) and excision repair cross-complementing group 1 (ERCC1) gene polymorphisms and the efficacy of pemetrexed-based first-line chemotherapy of mesothelioma patients. Fifty-nine mesothelioma patients (31 men with a median age of 62 years) treated in first-line chemotherapy with platinum in combination with pemetrexed or pemetrexed monotherapy were enrolled. Genomic DNA was isolated from peripheral blood. Using polymerase chain reaction and high resolution melt methods, the variable number of tandem repeat, the G>C single nucleotide polymorphism (SNP) in these repeats, and 6-base pair (bp) insertion/deletion polymorphism of the TS gene, the SNP of 677C>T in MTHFR, and 19007C>T in the ERCC1 gene were analyzed and correlated with disease control rate, progression-free survival (PFS), and overall survival (OS) of mesothelioma patients. Greater risk of early disease progression (PD), and shortening of PFS and OS were associated with several clinical factors (eg, anemia for early PD and OS), weight loss (for PFS and OS), and previous surgical treatment (for early PD, PFS, and OS). Insertion of 6-bp in both alleles of the TS gene (1494del6) was the only genetic factor that increased the incidence of early progression (P = .028) and shortening of median PFS (P = .06) in patients treated with pemetrexed-based chemotherapy. In multivariate analysis, the 1494del6 in the 3' untranslated region (UTR) of the TS gene also had a predictive role for PFS (P = .0185; hazard ratio, 2.3258 for +6/+6 homozygotes) in analyzed mesothelioma patients. Most analyzed polymorphisms in TS, MTHFR, and ERCC1 genes failed to predict outcome in mesothelioma patients treated with pemetrexed-based chemotherapy. However, different variants of 1494del6 in the 3' UTR of the TS gene were associated with differences in disease control rate and PFS of our patients. Copyright © 2014 Elsevier Inc. All rights reserved.

NOS3 genotype-dependent correlation between blood pressure and physical activity.

PubMed

Kimura, Tomomi; Yokoyama, Tetsuji; Matsumura, Yasuhiro; Yoshiike, Nobuo; Date, Chigusa; Muramatsu, Masaaki; Tanaka, Heizo

2003-02-01

Endothelium-dependent vasorelaxation plays an important role in reduction of blood pressure and is mediated through release of nitric oxide (NO), which is generated by constitutively expressed endothelial nitric oxide synthase (NOS3). Exercise also augments NO release and has been recommended for primary prevention and improvement of hypertension, but individual responses are highly variable. We therefore postulated that genetic polymorphisms of NOS3 might interact with physical activity level to differentially influence blood pressure level. We genotyped 832 healthy Japanese (mean age of 54.4+/-8.6 years, 372 men and 460 women) for a polymorphism of NOS3 in intron 4 (ecNOS4a/b), using the polymerase chain reaction method, and scored their habitual physical activity level by using the rate of energy expenditure per resting metabolic rate through an interview according to a semiquantitative assessment method. Only in the subjects who had the rarer a allele (aa+ba type), systolic blood pressure was found to be inversely correlated with physical activity level (P for linear trend=0.0496, for interaction=0.0071). Eventually, this polymorphism was significantly associated with the prevalence of systolic hypertension only in the subjects who were in the lowest tertile of physical activity level (OR=2.4, 95% CI, 1.1 to 5.6, P for interaction=0.0474). In the present study, we found a significant interaction between the genotype and physical activity level on systolic blood pressure. These results might allow a better understanding of the mechanism to improve hypertension by exercise and to thereby reduce the risk of cardiovascular disease.

Polymorphism in the Eruption Sequence of Primary Dentition: A Cross-sectional Study

PubMed Central

Bhojraj, Nandlal; Narayanappa

2017-01-01

Introduction Primary teeth have shown wide variations in their eruption time among different population. Population specific eruption ages are provided as mean with standard deviations or median ages with its percentile range. This alone will be insufficient for prediction of tooth eruption sequence because they provide no information on the frequency of sequence variation within the pairs of teeth. Norms of polymorphic variation in the eruption sequence can be more useful. Aim This study aims at providing norms for the sequence polymorphism in primary teeth among the children of Mysore population. Materials and Methods A cross-sectional study was designed with 1392 children, recruited from December 2015 to June 2016 by simple random sampling method. Tooth was recorded as present or absent. Across the entire possible intra quadrant tooth pair, cases of present-present, absent-absent, present-absent and absent-present and were counted and computed as percentages. Results Sequence polymorphisms were more common in 82-84 pairs of teeth. Significant polymorphic reverse sequence was observed in 52-54 (9%), 82-84 (35%) in males and 82-84 (18%) in females. There was no polymorphism in maxillary arch in females. Conclusion The present study provides the baseline data values for sequence variation in primary teeth eruption. To the best of investigators knowledge, there are no previous studies describing the sequence polymorphism in primary teeth in Indian population. The results of this study helps in assessment of eruption sequence problems in paediatric dentistry and in evaluation and prediction of tooth eruption sequence in individual child. PMID:28658912

Factor IX gene haplotypes in Amerindians.

PubMed

Franco, R F; Araújo, A G; Zago, M A; Guerreiro, J F; Figueiredo, M S

1997-02-01

We have determined the haplotypes of the factor IX gene for 95 Indians from 5 Brazilian Amazon tribes: Wayampí, Wayana-Apalaí, Kayapó, Arára, and Yanomámi. Eight polymorphisms linked to the factor IX gene were investigated: MseI (at 5', nt -698), BamHI (at 5', nt -561), DdeI (intron 1), BamHI (intron 2), XmnI (intron 3), TaqI (intron 4), MspI (intron 4), and HhaI (at 3', approximately 8 kb). The results of the haplotype distribution and the allele frequencies for each of the factor IX gene polymorphisms in Amerindians were similar to the results reported for Asian populations but differed from results for other ethnic groups. Only five haplotypes were identified within the entire Amerindian study population, and the haplotype distribution was significantly different among the five tribes, with one (Arára) to four (Wayampí) haplotypes being found per tribe. These findings indicate a significant heterogeneity among the Indian tribes and contrast with the homogeneous distribution of the beta-globin gene cluster haplotypes but agree with our recent findings on the distribution of alpha-globin gene cluster haplotypes and the allele frequencies for six VNTRs in the same Amerindian tribes. Our data represent the first study of factor IX-associated polymorphisms in Amerindian populations and emphasizes the applicability of these genetic markers for population and human evolution studies.

Circulating insulin-like growth factors and Alzheimer disease: A mendelian randomization study.

PubMed

Williams, Dylan M; Karlsson, Ida K; Pedersen, Nancy L; Hägg, Sara

2018-01-23

To examine whether genetically predicted variation in circulating insulin-like growth factor 1 (IGF1) or its binding protein, IGFBP3, are associated with risk of Alzheimer disease (AD), using a mendelian randomization study design. We first examined disease risk by genotypes of 9 insulin-like growth factor (IGF)-related single nucleotide polymorphisms (SNPs) using published summary genome-wide association statistics from the International Genomics of Alzheimer's Project (IGAP; n = 17,008 cases; 37,154 controls). We then assessed whether any SNP-disease results replicated in an independent sample derived from the Swedish Twin Registry (n = 984 cases; 10,304 controls). Meta-analyses of SNP-AD results did not suggest that variation in IGF1, IGFBP3, or the molar ratio of these affect AD risk. Only one SNP appeared to affect AD risk in IGAP data. This variant is located in the gene FOXO3, implicated in human longevity. In a meta-analysis of both IGAP and secondary data, the odds ratio of AD per FOXO3 risk allele was 1.04 (95% confidence interval 1.01-1.08; p = 0.008). These findings suggest that circulating IGF1 and IGFBP3 are not important determinants of AD risk. FOXO3 function may influence AD development via pathways that are independent of IGF signaling (i.e., pleiotropic actions). Copyright © 2017 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology.

Asthma treatment outcome in children is associated with vascular endothelial growth factor A (VEGFA) polymorphisms.

PubMed

Balantic, Mateja; Rijavec, Matija; Skerbinjek Kavalar, Maja; Suskovic, Stanislav; Silar, Mira; Kosnik, Mitja; Korosec, Peter

2012-06-01

Asthma is a common chronic disease characterized by airway inflammation and structural remodeling. Vascular endothelial growth factor (VEGF), a major regulator of angiogenesis, is elevated in asthma patients. VEGF contributes to airway responsiveness and remodeling. It has been shown that treatment of asthma patients decreases VEGF levels, and inhibition of VEGF diminishes asthma symptoms in mice. Therefore, polymorphisms in the vascular endothelial growth factor A (VEGFA) gene might be associated with asthma treatment response. This study enrolled 131 children with asthma treated with different therapies - specifically, the inhaled corticosteroid (ICS) fluticasone propionate or the leukotriene receptor antagonist (LTRA) montelukast. We performed an association analysis between improvement of lung function - assessed by measurement of the percentage of the predicted forced expiratory volume in 1 second (%predicted FEV(1)), the ratio between the FEV(1) and the forced vital capacity (FEV(1)/FVC) after 6 and 12 months of treatment, and asthma control after 12 months of treatment - and two polymorphisms, rs2146323 and rs833058, in the VEGFA gene. Polymorphism rs2146323 A>C in VEGFA was associated with response to ICS therapy. Asthma patients with the AA genotype had a greater improvement in the %predicted FEV(1) than those with the AC or CC genotype (p = 0.018). Conversely, the AA genotype in rs2146323 was associated with uncontrolled asthma in patients regularly receiving LTRA therapy (p = 0.020) and a worse FEV(1)/FVC ratio in patients who episodically used LTRA therapy (p = 0.044). Furthermore, polymorphism rs833058 C>T was associated with treatment response to episodically used LTRA therapy. A subgroup of patients with the TT genotype had an improvement in the %predicted FEV(1), compared with no improvement in patients with the CT or CC genotype (p = 0.029). Our results showed that treatment response to commonly used asthma therapies (ICS or LTRA) is associated with polymorphisms rs2146323 and rs833058 in VEGFA. With additional replication of this preliminary study, our findings could contribute to the development of individualized asthma therapy.

Molecular cloning, expression, IgE binding activities and in silico epitope prediction of Per a 9 allergens of the American cockroach

PubMed Central

Yang, Haiwei; Chen, Hao; Jin, Min; Xie, Hua; He, Shaoheng; Wei, Ji-Fu

2016-01-01

Per a 9 is a major allergen of the American cockroach (CR), which has been recognized as an important cause of imunoglobulin E-mediated type I hypersensitivity worldwide. However, it is not neasy to obtain a substantial quantity of this allergen for use in functional studies. In the present study, the Per a 9 gene was cloned and expressed in Escherichia coli (E. coli) systems. It was found that 13/16 (81.3%) of the sera from patients with allergies caused by the American CR reacted to Per a 9, as assessed by enzyme-linked immunosorbent assay, confirming that Per a 9 is a major allergen of CR. The induction of the expression of CD63 and CCR3 in passively sensitized basophils (from sera of patients with allergies caused by the American CR) by approximately 4.2-fold indicated that recombinant Per a 9 was functionally active. Three immunoinformatics tools, including the DNASTAR Protean system, Bioinformatics Predicted Antigenic Peptides (BPAP) system and the BepiPred 1.0 server were used to predict the potential B cell epitopes, while Net-MHCIIpan-2.0 and NetMHCII-2.2 were used to predict the T cell epitopes of Per a 9. As a result, we predicted 11 peptides (23–28, 39–46, 58–64, 91–118, 131–136, 145–154, 159–165, 176–183, 290–299, 309–320 and 338–344) as potential B cell linear epitopes. In T cell prediction, the Per a 9 allergen was predicted to have 5 potential T cell epitope sequences, 119–127, 194–202, 210–218, 239–250 and 279–290. The findings of our study may prove to be useful in the development of peptide-based vaccines to combat CR-induced allergies. PMID:27840974

Molecular cloning, expression, IgE binding activities and in silico epitope prediction of Per a 9 allergens of the American cockroach.

PubMed

Yang, Haiwei; Chen, Hao; Jin, Min; Xie, Hua; He, Shaoheng; Wei, Ji-Fu

2016-12-01

Per a 9 is a major allergen of the American cockroach (CR), which has been recognized as an important cause of imunoglobulin E-mediated type I hypersensitivity worldwide. However, it is not neasy to obtain a substantial quantity of this allergen for use in functional studies. In the present study, the Per a 9 gene was cloned and expressed in Escherichia coli (E. coli) systems. It was found that 13/16 (81.3%) of the sera from patients with allergies caused by the American CR reacted to Per a 9, as assessed by enzyme-linked immunosorbent assay, confirming that Per a 9 is a major allergen of CR. The induction of the expression of CD63 and CCR3 in passively sensitized basophils (from sera of patients with allergies caused by the American CR) by approximately 4.2-fold indicated that recombinant Per a 9 was functionally active. Three immunoinformatics tools, including the DNAStar Protean system, Bioinformatics Predicted Antigenic Peptides (BPAP) system and the BepiPred 1.0 server were used to predict the potential B cell epitopes, while Net-MHCIIpan-2.0 and NetMHCII-2.2 were used to predict the T cell epitopes of Per a 9. As a result, we predicted 11 peptides (23-28, 39-46, 58-64, 91-118, 131-136, 145-154, 159-165, 176-183, 290-299, 309-320 and 338-344) as potential B cell linear epitopes. In T cell prediction, the Per a 9 allergen was predicted to have 5 potential T cell epitope sequences, 119-127, 194-202, 210-218, 239-250 and 279-290. The findings of our study may prove to be useful in the development of peptide-based vaccines to combat CR-induced allergies.

TNFα G308A polymorphism is associated with resilience to sleep deprivation-induced psychomotor vigilance performance impairment in healthy young adults.

PubMed

Satterfield, Brieann C; Wisor, Jonathan P; Field, Stephanie A; Schmidt, Michelle A; Van Dongen, Hans P A

2015-07-01

Cytokines such as TNFα play an integral role in sleep/wake regulation and have recently been hypothesized to be involved in cognitive impairment due to sleep deprivation. We examined the effect of a guanine to adenine substitution at position 308 in the TNFα gene (TNFα G308A) on psychomotor vigilance performance impairment during total sleep deprivation. A total of 88 healthy women and men (ages 22-40) participated in one of five laboratory total sleep deprivation experiments. Performance on a psychomotor vigilance test (PVT) was measured every 2-3h. The TNFα 308A allele, which is less common than the 308G allele, was associated with greater resilience to psychomotor vigilance performance impairment during total sleep deprivation (regardless of time of day), and also provided a small performance benefit at baseline. The effect of genotype on resilience persisted when controlling for between-subjects differences in age, gender, race/ethnicity, and baseline sleep duration. The TNFα G308A polymorphism predicted less than 10% of the overall between-subjects variance in performance impairment during sleep deprivation. Nonetheless, the differential effect of the polymorphism at the peak of performance impairment was more than 50% of median performance impairment at that time, which is sizeable compared to the effects of other genotypes reported in the literature. Our findings provided evidence for a role of TNFα in the effects of sleep deprivation on psychomotor vigilance performance. Furthermore, the TNFα G308A polymorphism may have predictive potential in a biomarker panel for the assessment of resilience to psychomotor vigilance performance impairment due to sleep deprivation. Copyright © 2014 Elsevier Inc. All rights reserved.

Characterization of Clinical and Genetic Risk Factors Associated with Dyslipidemia after Kidney Transplantation

PubMed Central

Numakura, Kazuyuki; Kagaya, Hideaki; Yamamoto, Ryohei; Komine, Naoki; Saito, Mitsuru; Hiroshi, Tsuruta; Akihama, Susumu; Narita, Shintaro; Tsuchiya, Norihiko; Habuchi, Tomonori; Niioka, Takenori; Miura, Masatomo; Satoh, Shigeru

2015-01-01

We determined the prevalence of dyslipidemia in a Japanese cohort of renal allograft recipients and investigated clinical and genetic characteristics associated with having the disease. In total, 126 patients that received renal allograft transplants between February 2002 and August 2011 were studied, of which 44 recipients (34.9%) were diagnosed with dyslipidemia at 1 year after transplantation. Three clinical factors were associated with a risk of having dyslipidemia: a higher prevalence of disease observed among female than male patients (P = 0.021) and treatment with high mycophenolate mofetil (P = 0.012) and prednisolone (P = 0.023) doses per body weight at 28 days after transplantation. The genetic association between dyslipidemia and 60 previously described genetic polymorphisms in 38 putative disease-associated genes was analyzed. The frequency of dyslipidemia was significantly higher in patients with the glucocorticoid receptor (NR3C1) Bcl1 G allele than in those with the CC genotype (P = 0.001). A multivariate analysis revealed that the NR3C1 Bcl1 G allele was a significant risk factor for the prevalence of dyslipidemia (odds ratio = 4.6; 95% confidence interval = 1.8–12.2). These findings may aid in predicting a patient's risk of developing dyslipidemia. PMID:25944971

Genetic polymorphisms located in genes related to immune and inflammatory processes are associated with end-stage renal disease: a preliminary study

PubMed Central

2012-01-01

Background Chronic kidney disease progression has been linked to pro-inflammatory cytokines and markers of inflammation. These markers are also elevated in end-stage renal disease (ESRD), which constitutes a serious public health problem. Objective To investigate whether single nucleotide polymorphisms (SNPs) located in genes related to immune and inflammatory processes, could be associated with ESRD development. Design and methods A retrospective case-control study was carried out on 276 patients with ESRD and 288 control subjects. Forty-eight SNPs were genotyped via SNPlex platform. Logistic regression was used to assess the relationship between each sigle polymorphism and the development of ESRD. Results Four polymorphisms showed association with ESRD: rs1801275 in the interleukin 4 receptor (IL4R) gene (OR: 0.66 (95%CI = 0.46-0.95); p = 0.025; overdominant model), rs4586 in chemokine (C-C motif) ligand 2 (CCL2) gene (OR: 0.70 (95%CI = 0.54-0.90); p = 0.005; additive model), rs301640 located in an intergenic binding site for signal transducer and activator of transcription 4 (STAT4) (OR: 1.82 (95%CI = 1.17-2.83); p = 0.006; additive model) and rs7830 in the nitric oxide synthase 3 (NOS3) gene (OR: 1.31 (95%CI = 1.01-1.71); p = 0.043; additive model). After adjusting for multiple testing, results lost significance. Conclusion Our preliminary data suggest that four genetic polymorphisms located in genes related to inflammation and immune processes could help to predict the risk of developing ESRD. PMID:22817530

SRD5A gene polymorphism in Japanese men predicts prognosis of metastatic prostate cancer with androgen-deprivation therapy.

PubMed

Shiota, Masaki; Fujimoto, Naohiro; Yokomizo, Akira; Takeuchi, Ario; Itsumi, Momoe; Inokuchi, Junichi; Tatsugami, Katsunori; Uchiumi, Takeshi; Naito, Seiji

2015-09-01

De novo androgen synthesis is thought to be involved in the progression to castration-resistant prostate cancer (CRPC) during androgen-deprivation therapy (ADT). During androgen synthesis, 5α-reductase encoded by SRD5A catalyses testosterone into more active dihydrotestosterone and may be involved in the progression to CRPC. Then, this study aimed to reveal the association between genetic variations in SRD5A and the prognosis in metastatic prostate cancer. We studied the polymorphisms rs518673 and rs166050 in SRD5A1, and rs12470143, rs523349, rs676033 and rs2208532 in SRD5A2 as well as the time to CRPC progression and overall survival in 104 patients with metastatic prostate cancer that had undergone primary ADT. The association between the polymorphisms and the progression to CRPC as well as overall survival was examined. Patients carrying the more active GG genotype in SRD5A2 rs523349 exhibited a higher risk of the progression (hazard ration [95% confidence interval], 1.93 [1.14-3.14], p=0.016) and death (hazard ration [95% confidence interval], 2.14 [1.16-3.76], p=0.016), compared with less active GC/CC genotypes in SRD5A2 rs523349. High 5α-reductase activity due to the polymorphism in SRD5A2 may contribute to resistance to ADT. Furthermore, SRD5A2 rs523349 polymorphism may be a promising biomarker for metastatic prostate cancer patients treated with primary ADT and a molecular target for advanced prostate cancer. Copyright © 2015 Elsevier Ltd. All rights reserved.

Discovery and validation of vascular endothelial growth factor (VEGF) pathway polymorphisms in esophageal adenocarcinoma outcome.

PubMed

Eng, Lawson; Azad, Abul Kalam; Qiu, Xin; Kong, Qin Quinn; Cheng, Dangxiao; Ying, Nanjiao; Tse, Alvina; Kuang, Qin; Dodbiba, Lorin; Renouf, Daniel J; Marsh, Sharon; Savas, Sevtap; Mackay, Helen J; Knox, Jennifer J; Darling, Gail E; Wong, Rebecca K S; Xu, Wei; Liu, Geoffrey; Faluyi, Olusola O

2015-09-01

Polymorphisms in the vascular endothelial growth factor (VEGF)/angiogenesis pathway have been implicated previously in cancer risk, prognosis and response to therapy including in esophageal adenocarcinoma. Prior esophageal adenocarcinoma studies focused on using candidate polymorphisms, limiting the discovery of novel polymorphisms. Here, we applied the tagSNP (single nucleotide polymorphism) approach to identify new VEGF pathway polymorphisms associated with esophageal adenocarcinoma prognosis and validated them in an independent cohort of esophageal adenocarcinoma patients. In 231 esophageal adenocarcinoma patients of all stages/treatment plans, 58 genetic polymorphisms (18 KDR, 7 VEGFA and 33 FLT1) selected through tagging and assessment of predicted function were genotyped. Cox-proportional hazard models adjusted for important socio-demographic and clinico-pathological factors were applied to assess the association of genetic polymorphisms with overall survival (OS) and progression-free survival (PFS). Significantly associated polymorphisms were then validated in an independent cohort of 137 esophageal adenocarcinoma patients. Among the 231 discovery cohort patients, 86% were male, median diagnosis age was 64 years, 34% were metastatic at diagnosis and median OS and PFS were 20 and 12 months, respectively. KDR rs17709898 was found significantly associated with PFS (adjusted hazard ratio, aHR = 0.69, 95% confidence interval (CI): 0.53-0.90; P = 5.9E-3). FLT1 rs3794405 and rs678714 were significantly associated with OS (aHR = 1.44, 95% CI: 1.04-1.99; P = 0.03 and aHR = 1.50, 95% CI: 1.01-2.24; P = 0.045, respectively). No VEGFA polymorphisms were found significantly associated with either outcome. Upon validation, FLT1 rs3794405 remained strongly associated with OS (aHR = 1.59, 95% CI: 1.04-2.44; P = 0.03). FLT1 rs3794405 is significantly associated with OS in esophageal adenocarcinoma, whereby each variant allele confers a 45-60% increased risk of mortality. Validation and evaluation of this association in other cancer sites are warranted. © The Author 2015. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

Period3 gene in disorder of consciousness: The role of neuroimaging in understanding the relationship between genotype and sleep. A brief communication.

PubMed

Bedini, Gloria; Bersano, Anna; D'Incerti, Ludovico; Marotta, Giorgio; Rosazza, Cristina; Rossi Sebastiano, Davide; Franceschetti, Silvana; Sattin, Davide; Leonardi, Matilde; Nigri, Anna; Ferraro, Stefania; Parati, Eugenio Agostino

2017-10-15

Several methodologies including neuroimaging and sleep evaluation are being developed to complement the clinical bedside examinations in patients with disorder of consciousness (DOC). Recently, we demonstrated a possible association between Period3 (Per3) variable number tandem repeat (VNTR) polymorphism and functional impairment of DOC patients, speculating a possible role of this gene in sleep regulation. To assess whether the degree of structural and metabolic damage of the main brain areas involved in the sleep generation and homeostasis may influence the different outcome of DOC patients carrying the Per3 5/5 genotype in comparison to Per3 4/4 ones. For the present study, we reviewed 44 DOC patients from the Coma Research Centre of the Fondazione IRCCS Istituto Neurologico "C. Besta" of Milan. All patients underwent to polysomnographic sleep evaluation, cerebral structural magnetic resonance imaging (MRI) and 18 F-fluoro-2-deoxyglucose positron emission tomography (FDG-PET) analysis. Our DOC patients presented a moderate anatomical (median score 2) and metabolic damage (median value 2.36 SUVmean) of the sleep areas at both MRI and FDG-PET evaluation. Total sleep time seemed to be higher in 5/5 genotype DOC patients (median value Per3 5/5 , 221min, range 126-323min; median value Per3 4/4 , 167min, range 36-477min; and median value Per3 4/5 , 187min, range 29-422min). However, the MRI scores and FDG-PET values of whole brain, overall sleep areas, hypothalamus, midbrain and thalamus did not differ by genotype distribution. Although limited by the small sample size, our data might support the idea that Per3 genetic predisposition in DOC patients could affect impairment and residual cognitive functions through sleep homeostasis independently from structural and/or metabolic integrity of sleep areas. Copyright © 2017 Elsevier B.V. All rights reserved.

PER2 is downregulated by the LPS-induced inflammatory response in synoviocytes in rheumatoid arthritis and is implicated in disease susceptibility.

PubMed

Lee, Hwayoung; Nah, Seong-Su; Chang, Sung-Hae; Kim, Hyung-Ki; Kwon, Jun-Tack; Lee, Sanghyun; Cho, Ik-Hyun; Lee, Sang Won; Kim, Young Ock; Hong, Seung-Jae; Kim, Hak-Jae

2017-07-01

The clinical symptoms of rheumatoid arthritis (RA) present with circadian variation, with joint stiffness and pain more prominent in the early morning. The mammalian clock genes, which include circadian locomotor output cycles kaput, brain and muscle Arnt-like protein 1, period and cryptochrome, regulate circadian rhythms. In order to identify the association between genetic polymorphisms in the circadian clock gene period 2 (PER2) and RA, the present study genotyped three PER2 single nucleotide polymorphisms (SNPs), rs934945, rs6754875, and rs2304674, using genetic information from 256 RA patients and 499 control subjects. Primary cultured rheumatoid synovial cells were stimulated with 10 µM lipopolysaccharide (LPS). Total protein was then extracted from the synovial cells following 12 and 24 h, and PER2 protein expression was assayed by immunoblotting. The rs2304674 SNP demonstrated a significant association with susceptibility to RA following Bonferroni correction. However, statistical analysis indicated that the SNPs were not associated with any clinical features of patients with RA. Immunoblotting analysis demonstrated that PER2 protein expression was decreased by LPS‑induced inflammation in RA synovial cells; however, this was not observed in normal synovial cells. The results suggest that the PER2 gene may be a risk factor for RA, and expression of the PER2 protein may be affected by inflammation. Therefore, PER2 may contribute to the pathogenesis of RA.

A pipeline for the systematic identification of non-redundant full-ORF cDNAs for polymorphic and evolutionary divergent genomes: Application to the ascidian Ciona intestinalis

DOE PAGES

Gilchrist, Michael J.; Sobral, Daniel; Khoueiry, Pierre; ...

2015-05-27

Genome-wide resources, such as collections of cDNA clones encoding for complete proteins (full-ORF clones), are crucial tools for studying the evolution of gene function and genetic interactions. Non-model organisms, in particular marine organisms, provide a rich source of functional diversity. Marine organism genomes are, however, frequently highly polymorphic and encode proteins that diverge significantly from those of well-annotated model genomes. The construction of full-ORF clone collections from non-model organisms is hindered by the difficulty of predicting accurately the N-terminal ends of proteins, and distinguishing recent paralogs from highly polymorphic alleles. We also report a computational strategy that overcomes these difficulties,more » and allows for accurate gene level clustering of transcript data followed by the automated identification of full-ORFs with correct 5'- and 3'-ends. It is robust to polymorphism, includes paralog calling and does not require evolutionary proximity to well annotated model organisms. Here, we developed this pipeline for the ascidian Ciona intestinalis, a highly polymorphic member of the divergent sister group of the vertebrates, emerging as a powerful model organism to study chordate gene function, Gene Regulatory Networks and molecular mechanisms underlying human pathologies. Furthermore, using this pipeline we have generated the first full-ORF collection for a highly polymorphic marine invertebrate. It contains 19,163 full-ORF cDNA clones covering 60% of Ciona coding genes, and full-ORF orthologs for approximately half of curated human disease-associated genes.« less

A multicenter matched case-control analysis on seven polymorphisms from HMGB1 and RAGE genes in predicting hepatocellular carcinoma risk.

PubMed

Wang, Dan; Qi, Xiaoying; Liu, Fang; Yang, Chuanhua; Jiang, Wenguo; Wei, Xiaodan; Li, Xuri; Mi, Jia; Tian, Geng

2017-07-25

Based on 540 hepatocellular carcinoma patients and 540 age- and gender-matched controls, we tested the hypothesis that high mobility group protein box1 (HMGB1) and the receptor for advanced glycation end products (RAGE) genes are two potential candidate susceptibility genes for hepatocellular carcinoma in a multicenter hospital-based case-control analysis. The genotypes of seven widely-studied polymorphisms were determined, and their distributions respected the Hardy-Weinberg equilibrium. The mutant alleles of two polymorphisms, rs1045411 in HMGB1 gene and rs2070600 in RAGE gene, had significantly higher frequencies in patients than in controls (P < 0.001), with the power to detect this significance of being over 99.9%. Moreover, the above two polymorphisms increased the risk of developing hepatocellular carcinoma significantly, particularly for rs2070600 under the additive (odds ratio [OR] = 1.77; 95% confidence interval [CI]: 1.34-2.32; P < 0.001) and dominant (OR = 1.75; 95% CI: 1.23-2.50; P = 0.002) models after adjusting for body mass index, smoking and drinking. Haplotype analysis showed that the T-C-T haplotype (rs1045411-rs2249825-rs1415125) in HMGB1 gene was associated with a 2.47-fold (95% CI: 1.41-4.34; P = 0.002) increased risk of hepatocellular carcinoma compared with the commonest C-C-T haplotype after adjustment. In RAGE gene, the T-T-A-G (rs1800625-rs1800624-rs2070600-rs184003) (adjusted OR; 95% CI; P: 1.75; 1.02-3.03; 0.045) and T-T-A-T (adjusted OR; 95% CI; P: 1.95; 1.01-3.76; 0.048) haplotypes were associated with a marginally increased risk of hepatocellular carcinoma compared with the commonest T-T-G-G haplotype. In summary, we identified two risk-associated polymorphisms (rs1045411 and rs2070600), and more importantly a joint impact of seven polymorphisms from the HMGB1/RAGE axis in susceptibility to hepatocellular carcinoma.

DOE Office of Scientific and Technical Information (OSTI.GOV)

Sun, Wenhao; Jayaraman, Saivenkataraman; Chen, Wei

Predicting the conditions in which a compound adopts a metastable structure when it crystallizes out of solution is an unsolved and fundamental problem in materials synthesis, and one which, if understood and harnessed, could enable the rational design of synthesis pathways toward or away from metastable structures. Crystallization of metastable phases is particularly accessible via low-temperature solution-based routes, such as chimie douce and hydrothermal synthesis, but although the chemistry of the solution plays a crucial role in governing which polymorph forms, how it does so is poorly understood. Here, we demonstrate an ab initio technique to quantify thermodynamic parameters ofmore » surfaces and bulks in equilibrium with an aqueous environment, enabling the calculation of nucleation barriers of competing polymorphs as a function of solution chemistry, thereby predicting the solution conditions governing polymorph selection. We apply this approach to resolve the long-standing “calcite–aragonite problem”––the observation that calcium carbonate precipitates as the metastable aragonite polymorph in marine environments, rather than the stable phase calcite––which is of tremendous relevance to biomineralization, carbon sequestration, paleogeochemistry, and the vulnerability of marine life to ocean acidification. We identify a direct relationship between the calcite surface energy and solution Mg–Ca ion concentrations, showing that the calcite nucleation barrier surpasses that of metastable aragonite in solutions with Mg:Ca ratios consistent with modern seawater, allowing aragonite to dominate the kinetics of nucleation. The ability to quantify how solution parameters distinguish between polymorphs marks an important step toward the ab initio prediction of materials synthesis pathways in solution.« less

A Mendelian randomization study of testosterone and cognition in men

PubMed Central

Zhao, Jie V.; Lam, Tai Hing; Jiang, Chaoqiang; Cherny, Stacey S.; Liu, Bin; Cheng, Kar Keung; Zhang, Weisen; Leung, Gabriel M.; Schooling, C Mary

2016-01-01

Testosterone replacement for older men is increasingly common, with some observations suggesting a protective effect on cognitive function. We examined the association of endogenous testosterone with cognitive function among older men in a Mendelian randomization study using a separate-sample instrumental variable (SSIV) analysis estimator to minimize confounding and reverse causality. A genetic score predicting testosterone was developed in 289 young Chinese men from Hong Kong, based on selected testosterone-related single nucleotide polymorphisms (rs10046, rs1008805 and rs1256031). The association of genetically predicted testosterone with delayed 10-word recall score and Mini-Mental State Examination (MMSE) score was assessed at baseline and follow-up using generalized estimating equation among 4,212 older Chinese men from the Guangzhou Biobank Cohort Study. Predicted testosterone was not associated with delayed 10-word recall score (−0.02 per nmol/L testosterone, 95% confidence interval (CI) −0.06–0.02) or MMSE score (0.06, 95% CI −0.002–0.12). These estimates were similar after additional adjustment for age, education, smoking, use of alcohol, body mass index and the Framingham score. Our findings do not corroborate observed protective effects of testosterone on cognitive function among older men. PMID:26864717

Microsatellite markers characterized in the barn owl (Tyto alba) and of high utility in other owls (Strigiformes: AVES).

PubMed

Klein, Akos; Horsburgh, Gavin J; Küpper, Clemens; Major, Agnes; Lee, Patricia L M; Hoffmann, Gyula; Mátics, Róbert; Dawson, Deborah A

2009-11-01

We have identified 15 polymorphic microsatellite loci for the barn owl (Tyto alba), five from testing published owl loci and 10 from testing non-owl loci, including loci known to be of high utility in passerines and shorebirds. All 15 loci were sequenced in barn owl, and new primer sets were designed for eight loci. The 15 polymorphic loci displayed two to 26 alleles in 56-58 barn owls. When tested in 10 other owl species (n = 1-6 individuals), between four and nine loci were polymorphic per species. These loci are suitable for studies of population structure and parentage in owls. © 2009 Blackwell Publishing Ltd.

Pharmacogenetics-based area-under-curve model can predict efficacy and adverse events from axitinib in individual patients with advanced renal cell carcinoma.

PubMed

Yamamoto, Yoshiaki; Tsunedomi, Ryouichi; Fujita, Yusuke; Otori, Toru; Ohba, Mitsuyoshi; Kawai, Yoshihisa; Hirata, Hiroshi; Matsumoto, Hiroaki; Haginaka, Jun; Suzuki, Shigeo; Dahiya, Rajvir; Hamamoto, Yoshihiko; Matsuyama, Kenji; Hazama, Shoichi; Nagano, Hiroaki; Matsuyama, Hideyasu

2018-03-30

We investigated the relationship between axitinib pharmacogenetics and clinical efficacy/adverse events in advanced renal cell carcinoma (RCC) and established a model to predict clinical efficacy and adverse events using pharmacokinetic and gene polymorphisms related to drug metabolism and efflux in a phase II trial. We prospectively evaluated the area under the plasma concentration-time curve (AUC) of axitinib, objective response rate, and adverse events in 44 consecutive advanced RCC patients treated with axitinib. To establish a model for predicting clinical efficacy and adverse events, polymorphisms in genes including ABC transporters ( ABCB1 and ABCG2 ), UGT1A , and OR2B11 were analyzed by whole-exome sequencing, Sanger sequencing, and DNA microarray. To validate this prediction model, calculated AUC by 6 gene polymorphisms was compared with actual AUC in 16 additional consecutive patients prospectively. Actual AUC significantly correlated with the objective response rate ( P = 0.0002) and adverse events (hand-foot syndrome, P = 0.0055; and hypothyroidism, P = 0.0381). Calculated AUC significantly correlated with actual AUC ( P < 0.0001), and correctly predicted objective response rate ( P = 0.0044) as well as adverse events ( P = 0.0191 and 0.0082, respectively). In the validation study, calculated AUC prior to axitinib treatment precisely predicted actual AUC after axitinib treatment ( P = 0.0066). Our pharmacogenetics-based AUC prediction model may determine the optimal initial dose of axitinib, and thus facilitate better treatment of patients with advanced RCC.

Pharmacogenetics-based area-under-curve model can predict efficacy and adverse events from axitinib in individual patients with advanced renal cell carcinoma

PubMed Central

Yamamoto, Yoshiaki; Tsunedomi, Ryouichi; Fujita, Yusuke; Otori, Toru; Ohba, Mitsuyoshi; Kawai, Yoshihisa; Hirata, Hiroshi; Matsumoto, Hiroaki; Haginaka, Jun; Suzuki, Shigeo; Dahiya, Rajvir; Hamamoto, Yoshihiko; Matsuyama, Kenji; Hazama, Shoichi; Nagano, Hiroaki; Matsuyama, Hideyasu

2018-01-01

We investigated the relationship between axitinib pharmacogenetics and clinical efficacy/adverse events in advanced renal cell carcinoma (RCC) and established a model to predict clinical efficacy and adverse events using pharmacokinetic and gene polymorphisms related to drug metabolism and efflux in a phase II trial. We prospectively evaluated the area under the plasma concentration–time curve (AUC) of axitinib, objective response rate, and adverse events in 44 consecutive advanced RCC patients treated with axitinib. To establish a model for predicting clinical efficacy and adverse events, polymorphisms in genes including ABC transporters (ABCB1 and ABCG2), UGT1A, and OR2B11 were analyzed by whole-exome sequencing, Sanger sequencing, and DNA microarray. To validate this prediction model, calculated AUC by 6 gene polymorphisms was compared with actual AUC in 16 additional consecutive patients prospectively. Actual AUC significantly correlated with the objective response rate (P = 0.0002) and adverse events (hand-foot syndrome, P = 0.0055; and hypothyroidism, P = 0.0381). Calculated AUC significantly correlated with actual AUC (P < 0.0001), and correctly predicted objective response rate (P = 0.0044) as well as adverse events (P = 0.0191 and 0.0082, respectively). In the validation study, calculated AUC prior to axitinib treatment precisely predicted actual AUC after axitinib treatment (P = 0.0066). Our pharmacogenetics-based AUC prediction model may determine the optimal initial dose of axitinib, and thus facilitate better treatment of patients with advanced RCC. PMID:29682213

PER2 variants are associated with abdominal obesity, psycho-behavioral factors and attrition in the dietary treatment of obesity

USDA-ARS?s Scientific Manuscript database

The purpose was to test for association between polymorphisms in the circadian clock-related gene PER2 and attrition in patients prone to withdrawal from a behavioral weight-reduction-program based on the Mediterranean Diet. 454 overweight/obese subjects (women= 380, men= 74), aged 20-65 years, who ...

Vector Adaptive/Predictive Encoding Of Speech

NASA Technical Reports Server (NTRS)

Chen, Juin-Hwey; Gersho, Allen

1989-01-01

Vector adaptive/predictive technique for digital encoding of speech signals yields decoded speech of very good quality after transmission at coding rate of 9.6 kb/s and of reasonably good quality at 4.8 kb/s. Requires 3 to 4 million multiplications and additions per second. Combines advantages of adaptive/predictive coding, and code-excited linear prediction, yielding speech of high quality but requires 600 million multiplications and additions per second at encoding rate of 4.8 kb/s. Vector adaptive/predictive coding technique bridges gaps in performance and complexity between adaptive/predictive coding and code-excited linear prediction.

Evaluation of Prediction of Polymorphisms of DNA Repair Genes on the Efficacy of Platinum-Based Chemotherapy in Patients With Non-Small Cell Lung Cancer: A Network Meta-Analysis.

PubMed

Yu, Shao-Nan; Liu, Gui-Feng; Li, Xue-Feng; Fu, Bao-Hong; Dong, Li-Xin; Zhang, Shu-Hua

2017-12-01

This network meta-analysis (NMA) was conducted to compare the predictive value of 14 SNPs in eight DNA repair genes on the efficacy of platinum-based chemotherapy in patients with non-small cell lung cancer (NSCLC). These included ERCC1 (rs11615, rs3212986, rs3212948), XRCC1 (rs25487, rs25489, rs1799782), XPD (rs13181, rs1799793), XPG (rs1047768, rs17655), XPA (rs1800975), XRCC3 (rs861539), APE1 (rs3136820), and RRM1 (rs1042858). The PubMed and Cochrane library databases were reviewed from their inception to February 2017 and studies which met our inclusion criteria were included in our investigation. This network meta-analysis combines direct and indirect evidence to assess the predictive value of 14 SNPs in eight DNA repair genes on the efficacy of platinum-based chemotherapy in NSCLC. We evaluated the predictive value through the use of the odd ratios (OR) and drawing surface under the cumulative ranking curves (SUCRA). A total of 26 eligible cohort studies were enrolled in this NMA. The pairwise meta-analysis indicated that in terms of overall response ratio (ORR), ERCC1 (rs11615), XRCC1 (rs25487, rs1799782), and XPD (rs13181) polymorphisms are associated with the efficacy of platinum-based chemotherapy in NSCLC. The result of this NMA suggests that there is no significant difference in predictive value of 8 DNA repair genes on the efficacy of platinum-based chemotherapy in NSCLC patients. The rank of SUCRA values of the 14 SNPs in the eight DNA repair genes were: XPD (rs1799793)→ERCC1 (rs3212986)→XPA(rs1800975)→ERCC1(rs3212948)→XRCC1(rs25487)→XRCC3(rs861539)→APE1(rs3136820)→ERCC1(rs11615)→XRCC1(rs1799782)→RRM1(rs1042858)→XPD(rs13181)→XPG (rs1047768)→XPG(rs17655)→XRCC1(rs25489). ERCC1(rs11615), XRCC1(rs25487, rs1799782) and XPD(rs13181) polymorphisms were better predictors in evaluating the efficacy of platinum-based chemotherapy in NSCLC patients. J. Cell. Biochem. 118: 4782-4791, 2017. © 2017 Wiley Periodicals, Inc. © 2017 Wiley Periodicals, Inc.

A functional variant of the serotonin transporter gene (SLC6A4) moderates impulsive choice in attention-deficit/hyperactivity disorder boys and siblings.

PubMed

Sonuga-Barke, Edmund J S; Kumsta, Robert; Schlotz, Wolff; Lasky-Su, Jessica; Marco, Rafaela; Miranda, Ana; Mulas, Fernando; Oades, Robert D; Banaschewski, Tobias; Mueller, Ueli; Andreou, Penny; Christiansen, Hanna; Gabriels, Isabel; Uebel, Henrik; Kuntsi, Jonna; Franke, Barbara; Buitelaar, Jan; Ebstein, Richard; Gill, Michael; Anney, Richard; Roeyers, Herbert; Rothenberger, Aribert; Sergeant, Joseph; Steinhausen, Hans Christoph; Asherson, Philip; Faraone, Stephen V

2011-08-01

Impulsive drive for immediate reward (IDIR) and delay aversion are dissociable elements of the preference for immediate over delayed rewards seen in attention-deficit/hyperactivity disorder (ADHD). We hypothesized that IDIR would be associated with dopamine regulating genes and delay aversion would be associated with serotonin-regulating genes. Impulsive drive for immediate reward and delay aversion were measured in 459 male children and adolescents (328 ADHD and 131 unaffected siblings) with a laboratory choice task. The sample was genotyped for the 5HTT (SLC6A4) promoter serotonin-transporter-linked polymorphic region polymorphism and a DAT1 (SLC6A3) 40-base pair variable number tandem repeat located in the 3'-untranslated region of the gene. There was no effect of dopamine transporter (DAT)1 on IDIR. As predicted, serotonin-transporter-linked polymorphic region s-allele carriers were more delay averse. This effect was driven by the s/l genotype in the ADHD group. These results were not altered by taking account of the rs25531 A/G single nucleotide polymorphism and were independent of age, IQ, and oppositional defiant disorder symptoms. The results support the genetic distinctiveness of IDIR and delay aversion in ADHD and implicate serotonin function in delay aversion. Possible explanations of the heterosis effect in the ADHD cases are presented. Copyright © 2011 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.

Molecular genetics of the platelet serotonin system in first-degree relatives of patients with autism

PubMed Central

Cross, Sarah; Kim, Soo-Jeong; Weiss, Lauren A.; Delahanty, Ryan J.; Sutcliffe, James S.; Leventhal, Bennett L.; Cook, Edwin H.; Veenstra-VanderWeele, Jeremy

2009-01-01

Elevated platelet serotonin (5-HT) is found in a subset of children with autism and in some of their first-degree relatives. Indices of the platelet serotonin system, including whole blood serotonin (5-HT), 5-HT binding affinity for the serotonin transporter (Km), 5-HT uptake (Vmax), and lysergic acid diethylamide (LSD) receptor binding, were previously studied in twenty-four first-degree relatives of probands with autism, half of whom were selected for elevated whole blood 5-HT levels. All subjects were then genotyped for selected polymorphisms at the SLC6A4, HTR7, HTR2A, ITGB3, and TPH1 loci. Previous studies allowed an a priori prediction of SLC6A4 haplotypes that separated the subjects into three groups that showed significantly different 5-HT binding affinity (Km, p = 0.005) and 5-HT uptake rate (Vmax, p = 0.046). Genotypes at four individual polymorphisms in SLC6A4 were not associated with platelet 5-HT indices. Haplotypes at SLC6A4 and individual genotypes of polymorphisms at SLC6A4, HTR7, HTR2A, ITGB3, and TPH1 showed no significant association with whole blood 5-HT. Haplotype analysis of two polymorphisms in TPH1 revealed a nominally significant association with whole blood 5-HT (p = 0.046). These initial studies of indices of the 5-HT system with several SNPs at loci in this system generate hypotheses for testing in other samples. PMID:17406648

Missense Gamma-Aminobutyric Acid Receptor Polymorphisms Are Associated with Reaction Time, Motor Time, and Ethanol Effects in Vivo.

PubMed

García-Martín, Elena; Ramos, María I; Cornejo-García, José A; Galván, Segismundo; Perkins, James R; Rodríguez-Santos, Laura; Alonso-Navarro, Hortensia; Jiménez-Jiménez, Félix J; Agúndez, José A G

2018-01-01

Background: The Gamma-aminobutyric acid type A receptor (GABA-A receptor) is affected by ethanol concentrations equivalent to those reached during social drinking. At these concentrations, ethanol usually causes impairment in reaction and motor times in most, but not all, individuals. Objectives: To study the effect of GABA-A receptor variability in motor and reaction times, and the effect of low ethanol doses. Methods: Two hundred and fifty healthy subjects received one single dose of 0.5 g/Kg ethanol per os . Reaction and motor times were determined before ethanol challenge (basal), and when participants reached peak ethanol concentrations. We analyzed all common missense polymorphisms described in the 19 genes coding for the GABA-A receptor subunits by using TaqMan probes. Results: The GABRA6 rs4454083 T/C polymorphisms were related to motor times, with individuals carrying the C/C genotype having faster motor times, both, at basal and at peak ethanol concentrations. The GABRA4 rs2229940 T/T genotype was associated to faster reaction times and with lower ethanol effects, determined as the difference between basal reaction time and reaction time at peak concentrations. All these associations remained significant after correction for multiple comparisons. No significant associations were observed for the common missense SNPs GABRB3 rs12910925, GABRG2 rs211035, GABRE rs1139916, GABRP rs1063310, GABRQ rs3810651, GABRR1 rs12200969 or rs1186902, GABRR2 rs282129, and GABRR3 rs832032. Conclusions: This study provides novel information supporting a role of missense GABA-A receptor polymorphisms in reaction time, motor time and effects of low ethanol doses in vivo .

Tissue identity testing of cancer by short tandem repeat polymorphism: pitfalls of interpretation in the presence of microsatellite instability.

PubMed

Much, Melissa; Buza, Natalia; Hui, Pei

2014-03-01

Tissue identity testing by short tandem repeat (STR) polymorphism offers discriminating power in resolving tissue mix-up or contamination. However, one caveat is the presence of microsatellite unstable tumors, in which genetic alterations may drastically change the STR wild-type polymorphism leading to unexpected allelic discordance. We examined how tissue identity testing results can be altered by the presence of microsatellite instability (MSI). Eleven cases of MSI-unstable (9 intestinal and 2 endometrial adenocarcinomas) and 10 cases of MSI-stable tumors (all colorectal adenocarcinomas) were included. All had been previously tested by polymerase chain reaction testing at 5 National Cancer Institute (NCI) recommended MSI loci and/or immunohistochemistry for DNA mismatch repair proteins (MLH1, MSH2, MSH6, and PMS2). Tissue identity testing targeting 15 STR loci was performed using AmpF/STR Identifiler Amplification. Ten of 11 MSI-unstable tumors demonstrated novel alleles at 5 to 12 STR loci per case and frequently with 3 or more allelic peaks. However, all affected loci showed identifiable germline allele(s) in MSI-high tumors. A wild-type allelic profile was seen in 7 of 10 MSI-stable tumors. In the remaining 3 cases, isolated novel alleles were present at a unique single locus in addition to germline alleles. Loss of heterozygosity was observed frequently in both MSI-stable (6/11 cases) and MSI-unstable tumors (8/10 cases). In conclusion, MSI may significantly alter the wild-type allelic polymorphism, leading to potential interpretation errors of STR genotyping. Careful examination of the STR allelic pattern, high index of suspicion, and follow-up MSI testing are crucial to avoid erroneous conclusions and subsequent clinical and legal consequences. Copyright © 2014 Elsevier Inc. All rights reserved.

Effect modification by vitamin D receptor genetic polymorphisms in the association between cumulative lead exposure and pulse pressure: a longitudinal study.

PubMed

Jhun, Min A; Hu, Howard; Schwartz, Joel; Weisskopf, Marc G; Nie, Linda H; Sparrow, David; Vokonas, Pantel S; Park, Sung Kyun

2015-01-13

Although the association between lead and cardiovascular disease is well established, potential mechanisms are still poorly understood. Calcium metabolism plays a role in lead toxicity and thus, vitamin D receptor (VDR) polymorphisms have been suggested to modulate the association between lead and health outcomes. We investigated effect modification by VDR genetic polymorphisms in the association between cumulative lead exposure and pulse pressure, a marker of arterial stiffness. We examined 727 participants (3,100 observations from follow-ups from 1991 to 2011) from the Normative Aging Study (NAS), a longitudinal study of aging. Tibia and patella bone lead levels were measured using K-x-ray fluorescence. Four single nucleotide polymorphisms (SNPs) in the VDR gene, Bsm1, Taq1, Apa1, and Fok1, were genotyped. Linear mixed effects models with random intercepts were implemented to take into account repeated measurements. Adjusting for potential confounders, pulse pressure was 2.5 mmHg (95% CI: 0.4-4.7) and 1.9 mmHg (95% CI: 0.1-3.8) greater per interquartile range (IQR) increase in tibia lead (15 μg/g) and patella lead (20 μg/g), respectively, in those with at least one minor frequency allele in Bsm1 compared with those with major frequency allele homozygotes. The observed interaction effect between bone lead and the Bsm1 genotype persists over time during the follow-up. Similar results were observed in effect modification by Taq1. This study suggests that subjects with the minor frequency alleles of VDR Bsm1 or Taq1 may be more susceptible to cumulative lead exposure-related elevated pulse pressure.

Genetic Variants Related to Height and Risk of Atrial Fibrillation

PubMed Central

Rosenberg, Michael A.; Kaplan, Robert C.; Siscovick, David S.; Psaty, Bruce M.; Heckbert, Susan R.; Newton-Cheh, Christopher; Mukamal, Kenneth J.

2014-01-01

Increased height is a known independent risk factor for atrial fibrillation (AF). However, whether genetic determinants of height influence risk is uncertain. In this candidate gene study, we examined the association of 209 height-associated single-nucleotide polymorphisms (SNPs) with incident AF in 3,309 persons of European descent from the Cardiovascular Health Study, a prospective cohort study of older adults (aged ≥65 years) enrolled in 1989–1990. After a median follow-up period of 13.2 years, 879 participants developed incident AF. The height-associated SNPs together explained approximately 10% of the variation in height (P = 6.0 × 10−8). Using an unweighted genetic height score, we found a nonsignificant association with risk of AF (per allele, hazard ratio = 1.01, 95% confidence interval: 1.00, 1.02; P = 0.06). In weighted analyses, we found that genetically predicted height was strongly associated with AF risk (per 10 cm, hazard ratio = 1.30, 95% confidence interval: 1.03, 1.64; P = 0.03). Importantly, for all models, the inclusion of actual height completely attenuated the genetic height effect. Finally, we identified 1 nonsynonymous SNP (rs1046934) that was independently associated with AF and may warrant future study. In conclusion, we found that genetic determinants of height appear to increase the risk of AF, primarily via height itself. This approach of examining SNPs associated with an intermediate phenotype should be considered as a method for identifying novel genetic targets. PMID:24944287

Effects of the BDNF Val66Met Polymorphism on Anxiety-Like Behavior Following Nicotine Withdrawal in Mice.

PubMed

Lee, Bridgin G; Anastasia, Agustin; Hempstead, Barbara L; Lee, Francis S; Blendy, Julie A

2015-12-01

Nicotine withdrawal is characterized by both affective and cognitive symptoms. Identifying genetic polymorphisms that could affect the symptoms associated with nicotine withdrawal are important in predicting withdrawal sensitivity and identifying personalized cessation therapies. In the current study we used a mouse model of a non-synonymous single nucleotide polymorphism in the translated region of the brain-derived neurotrophic factor (BDNF) gene that substitutes a valine (Val) for a methionine (Met) amino acid (Val66Met) to examine the relationship between the Val66Met single nucleotide polymorphism and nicotine dependence. This study measured proBDNF and the BDNF prodomain levels following nicotine and nicotine withdrawal and examined a mouse model of a common polymorphism in this protein (BDNF(Met/Met)) in three behavioral paradigms: novelty-induced hypophagia, marble burying, and the open-field test. Using the BDNF knock-in mouse containing the BDNF Val66Met polymorphism we found: (1) blunted anxiety-like behavior in BDNF(Met/Met) mice following withdrawal in three behavioral paradigms: novelty-induced hypophagia, marble burying, and the open-field test; (2) the anxiolytic effects of chronic nicotine are absent in BDNF(Met/Met) mice; and (3) an increase in BDNF prodomain in BDNF(Met/Met) mice following nicotine withdrawal. Our study is the first to examine the effect of the BDNF Val66Met polymorphism on the affective symptoms of withdrawal from nicotine in mice. In these mice, a single-nucleotide polymorphism in the translated region of the BDNF gene can result in a blunted withdrawal, as measured by decreased anxiety-like behavior. The significant increase in the BDNF prodomain in BDNF(Met/Met) mice following nicotine cessation suggests a possible role of this ligand in the circuitry remodeling after withdrawal. © The Author 2015. Published by Oxford University Press on behalf of the Society for Research on Nicotine and Tobacco. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

Genetic variability in Brazilian wheat cultivars assessed by microsatellite markers

PubMed Central

2009-01-01

Wheat (Triticum aestivum) is one of the most important food staples in the south of Brazil. Understanding genetic variability among the assortment of Brazilian wheat is important for breeding. The aim of this work was to molecularly characterize the thirty-six wheat cultivars recommended for various regions of Brazil, and to assess mutual genetic distances, through the use of microsatellite markers. Twenty three polymorphic microsatellite markers (PMM) delineated all 36 of the samples, revealing a total of 74 simple sequence repeat (SSR) alleles, i.e. an average of 3.2 alleles per locus. Polymorphic information content (PIC value) calculated to assess the informativeness of each marker ranged from 0.20 to 0.79, with a mean of 0.49. Genetic distances among the 36 cultivars ranged from 0.10 (between cultivars Ocepar 18 and BRS 207) to 0.88 (between cultivars CD 101 and Fudancep 46), the mean distance being 0.48. Twelve groups were obtained by using the unweighted pair-group method with arithmetic means analysis (UPGMA), and thirteen through the Tocher method. Both methods produced similar clusters, with one to thirteen cultivars per group. The results indicate that these tools may be used to protect intellectual property and for breeding and selection programs. PMID:21637519

Analysis of genetic diversity in pigeon pea germplasm using retrotransposon-based molecular markers.

PubMed

Maneesha; Upadhyaya, Kailash C

2017-09-01

Pigeon pea (Cajanus cajan), an important legume crop is predominantly cultivated in tropical and subtropical regions of Asia and Africa. It is normally considered to have a low degree of genetic diversity, an impediment in undertaking crop improvement programmes.We have analysed genetic polymorphism of domesticated pigeon pea germplasm (47 accessions) across the world using earlier characterized panzee retrotransposon-based molecularmarkers. Itwas conjectured that since retrotransposons are interspersed throughout the genome, retroelements-based markers would be able to uncover polymorphism possibly inherent in the diversity of retroelement sequences. Two PCR-based techniques, sequence-specific amplified polymorphism (SSAP) and retrotransposon microsatellite amplified polymorphism (REMAP) were utilized for the analyses.We show that a considerable degree of polymorphism could be detected using these techniques. Three primer combinations in SSAP generated 297 amplified products across 47 accessions with an average of 99 amplicons per assay. Degree of polymorphism varied from 84-95%. In the REMAP assays, the number of amplicons was much less but up to 73% polymorphism could be detected. On the basis of similarity coefficients, dendrograms were constructed. The results demonstrate that the retrotransposon-based markers could serve as a better alternative for the assessment of genetic diversity in crops with apparent low genetic base.

Relations of blood pressure to angiotensinogen gene T174M polymorphism and alcohol intake.

PubMed

Takashima, Yutaka; Kokaze, Akatsuki; Matsunaga, Naomi; Yoshida, Masao; Sekiguchi, Kanako; Sekine, Yasuko; Sumiya, Yu

2003-07-01

To clarify the interactive effects of alcohol intake and angiotensinogen gene codon 174 (T174M) polymorphisms on blood pressure in Japanese male workers. On the basis of data from health examinations, nutrition survey and T174M genotype analysis conducted for 185 Japanese male workers at 2000, the prevalence of high-normal blood pressure (HNBP) and hypertension were compared between the four subgroups crossed by two T174M genotype categories ('TT' type, and 'TM or MM' type) and two alcohol intake categories (less than 13.7 g per day, and 13.7 g or more per day). Furthermore, for 95 subjects who had been normotensive at 1998 among them, risk of development into HNBP or hypertension at 2000 were compared across the four subgroups. The findings showed that the HNBP prevalence adjusted for age, body mass index, smoking habits and sodium intake in 2000 was significantly (p=0.03) greater in 'TM or MM' type (57.9%) than in 'TT' type (24.9%) in subjects with 13.7 g or more of daily alcohol intake, whereas no difference in this parameter was found between the two genotypes in those with less than 13.7 g of daily alcohol intake (18.2% and 18.3%, respectively). The risk for development into HNBP at 2000 was also greatest in 'TM or MM' type with 13.7 g or more of daily alcohol intake among the four subgroups, although there were not significant differences between the four subgroups. The prevalence of hypertension or development risk for hypertension did not significantly differ between the four subgroups. Therefore, it can be seen that alcohol drinking might be specifically associated with the HNBP in M allele carriers of angiotensinogen gene T174M polymorphism.

Association between TPO Asn698Thr and Thr725Pro gene polymorphisms and serum anti-TPO levels in Iranian patients with subclinical hypothyroidism.

PubMed

Khoshi, Amirhosein; Sirghani, Alireza; Ghazisaeedi, Mehran; Mahmudabadi, Ali Zare; Azimian, Amir

2017-01-01

Subclinical hypothyroidism (SCH) is defined as high levels of TSH in the presence of normal levels of serum FT4. Since thyroid peroxidase (TPO) plays a key role in thyroid hormone synthesis, variations in the TPO gene can change the enzyme structure and result in the production of anti-TPO antibodies. The aim of this study was to examine the relationship between the Asn698Thr (A2095C) and Thr725Pro (A2173C) polymorphisms of the TPO gene and anti-TPO levels in patients with SCH. In this study, 150 individuals (75 cases and 75 controls), aged 19-75 years, were selected randomly by a clinician. The thyroid function tests included were FT3, FT4, TSH and anti-TPO antibodies using ELISA. The TPO gene polymorphisms were examined by PCR-RFLP. Anti-TPO levels in the experimental group was significantly increased (P=0.020). The A2095C genotype frequency in the experimental and control groups were 37.3% vs 34.7% for the AA healthy genotype, 20% vs 46.7% for AC and 42.7% vs 18.6% for CC, respectively (P=0.001). The A2173C genotype frequency in the experimental and control groups were 22.6% vs 68% for healthy AA, 40% vs 25.3% for AC and 37.4% vs 6.7% for CC, respectively (P <0.001). The increased anti-TPO antibodies were significantly associated with the A2173C polymorphism (P=0.035). The findings showed that the chance (odds ratio) of developing subclinical hypothyroidism in individuals who had C alleles was 1.5 and 5.6-fold higher than in individuals without these alleles in the A2095C and A2173C regions, respectively. Determination of anti-TPO antibody levels and exon 12 TPO gene polymorphisms in patients with SCH can be helpful for prediction of overt hypothyroidism.

E2F transcription factor 2 variants as predictive biomarkers for recurrence risk in patients with squamous cell carcinoma of the oropharynx.

PubMed

Li, Yuncheng; Sturgis, Erich M; Zhu, Lijun; Cao, Xiaoli; Wei, Qingyi; Zhang, Hua; Li, Guojun

2017-04-01

Because E2F transcription factor 2 (E2F2) promoter polymorphisms have been implicated in carcinogenesis and prognosis, we investigated associations between genetic variants in five E2F2 promoter polymorphisms and recurrence risk of squamous cell carcinoma of the oropharynx (SCCOP) in 1 008 patients. A log-rank test and multivariable Cox models were used to assess the associations. Compared with patients with variant genotypes of E2F2-rs2742976 and E2F2-rs3218123, patients with common homozygous genotypes had better disease-free survival (both log-rank, P < 0.001) and lower SCCOP recurrence risk (HR, 0.4, 95% CI, 0.3-0.6 and HR, 0.3, 95% CI, 0.2-0.5, respectively) after multivariable adjustment. Furthermore, among patients with HPV16-positive tumors, those with common homozygous genotypes of E2F2-rs2742976 and E2F2-rs3218123 had better disease-free survival rates (both log-rank, P < 0.001) and lower recurrence risk (HR, 0.1, 95% CI, 0.1-0.4 and HR, 0.1, 95% CI, 0.0-0.2, respectively) than patients with variant genotypes. However, no significant differences were found for the other three polymorphisms. After combining the risk genotypes of the five polymorphisms and using the high-risk group (2-5 risk genotypes) as the reference group, we found that the low-risk groups (0 or 1 risk genotype) had significantly lower recurrence risk among all patients (HR, 0.4, 95% CI, 0.3-0.6) and among HPV16-positive patients (HR, 0.2, 95% CI, 0.1-0.5). Our findings suggest that E2F2 polymorphisms may individually or jointly modify SCCOP recurrence risk, particularly for SCCOP patients with HPV16-positive tumors. © 2017 Wiley Periodicals, Inc. © 2017 Wiley Periodicals, Inc.

Computing the melting point and thermodynamic stability of the orthorhombic and monoclinic crystalline polymorphs of the ionic liquid 1-n-butyl-3-methylimidazolium chloride

NASA Astrophysics Data System (ADS)

Jayaraman, Saivenkataraman; Maginn, Edward J.

2007-12-01

The melting point, enthalpy of fusion, and thermodynamic stability of two crystal polymorphs of the ionic liquid 1-n-butyl-3-methylimidazolium chloride are calculated using a thermodynamic integration-based atomistic simulation method. The computed melting point of the orthorhombic phase ranges from 365 to 369 K, depending on the classical force field used. This compares reasonably well with the experimental values, which range from 337 to 339 K. The computed enthalpy of fusion ranges from 19 to 29 kJ/mol, compared to the experimental values of 18.5-21.5 kJ/mol. Only one of the two force fields evaluated in this work yielded a stable monoclinic phase, despite the fact that both give accurate liquid state densities. The computed melting point of the monoclinic polymorph was found to be 373 K, which is somewhat higher than the experimental range of 318-340 K. The computed enthalpy of fusion was 23 kJ/mol, which is also higher than the experimental value of 9.3-14.5 kJ/mol. The simulations predict that the monoclinic form is more stable than the orthorhombic form at low temperature, in agreement with one set of experiments but in conflict with another. The difference in free energy between the two polymorphs is very small, due to the fact that a single trans-gauche conformational difference in an alkyl sidechain distinguishes the two structures. As a result, it is very difficult to construct simple classical force fields that are accurate enough to definitively predict which polymorph is most stable. A liquid phase analysis of the probability distribution of the dihedral angles in the alkyl chain indicates that less than half of the dihedral angles are in the gauche-trans configuration that is adopted in the orthorhombic crystal. The low melting point and glass forming tendency of this ionic liquid is likely due to the energy barrier for conversion of the remaining dihedral angles into the gauche-trans state. The simulation procedure used to perform the melting point calculations is an extension of the so-called pseudosupercritical path sampling procedure. This study demonstrates that the method can be effectively applied to quite complex systems such as ionic liquids and that the appropriate choice of tethering potentials for a key step in the thermodynamic path can enable first order phase transitions to be avoided.

Genetic Variants in the Apoptosis Gene BCL2L1 Improve Response to Interferon-Based Treatment of Hepatitis C Virus Genotype 3 Infection

PubMed Central

Clausen, Louise Nygaard; Weis, Nina; Ladelund, Steen; Madsen, Lone; Lunding, Suzanne; Tarp, Britta; Christensen, Peer Brehm; Krarup, Henrik Bygum; Møller, Axel; Gerstoft, Jan; Clausen, Mette Rye; Benfield, Thomas

2015-01-01

Genetic variation upstream of the apoptosis pathway has been associated with outcome of hepatitis C virus (HCV) infection. We investigated genetic polymorphisms in the intrinsic apoptosis pathway to assess their influence on sustained virological response (SVR) to pegylated interferon-α and ribavirin (pegIFN/RBV) treatment of HCV genotypes 1 and 3 infections. We conducted a candidate gene association study in a prospective cohort of 201 chronic HCV-infected individuals undergoing treatment with pegIFN/RBV. Differences between groups were compared in logistic regression adjusted for age, HCV viral load and interleukin 28B genotypes. Four single nucleotide polymorphisms (SNPs) located in the B-cell lymphoma 2-like 1 (BCL2L1) gene were significantly associated with SVR. SVR rates were significantly higher for carriers of the beneficial rs1484994 CC genotypes. In multivariate logistic regression, the rs1484994 SNP combined CC + TC genotypes were associated with a 3.4 higher odds ratio (OR) in SVR for the HCV genotype 3 (p = 0.02). The effect estimate was similar for genotype 1, but the association did not reach statistical significance. In conclusion, anti-apoptotic SNPs in the BCL2L1 gene were predictive of SVR to pegIFN/RBV treatment in HCV genotypes 1 and 3 infected individuals. These SNPs may be used in prediction of SVR, but further studies are needed. PMID:25648321

Landscape heterogeneity predicts gene flow in a widespread polymorphic bumble bee, Bombus bifarius (Hymentoptera: Apidae).

USDA-ARS?s Scientific Manuscript database

Bombus bifarius is a widespread bumble bee that occurs in montane regions of western North America. This species has several major color polymorphisms, and shows evidence of genetic structuring among regional populations. We test whether this structure is evidence for discrete gene flow barriers tha...

Adaptive divergence in the monkey flower Mimulus guttatus is maintained by a chromosomal inversion

PubMed Central

Twyford, Alex D.; Friedman, Jannice

2015-01-01

Organisms exhibit an incredible diversity of life history strategies as adaptive responses to environmental variation. The establishment of novel life history strategies involves multilocus polymorphisms, which will be challenging to establish in the face of gene flow and recombination. Theory predicts that adaptive allelic combinations may be maintained and spread if they occur in genomic regions of reduced recombination, such as chromosomal inversion polymorphisms, yet empirical support for this prediction is lacking. Here, we use genomic data to investigate the evolution of divergent adaptive ecotypes of the yellow monkey flower Mimulus guttatus. We show that a large chromosomal inversion polymorphism is the major region of divergence between geographically widespread annual and perennial ecotypes. In contrast, ∼40,000 single nucleotide polymorphisms in collinear regions of the genome show no signal of life history, revealing genomic patterns of diversity have been shaped by localized homogenizing gene flow and large‐scale Pleistocene range expansion. Our results provide evidence for an inversion capturing and protecting loci involved in local adaptation, while also explaining how adaptive divergence can occur with gene flow. PMID:25879251

Genomic Prediction for Quantitative Traits Is Improved by Mapping Variants to Gene Ontology Categories in Drosophila melanogaster

PubMed Central

Edwards, Stefan M.; Sørensen, Izel F.; Sarup, Pernille; Mackay, Trudy F. C.; Sørensen, Peter

2016-01-01

Predicting individual quantitative trait phenotypes from high-resolution genomic polymorphism data is important for personalized medicine in humans, plant and animal breeding, and adaptive evolution. However, this is difficult for populations of unrelated individuals when the number of causal variants is low relative to the total number of polymorphisms and causal variants individually have small effects on the traits. We hypothesized that mapping molecular polymorphisms to genomic features such as genes and their gene ontology categories could increase the accuracy of genomic prediction models. We developed a genomic feature best linear unbiased prediction (GFBLUP) model that implements this strategy and applied it to three quantitative traits (startle response, starvation resistance, and chill coma recovery) in the unrelated, sequenced inbred lines of the Drosophila melanogaster Genetic Reference Panel. Our results indicate that subsetting markers based on genomic features increases the predictive ability relative to the standard genomic best linear unbiased prediction (GBLUP) model. Both models use all markers, but GFBLUP allows differential weighting of the individual genetic marker relationships, whereas GBLUP weighs the genetic marker relationships equally. Simulation studies show that it is possible to further increase the accuracy of genomic prediction for complex traits using this model, provided the genomic features are enriched for causal variants. Our GFBLUP model using prior information on genomic features enriched for causal variants can increase the accuracy of genomic predictions in populations of unrelated individuals and provides a formal statistical framework for leveraging and evaluating information across multiple experimental studies to provide novel insights into the genetic architecture of complex traits. PMID:27235308

Preliminary conceptual model for mineral evolution in Yucca Mountain

DOE Office of Scientific and Technical Information (OSTI.GOV)

Duffy, C.J.

1993-12-01

A model is presented for mineral alteration in Yucca Mountain, Nevada, that suggests that the mineral transformations observed there are primarily controlled by the activity of aqueous silica. The rate of these reactions is related to the rate of evolution of the metastable silica polymorphs opal-CT and cristobalite assuming that a{sub SiO{sub 2(aq)}} is fixed at the equilibrium solubility of the most soluble silica polymorph present. The rate equations accurately predict the present depths of disappearance of opal-CT and cristobalite. The rate equations have also been used to predict the extent of future mineral alteration that may result from emplacementmore » of a high-level nuclear waste repository in Yucca Mountain. Relatively small changes in mineralogy are predicted, but these predictions are based on the assumption that emplacement of a repository would not increase the pH of water in Yucca Mountain nor increase its carbonate content. Such changes may significantly increase mineral alteration. Some of the reactions currently occurring in Yucca Mountain consume H{sup +} and CO{sub 3}{sup 2{minus}}. Combining reaction rate models for these reactions with water chemistry data may make it possible to estimate water flux through the basal vitrophyre of the Topopah Spring Member and to help confirm the direction and rate of flow of groundwater in Yucca Mountain.« less

Identification and characterization of transcript polymorphisms in soybean lines varying in oil composition and content.

PubMed

Goettel, Wolfgang; Xia, Eric; Upchurch, Robert; Wang, Ming-Li; Chen, Pengyin; An, Yong-Qiang Charles

2014-04-23

Variation in seed oil composition and content among soybean varieties is largely attributed to differences in transcript sequences and/or transcript accumulation of oil production related genes in seeds. Discovery and analysis of sequence and expression variations in these genes will accelerate soybean oil quality improvement. In an effort to identify these variations, we sequenced the transcriptomes of soybean seeds from nine lines varying in oil composition and/or total oil content. Our results showed that 69,338 distinct transcripts from 32,885 annotated genes were expressed in seeds. A total of 8,037 transcript expression polymorphisms and 50,485 transcript sequence polymorphisms (48,792 SNPs and 1,693 small Indels) were identified among the lines. Effects of the transcript polymorphisms on their encoded protein sequences and functions were predicted. The studies also provided independent evidence that the lack of FAD2-1A gene activity and a non-synonymous SNP in the coding sequence of FAB2C caused elevated oleic acid and stearic acid levels in soybean lines M23 and FAM94-41, respectively. As a proof-of-concept, we developed an integrated RNA-seq and bioinformatics approach to identify and functionally annotate transcript polymorphisms, and demonstrated its high effectiveness for discovery of genetic and transcript variations that result in altered oil quality traits. The collection of transcript polymorphisms coupled with their predicted functional effects will be a valuable asset for further discovery of genes, gene variants, and functional markers to improve soybean oil quality.

Combination of polymorphisms within the HDAC1 and HDAC3 gene predict tumor recurrence in hepatocellular carcinoma patients that have undergone transplant therapy.

PubMed

Yang, Zhe; Zhou, Lin; Wu, Li-Ming; Xie, Hai-Yang; Zhang, Feng; Zheng, Shu-Sen

2010-12-01

Histone deacetylases (HDACs) have been reported to be poor prognostic indicators in patients with cancer. However, no data are available for the role of single nucleotide polymorphism (SNP) of class I HDAC in hepato-cellular carcinoma (HCC). Therefore, we investigated the association of class I HDAC isoforms genomic polymorphisms with risk of HCC and tumor recurrence following liver transplantation (LT). One hundred and ninety-six Chinese subjects consisting of 97 HCC patients and 99 controls were enrolled in this study. Nine polymorphisms of the HDAC1, HDAC2, and HDAC3 gene (rs2530223, rs1741981, rs2547547, rs13204445, rs6568819, rs10499080, rs11741808, rs2475631, rs11391) were examined using Applied Biosystems SNaP-Shot and TaqMan technology. We found no significant difference in genotype frequencies between the HCC cases and controls. In terms of tumor recurrence following LT, patients carrying the T allele of HDAC1 SNP rs1741981 showed a favorable outcome for recurrence free survival when compared with patients homozygous for CC. In addition, the same significant trend was observed in HDAC3 SNP rs2547547. Kaplan-Meier analysis showed that the combination of the T variant allele (CT+TT) of HDAC1 SNP rs1741981 and the homozygous TT variant allele of HDAC3 SNP rs2547547 was the most favorable prognostic factor. The risk for postoperative tumor recurrence was about 2.2-fold lower for patients with this genotype combination compared with carriers of the HDAC1 SNP rs1741981 CC and HDAC3 SNP rs2547547 CT genotype combination (hazard ratio: 2.235, p=0.003). Our data suggest that combined analysis of HDAC1 SNP rs1741981 and HDAC3 SNP rs2547547 may be a potential genetic marker for HCC recurrence in LT patients.

Association between polymorphisms in renin-angiotensin system genes and primary ovarian insufficiency in Korean women.

PubMed

Jung, Yong Wook; Jeon, Young Joo; Park, Hye Mi; Lee, Bo Eun; Rah, Hyungchul; Lee, Woo Sik; Yoon, Tae Ki; Kim, Nam Keun

2013-05-01

The purpose of this study was to evaluate the relationship between angiotensin-converting enzyme (ACE; insertion/deletion), angiotensinogen (AGT M235T), and angiotensin II type 1 receptor (AT1R 1166A>C) and the prevalence of primary ovarian insufficiency (POI) in Korean women. A total of 133 women with POI and 238 controls were genotyped for polymorphic sites in each gene using polymerase chain reaction-restriction fragment length polymorphism analysis. ACE ID and ID + II variants occurred more frequently in women with POI than in controls (odds ratio [OR], 1.830; 95% CI, 1.040-3.221; P = 0.040; and OR, 1.797; 95% CI, 1.055-3.060; P = 0.031, respectively). The AT1R 1166AC genotype occurred more frequently in participants with POI than in controls (OR, 3.171; 95% CI, 1.562-6.436; P = 0.002). Comparing the combined genotype frequencies of ACE/AT1R revealed that the frequencies of ID/AA, ID/AC, and II/AC were higher in participants than in controls (OR, 1.916; 95% CI, 1.053-3.485; P = 0.043; OR, 3.544; 95% CI, 1.207-10.407; P = 0.036; and OR, 7.875; 95% CI, 2.224-27.881; P = 0.001, respectively). The TT/AC genotype for combined genotyping of AGT/AT1R was more frequently observed in the POI group than in the control group (OR, 3.472; 95% CI, 1.450-8.313; P = 0.006). In multifactor dimensionality reduction-based haplotype analysis, the I-T-C genotype of ACE/AGT/AT1R was a possible predisposing factor for POI (OR, 4.678; 95% CI, 1.721-12.717; P = 0.002). This study demonstrates that polymorphisms in the renin-angiotensin system are related to the prevalence of POI. Thus, these renin-angiotensin system genes may serve as a novel marker for predicting the development of POI.

The CHRNA3 rs578776 Variant is Associated with an Intrinsic Reward Sensitivity Deficit in Smokers.

PubMed

Robinson, Jason D; Versace, Francesco; Lam, Cho Y; Minnix, Jennifer A; Engelmann, Jeffrey M; Cui, Yong; Karam-Hage, Maher; Shete, Sanjay S; Tomlinson, Gail E; Chen, Tina T-L; Wetter, David W; Green, Charles E; Cinciripini, Paul M

2013-01-01

A compromised brain reward system has been postulated as a key feature of drug dependence. We examined whether several polymorphisms of genes found to regulate nicotinic acetylcholine receptor (nAChR) and dopamine expression were related to an intrinsic reward sensitivity (IRS) deficit we previously identified among a subgroup of smokers using event-related potentials (ERPs). We examined genetic polymorphisms within the CHRNA5-A3-B4 gene cluster (CHRNA3 rs578776, CHRNA5 rs16969968, LOC123688 rs8034191, and CHRNA3 rs1051730), the ANKK1 gene (rs1800497), and the D2 dopamine receptor gene (DRD2 rs1079597, DRD2 rs1799732) from 104 smokers of European ancestry in a smoking cessation trial. Prior to treatment, we recorded ERPs evoked by emotional (both pleasant and unpleasant), neutral, and cigarette-related pictures. Smokers were assigned to two groups (IRS+/IRS-) based on the amplitude of the late positive potential (LPP) component to the pictures, a neural marker of motivational salience. Smokers (n = 42) with blunted brain responses to intrinsically rewarding (pleasant) pictures and enhanced responses to cigarette pictures were assigned to the IRS- group, while smokers (n = 62) with the opposite pattern of LPP responding were assigned to the IRS+ group. Carriers of the protective minor T allele (T/T, C/T) of the CHRNA3 rs578776 were less likely to be members of the IRS- group than those homozygous for the at-risk C allele (C/C). The CHRNA3 rs578776 polymorphism did not differ on questionnaires of nicotine dependence, depressed mood, or trait affective disposition and did not predict abstinence at 6 months after the quit date. These results suggest that polymorphisms of genes influencing nAChR expression are related to an endophenotype of reward sensitivity in smokers.

Candidate genes have sex-specific effects on timing of spring migration and moult speed in a long-distance migratory bird.

PubMed

Bazzi, Gaia; Podofillini, Stefano; Gatti, Emanuele; Gianfranceschi, Luca; Cecere, Jacopo G; Spina, Fernando; Saino, Nicola; Rubolini, Diego

2017-10-01

The timing of major life-history events, such as migration and moult, is set by endogenous circadian and circannual clocks, that have been well characterized at the molecular level. Conversely, the genetic sources of variation in phenology and in other behavioral traits have been sparsely addressed. It has been proposed that inter-individual variability in the timing of seasonal events may arise from allelic polymorphism at phenological candidate genes involved in the signaling cascade of the endogenous clocks. In this study of a long-distance migratory passerine bird, the willow warbler Phylloscopus trochilus , we investigated whether allelic variation at 5 polymorphic loci of 4 candidate genes ( Adcyap1 , Clock , Creb1 , and Npas2 ), predicted 2 major components of the annual schedule, namely timing of spring migration across the central Mediterranean sea and moult speed, the latter gauged from ptilochronological analyses of tail feathers moulted in the African winter quarters. We identified a novel Clock gene locus ( Clock region 3) showing polyQ polymorphism, which was however not significantly associated with any phenotypic trait. Npas2 allele size predicted male (but not female) spring migration date, with males bearing longer alleles migrating significantly earlier than those bearing shorter alleles. Creb1 allele size significantly predicted male (but not female) moult speed, longer alleles being associated with faster moult. All other genotype-phenotype associations were statistically non-significant. These findings provide new evidence for a role of candidate genes in modulating the phenology of different circannual activities in long-distance migratory birds, and for the occurrence of sex-specific candidate gene effects.

IRIS TOXICOLOGICAL REVIEW AND SUMMARY ...

EPA Pesticide Factsheets

The Draft Toxicological Review was developed to evaluate both the cancer and non cancer human health risks from environmental exposure to vinyl chloride. A reference concentration (RfC), and a reference dose (RfD) were developed based upon induction of liver cell polymorphism in a chronic dietary study utilizing Wistar rats. An RfC of 1E-1 mg/m3 and an RfD of 5E-3 mg/kg-d are recommended. On the basis of sufficient evidence for carcinogenicity in human epidemiology studies vinyl chloride is reaffirmed to be a known human carcinogen. Cancer potencies were derived for oral and inhalation exposure. An oral slope factor of 1.3 per (mg/kg-day) for continuous exposure during adulthood and 2.5 per (mg/kg-day) for continuous lifetime exposure from birth, based upon a chronic dietary study in female Wistar rats is recommended; an inhalation unit risk of 4.3 E-6 per (55g/m3) for continuous exposure during adulthood and 8.7 E-6 per (55g/m3) for continuous lifetime exposure from birth is also recommended, based upon exposure of male and female Sprague Dawley rats and Swiss mice, via inhalation, for a lifetime. A PBPK model was used in the derivation of the RfC, RfD, and cancer potency estimates. Its use is based on the assumption that equal tissue concentrations of reactive metabolite, chlorethylene oxide or chloracetaldehyde, at the critical target site will result in equivalent toxicity between species.

Associations between a fatty acid desaturase gene polymorphism and blood arachidonic acid compositions in Japanese elderly.

PubMed

Horiguchi, Sayaka; Nakayama, Kazuhiro; Iwamoto, Sadahiko; Ishijima, Akiko; Minezaki, Takayuki; Baba, Mamiko; Kontai, Yoshiko; Horikawa, Chika; Kawashima, Hiroshi; Shibata, Hiroshi; Kagawa, Yasuo; Kawabata, Terue

2016-02-01

We investigated whether the single nucleotide polymorphism rs174547 (T/C) of the fatty acid desaturase-1 gene, FADS1, is associated with changes in erythrocyte membrane and plasma phospholipid (PL) long-chain polyunsaturated fatty acid (LCPUFA) composition in elderly Japanese participants (n=124; 65 years or older; self-feeding and oral intake). The rs174547 C-allele carriers had significantly lower arachidonic acid (ARA; n-6 PUFA) and higher linoleic acid (LA, n-6 PUFA precursor) levels in erythrocyte membrane and plasma PL (15% and 6% ARA reduction, respectively, per C-allele), suggesting a low LA to ARA conversion rate in erythrocyte membrane and plasma PL of C-allele carriers. α-linolenic acid (n-3 PUFA precursor) levels were higher in the plasma PL of C-allele carriers, whereas levels of the n-3 LCPUFAs eicosapentaenoic acid (EPA) or docosahexaenoic acid (DHA) were unchanged in erythrocyte membrane and plasma PL. Thus, rs174547 genotypes were significantly associated with different ARA compositions of the blood of elderly Japanese. Copyright © 2015 Elsevier Ltd. All rights reserved.

Unexpected combined effects of NADH dehydrogenase subunit-2 237 Leu/Met polymorphism and green tea consumption on renal function in male Japanese health check-up examinees: a cross-sectional study.

PubMed

Kokaze, Akatsuki; Ishikawa, Mamoru; Matsunaga, Naomi; Karita, Kanae; Yoshida, Masao; Ohtsu, Tadahiro; Ochiai, Hirotaka; Shirasawa, Takako; Nanri, Hinako; Hoshino, Hiromi; Takashima, Yutaka

2013-11-20

NADH dehydrogenase subunit-2 237 leucine/methionine (ND2-237 Leu/Met) polymorphism is associated with longevity in Japanese. A previous study has shown that ND2-237 Leu/Met polymorphism modulates the effects of green tea consumption on risk of hypertension. For men with ND2-237Leu, habitual green tea consumption may reduce the risk of hypertension. Moreover, there is a combined effect of ND2-237 Leu/Met polymorphism and alcohol consumption on risk of mildly decreased estimated glomerular filtration rate (eGFR) (<90 ml/min/1.73 m2). Several beneficial effects of green tea on the kidney have been reported. The objective of this study was to investigate whether ND2-237 Leu/Met polymorphism modifies the effects of green tea consumption on risk of mildly decreased eGFR in male Japanese health check-up examinees. For ND2-237Leu genotypic men, after adjustment for confounding factors, green tea consumption may increase the risk of mildly decreased eGFR (P for trend = 0.016). The adjusted odds ratio (OR) for mildly decreased eGFR was significantly higher in subjects with ND2-237Leu who consume ≥6 cups of green tea per day than those who consume ≤1 cup of green tea per day (adjusted OR = 5.647, 95% confidence interval: 1.528-20.88, P = 0.009). On the other hand, for ND2-237Met genotypic men, green tea consumption does not appear to determine the risk of mildly decreased eGFR. The present results suggest that ND2-237 Leu/Met polymorphism unexpectedly modifies the effects of green tea consumption on eGFR and the risk of mildly decreased eGFR in male Japanese subjects.

Unexpected combined effects of NADH dehydrogenase subunit-2 237 Leu/Met polymorphism and green tea consumption on renal function in male Japanese health check-up examinees: a cross-sectional study

PubMed Central

2013-01-01

Background NADH dehydrogenase subunit-2 237 leucine/methionine (ND2-237 Leu/Met) polymorphism is associated with longevity in Japanese. A previous study has shown that ND2-237 Leu/Met polymorphism modulates the effects of green tea consumption on risk of hypertension. For men with ND2-237Leu, habitual green tea consumption may reduce the risk of hypertension. Moreover, there is a combined effect of ND2-237 Leu/Met polymorphism and alcohol consumption on risk of mildly decreased estimated glomerular filtration rate (eGFR) (<90 ml/min/1.73 m2). Several beneficial effects of green tea on the kidney have been reported. The objective of this study was to investigate whether ND2-237 Leu/Met polymorphism modifies the effects of green tea consumption on risk of mildly decreased eGFR in male Japanese health check-up examinees. Results For ND2-237Leu genotypic men, after adjustment for confounding factors, green tea consumption may increase the risk of mildly decreased eGFR (P for trend = 0.016). The adjusted odds ratio (OR) for mildly decreased eGFR was significantly higher in subjects with ND2-237Leu who consume ≥6 cups of green tea per day than those who consume ≤1 cup of green tea per day (adjusted OR = 5.647, 95% confidence interval: 1.528-20.88, P = 0.009). On the other hand, for ND2-237Met genotypic men, green tea consumption does not appear to determine the risk of mildly decreased eGFR. Conclusion The present results suggest that ND2-237 Leu/Met polymorphism unexpectedly modifies the effects of green tea consumption on eGFR and the risk of mildly decreased eGFR in male Japanese subjects. PMID:24252463

Phenotypic Manifestation of Genetic Risk for Schizophrenia During Adolescence in the General Population.

PubMed

Jones, Hannah J; Stergiakouli, Evie; Tansey, Katherine E; Hubbard, Leon; Heron, Jon; Cannon, Mary; Holmans, Peter; Lewis, Glyn; Linden, David E J; Jones, Peter B; Davey Smith, George; O'Donovan, Michael C; Owen, Michael J; Walters, James T; Zammit, Stanley

2016-03-01

Schizophrenia is a highly heritable, polygenic condition characterized by a relatively diverse phenotype and frequent comorbid conditions, such as anxiety and depression. At present, limited evidence explains how genetic risk for schizophrenia is manifest in the general population. To investigate the extent to which genetic risk for schizophrenia is associated with different phenotypes during adolescence in a population-based birth cohort. This cohort study used data from the Avon Longitudinal Study of Parents and Children (ALSPAC). Of 14,062 children in the birth cohort, genetic data were available for 9912 adolescents. Data were collected periodically from September 6, 1990, and collection is ongoing. Data were analyzed from March 4 to August 13, 2015. Polygenic risk scores (PRSs) for schizophrenia generated for individuals in the ALSPAC cohort using results of the second Psychiatric Genomics Consortium Schizophrenia genome-wide association study as a training set. Logistic regression was used to assess associations between the schizophrenia PRS and (1) psychotic experiences (Psychosis-Like Symptom Interview at 12 and 18 years of age), (2) negative symptoms (Community Assessment of Psychic Experiences at 16.5 years of age), (3) depressive disorder (Development and Well-Being Assessment at 15.5 years of age), and (4) anxiety disorder (Development and Well-Being Assessment at 15.5 years of age) in adolescence. Of the 8230 ALSPAC participants whose genetic data passed quality control checks (51.2% male, 48.8% female), 3676 to 5444 participated in assessments from 12 to 18 years of age. The PRSs created using single-nucleotide polymorphisms with a training-set P ≤ .05 threshold were associated with negative symptoms (odds ratio [OR] per SD increase in PRS, 1.21; 95% CI, 1.08-1.36; R(2) = 0.007) and anxiety disorder (OR per SD increase in PRS, 1.17; 95% CI, 1.06- 1.29; R(2) = 0.005). No evidence was found of an association between schizophrenia PRS and psychotic experiences (OR per SD increase in PRS, 1.08; 95% CI, 0.98-1.19; R(2) = 0.001) or depressive disorder (OR per SD increase in PRS, 1.02; 95% CI, 0.91-1.13; R(2) = 0.00005). Results were mostly consistent across different training-set P value thresholds and using different cutoffs and measures of the psychopathological outcomes. This study demonstrates polygenic overlaps between common genetic polymorphisms associated with schizophrenia and negative symptoms and anxiety disorder but not with psychotic experiences or depression. Because the genetic risk for schizophrenia appears to be manifest as anxiety and negative symptoms during adolescence, a greater focus on these phenotypes rather than on psychotic experiences might be required for prediction of transition in at-risk samples.

Role of 2 common variants of 5HT2A gene in medication overuse headache.

PubMed

Terrazzino, Salvatore; Sances, Grazia; Balsamo, Francesca; Viana, Michele; Monaco, Francesco; Bellomo, Giorgio; Martignoni, Emilia; Tassorelli, Cristina; Nappi, Giuseppe; Canonico, Pier Luigi; Genazzani, Armando A

2010-11-01

The aim of the present study was to evaluate a possible involvement of 2 polymorphisms of the serotonin 5HT2A receptor gene (A-1438G and C516T) as risk factors for medication overuse headache (MOH) and whether the presence of these polymorphic variants might determine differences within MOH patients in monthly drug consumption. Despite a growing scientific interest in the mechanisms underlying the pathophysiology of MOH, few studies have focused on the role of genetics in the development of the disease, as well as on the genetic determinants of the inter-individual variability in the number of drug doses taken per month. Our study was performed by polymerase chain reaction (PCR) and PCR-restriction fragment length polymorphism on genomic DNA extracted from peripheral blood of 227 MOH patients and 312 control subjects. Genotype-specific risks were estimated as odds ratios with associated 95% confidence intervals by unconditional logistic regression and adjusted for age and gender. A stepwise multiple linear regression analysis was employed to identify significant predictors of the number of drug doses taken per month. No significant association was found between 5HT2A A and 1438G and C516T gene polymorphisms and MOH risk. In contrast, a higher consumption of monthly drug doses was observed among 516T 5HT2A carriers (median 50, range 13-120) compared to 516CC patients (median 30, range 12-128) (Mann-Whitney U-test, P = .018). In the stepwise multiple regression analysis, C516T 5HT2A polymorphism (P = .018) and class of overused drug (P = .047) emerged as significant, independent predictors of the monthly drug consumption in MOH patients. Although our results do not support a major role of the A-1438G and C516T polymorphic variants of the 5HT2A gene in the susceptibility of MOH, our findings support an influence of the C516T polymorphism on the number of symptomatic drug doses taken and, possibly, on the drug-seeking behavior in these patients. © 2010 American Headache Society.

Determination of genetic diversity among Saccharina germplasm using ISSR and RAPD markers.

PubMed

Cui, Cuiju; Li, Yan; Liu, Yanling; Li, Xiaojie; Luo, Shiju; Zhang, Zhuangzhi; Wu, Ruina; Liang, Guangjin; Sun, Juan; Peng, Jie; Tian, Pingping

2017-02-01

Various species of genus Saccharina are economically important brown macroalgae cultivated in China. The genetic background of the conserved Saccharina germplasm was not clear. In this report, DNA-based molecular markers such as inter simple sequence repeats (ISSR) and random amplified polymorphic DNA (RAPD) were used to assess the genetic diversity and phylogenetic relationships among 48 Saccharina germplasms. A total of 50 ISSR and 50 RAPD primers were tested, of which only 33 polymorphic primers (17 ISSR and 16 RAPD) had an amplified clear and reproducible profile, and could be used. Seventeen ISSR primers yielded a total of 262 bands, of which 256 were polymorphic, and 15.06 polymorphic bands per primer were amplified from 48 kelp gametophytes. Sixteen RAPD primers produced 355 bands, of which 352 were polymorphic, and 22 polymorphic bands per primer were observed across 48 individuals. The simple matching coefficient of ISSR, RAPD and pooled ISSR and RAPD dendrograms ranged from 0.568 to 0.885, 0.670 to 0.873, and 0.667 to 0.862, revealing high genetic diversity. Based on the unweighted pair group method with the arithmetic averaging algorithm (UPGMA) cluster analysis and the principal components analysis (PCA) of ISSR data, the 48 gametophytes were divided into three main groups. The Mantel test revealed a similar polymorphism distribution pattern between ISSR and RAPD markers, the correlation coefficient r was 0.62, and the results indicated that both ISSR and RAPD markers were effective to assess the selected gametophytes, while matrix correlation of the ISSR marker system (r=0.78) was better than that of the RAPD marker system (r=0.64). Genetic analysis data from this study were helpful in understanding the genetic relationships among the selected 17 kelp varieties (or lines) and provided guidance for molecular-assisted selection for parental gametophytes of hybrid kelp breeding. Copyright © 2016 Académie des sciences. Published by Elsevier Masson SAS. All rights reserved.

GESPA: classifying nsSNPs to predict disease association.

PubMed

Khurana, Jay K; Reeder, Jay E; Shrimpton, Antony E; Thakar, Juilee

2015-07-25

Non-synonymous single nucleotide polymorphisms (nsSNPs) are the most common DNA sequence variation associated with disease in humans. Thus determining the clinical significance of each nsSNP is of great importance. Potential detrimental nsSNPs may be identified by genetic association studies or by functional analysis in the laboratory, both of which are expensive and time consuming. Existing computational methods lack accuracy and features to facilitate nsSNP classification for clinical use. We developed the GESPA (GEnomic Single nucleotide Polymorphism Analyzer) program to predict the pathogenicity and disease phenotype of nsSNPs. GESPA is a user-friendly software package for classifying disease association of nsSNPs. It allows flexibility in acceptable input formats and predicts the pathogenicity of a given nsSNP by assessing the conservation of amino acids in orthologs and paralogs and supplementing this information with data from medical literature. The development and testing of GESPA was performed using the humsavar, ClinVar and humvar datasets. Additionally, GESPA also predicts the disease phenotype associated with a nsSNP with high accuracy, a feature unavailable in existing software. GESPA's overall accuracy exceeds existing computational methods for predicting nsSNP pathogenicity. The usability of GESPA is enhanced by fast SQL-based cloud storage and retrieval of data. GESPA is a novel bioinformatics tool to determine the pathogenicity and phenotypes of nsSNPs. We anticipate that GESPA will become a useful clinical framework for predicting the disease association of nsSNPs. The program, executable jar file, source code, GPL 3.0 license, user guide, and test data with instructions are available at http://sourceforge.net/projects/gespa.

Circulating brain-derived neurotrophic factor concentrations and the risk of cardiovascular disease in the community.

PubMed

Kaess, Bernhard M; Preis, Sarah R; Lieb, Wolfgang; Beiser, Alexa S; Yang, Qiong; Chen, Tai C; Hengstenberg, Christian; Erdmann, Jeanette; Schunkert, Heribert; Seshadri, Sudha; Vasan, Ramachandran S; Assimes, Themistocles L; Deloukas, Panos; Holm, Hilma; Kathiresan, Sekar; König, Inke R; McPherson, Ruth; Reilly, Muredach P; Roberts, Robert; Samani, Nilesh J; Stewart, Alexandre F R

2015-03-11

Brain-derived neurotrophic factor (BDNF) is a pleiotropic peptide involved in maintaining endothelial integrity. It is unknown if circulating BDNF levels are associated with risk of cardiovascular disease (CVD). We prospectively investigated the association of circulating BDNF levels with cardiovascular events and mortality in 3687 participants (mean age 65 years, 2068 women) from the Framingham Heart Study (FHS). Using a common nonsynonomous single nucleotide polymorphism (SNP) in the BDNF gene (rs6265), we then performed a Mendelian randomization experiment in the CARDIoGRAM (Coronary ARtery DIsease Genome-Wide Replication And Meta-Analysis) consortium (>22,000 coronary artery disease [CAD] cases, >60,000 controls) to investigate whether SNP rs6265 was associated with CAD in CARDIoGRAM and, if so, whether the effect estimate differed from that predicted based on FHS data. On follow-up (median 8.9 years), 467 individuals (261 women) in FHS experienced a CVD event, and 835 (430 women) died. In multivariable-adjusted Cox regression, serum BDNF was associated inversely with CVD risk (hazard ratio [HR] per 1-SD increase 0.88, 95% CI 0.80 to 0.97, P=0.01) and with mortality (HR 0.87, 95% CI 0.80 to 0.93, P=0.0002). SNP rs6265 was associated with BDNF concentrations (0.772 ng/mL increase per minor allele copy) in FHS. In CARDIoGRAM, SNP rs6265 was associated with CAD (odds ratio 0.957, 95% CI 0.923 to 0.992), a magnitude consistent with the predicted effect (HR per minor allele copy 0.99, 95% CI 0.98 to 1.0; P=0.06 for difference between predicted and observed effect). Higher serum BDNF is associated with a decreased risk of CVD and mortality. Mendelian randomization suggests a causal protective role of BDNF in the pathogenesis of CVD. © 2015 The Authors. Published on behalf of the American Heart Association, Inc., by Wiley Blackwell.

Five Polymorphisms and Breast Cancer Risk: Results from the Breast Cancer Association Consortium

PubMed Central

Gaudet, Mia M.; Milne, Roger L.; Cox, Angela; Camp, Nicola J.; Goode, Ellen L.; Humphreys, Manjeet K.; Dunning, Alison M.; Morrison, Jonathan; Giles, Graham G.; Severi, Gianluca; Baglietto, Laura; English, Dallas R.; Couch, Fergus J.; Olson, Janet E.; Wang, Xianshu; Chang-Claude, Jenny; Flesch-Janys, Dieter; Abbas, Sascha; Salazar, Ramona; Mannermaa, Arto; Kataja, Vesa; Kosma, Veli-Matti; Lindblom, Annika; Margolin, Sara; Heikkinen, Tuomas; Kämpjärvi, Kati; Aaltonen, Kirsimari; Nevanlinna, Heli; Bogdanova, Natalia; Coinac, Irina; Schürmann, Peter; Dörk, Thilo; Bartram, Claus R.; Schmutzler, Rita K.; Tchatchou, Sandrine; Burwinkel, Barbara; Brauch, Hiltrud; Torres, Diana; Hamann, Ute; Justenhoven, Christina; Ribas, Gloria; Arias, José I.; Benitez, Javier; Bojesen, Stig E.; Nordestgaard, Børge G.; Flyger, Henrik L.; Peto, Julian; Fletcher, Olivia; Johnson, Nichola; Silva, Isabel dos Santos; Fasching, Peter A.; Beckmann, Matthias W.; Strick, Reiner; Ekici, Arif B.; Broeks, Annegien; Schmidt, Marjanka K.; van Leeuwen, Flora E.; Van’t Veer, Laura J.; Southey, Melissa C.; Hopper, John L.; Apicella, Carmel; Haiman, Christopher A.; Henderson, Brian E.; Le Marchand, Loic; Kolonel, Laurence N.; Kristensen, Vessela; Alnæs, Grethe Grenaker; Hunter, David J.; Kraft, Peter; Cox, David G.; Hankinson, Susan E.; Seynaeve, Caroline; Vreeswijk, Maaike P.G.; Tollenaar, Rob A.E.M.; Devilee, Peter; Chanock, Stephen; Lissowska, Jolanta; Brinton, Louise; Peplonska, Beata; Czene, Kamila; Hall, Per; Li, Yuqing; Liu, Jianjun; Balasubramanian, Sabapathy; Rafii, Saeed; Reed, Malcolm W.R.; Pooley, Karen A.; Conroy, Don; Baynes, Caroline; Kang, Daehee; Yoo, Keun-Young; Noh, Dong-Young; Ahn, Sei-Hyun; Shen, Chen-Yang; Wang, Hui-Chun; Yu, Jyh-Cherng; Wu, Pei-Ei; Anton-Culver, Hoda; Ziogoas, Argyrios; Egan, Kathleen; Newcomb, Polly; Titus-Ernstoff, Linda; Dietz, Amy Trentham; Sigurdson, Alice J.; Alexander, Bruce H.; Bhatti, Parveen; Allen-Brady, Kristina; Cannon-Albright, Lisa A.; Wong, Jathine; Chenevix-Trench, Georgia; Spurdle, Amanda B.; Beesley, Jonathan; Pharoah, Paul D.P.; Easton, Doug F.; Garcia-Closas, Montserrat

2009-01-01

Previous studies have suggested that minor alleles for ERCC4 rs744154, TNF rs361525, CASP10 rs13010627, PGR rs1042838, and BID rs8190315 may influence breast cancer risk, but the evidence is inconclusive due to their small sample size. These polymorphisms were genotyped in more than 30,000 breast cancer cases and 30,000 controls, primarily of European descent, from 30 studies in the Breast Cancer Association Consortium. We calculated odds ratios (OR) and 95% confidence intervals (95% CI) as a measure of association. We found that the minor alleles for these polymorphisms were not related to invasive breast cancer risk overall in women of European descent: ECCR4 per-allele OR (95% CI) = 0.99 (0.97–1.02), minor allele frequency = 27.5%; TNF 1.00 (0.95–1.06), 5.0%; CASP10 1.02 (0.98–1.07), 6.5%; PGR 1.02 (0.99–1.06), 15.3%; and BID 0.98 (0.86–1.12), 1.7%. However, we observed significant between-study heterogeneity for associations with risk for single-nucleotide polymorphisms (SNP) in CASP10, PGR, and BID. Estimates were imprecise for women of Asian and African descent due to small numbers and lower minor allele frequencies (with the exception of BID SNP). The ORs for each copy of the minor allele were not significantly different by estrogen or progesterone receptor status, nor were any significant interactions found between the polymorphisms and age or family history of breast cancer. In conclusion, our data provide persuasive evidence against an overall association between invasive breast cancer risk and ERCC4 rs744154, TNF rs361525, CASP10 rs13010627, PGR rs1042838, and BID rs8190315 genotypes among women of European descent. PMID:19423537

NUDT15 and TPMT genetic polymorphisms are related to 6-mercaptopurine intolerance in children treated for acute lymphoblastic leukemia at the Children's Cancer Center of Lebanon.

PubMed

Zgheib, Nathalie K; Akika, Reem; Mahfouz, Rami; Aridi, Carol Al; Ghanem, Khaled M; Saab, Raya; Abboud, Miguel R; Tarek, Nidale; El Solh, Hassan; Muwakkit, Samar A

2017-01-01

Interindividual variability in thiopurine-related toxicity could not be completely explained by thiopurine S-methyltransferase (TPMT) polymorphisms, as a number of patients who are homozygous wild type or normal for TPMT still develop toxicity that necessitates 6-mercaptopurine (MP) dose reduction or protocol interruption. Recently, few studies reported on an inherited nucleoside diphosphate-linked moiety X motif 15 (NUDT15) c.415C>T low-function variant that is associated with decreased thiopurine metabolism and leukopenia in childhood acute lymphoblastic leukemia (ALL) and other diseases. The aim of this study is to measure the frequency of TPMT and NUDT15 polymorphisms and assess whether they are predictors of MP intolerance in children treated for ALL. One hundred thirty-seven patients with ALL of whom 121 were Lebanese were evaluated. MP dose intensity was calculated as the ratio of the tolerated MP dose to planned dose during continuation phase to maintain an absolute neutrophil count (ANC) dose above 300 per μl. One patient was NUDT15 heterozygous TC and tolerated only 33.33% of the planned MP dose, which was statistically significantly different from the median-tolerated MP dose intensity of the rest of the cohort (76.00%). Three patients had the TPMT*3A haplotype and tolerated 40.00-66.66% of the planned MP dose, which was also statistically significantly different from the rest of the cohort. This is the first report on the association of TPMT and NUDT15 polymorphisms with MP dose intolerance in Arab patients with ALL. Genotyping for additional polymorphisms may be warranted for potential gene/allele-dose effect. © 2016 Wiley Periodicals, Inc.

MicroRNA‑499 rs3746444 A/G polymorphism functions as a biomarker to predict recurrence following endoscopic submucosal dissection in primary early gastric cancer.

PubMed

Shi, Huiyong; Yang, Xiangshan; Zhen, Yanan; Huo, Shoujun; Xiao, Ruixue; Xu, Zhongfa

2017-05-01

The aim of the present study was to investigate the molecular mechanism, including the potential regulatory and signaling pathways, of platelet‑derived growth factor receptor β (PDGFRB), which underlies the recurrence of early gastric cancer (EGC) following endoscopic submucosal dissection (ESD). Online microRNA (miRNA) target prediction tools were used, which identified PDGFRB as the candidate target gene of miR‑499a in gastric cancer cells, and PFGRBR was then confirmed as the direct gene using a luciferase reporter assay system. The Kaplan‑Meier method was used to plot recurrence‑free curves, which were compared between genotype groups. A negative regulatory association between miR‑499a and PDGFRB was established by investigating the relative luciferase activity at different concentrations of miR‑499a mimics. Furthermore, as the rs3746444 polymorphism has been previously reported to interfere with the expression of miR‑499a, the present study investigated the expression levels of different genotypes, including TT (n=20), TC (n=9) and CC (n=3), the results of which supported the hypothesis that the presence of the minor allele (C) of the rs3746444 polymorphism compromised the expression of miR‑499a. The present study also performed polymerase chain reaction and western blot analyses to examine the mRNA and protein expression levels of PFGRBR among different genotypes or cells treated with different concentrations of miR‑499a mimics/inhibitors, which indicated the negative regulatory association between miR‑499a and PDGFRB. The present study also investigated the relative viabilities of EGC cells transfected with miR‑499a mimics (50 and 100 nM) and miR‑499a inhibitors (100 nM), and confirmed that miR‑499a negatively interfered with the viability of the EGC cells. The miR‑499a rs3746444 polymorphism was also recognized as a biomarker to predict recurrence following ESD in patients with EGC via analyzing the recurrence‑free rates among patients with EGC with different genotypes. The results showed that PDGFRB was validated as a target of miR‑499a, and rs3746444 was identified as a potential biomarker to predict the recurrence of EGC following ESD.

Polymorphic microsatellite DNA markers for the Florida manatee (Trichechus manatus latirostris)

USGS Publications Warehouse

Pause, K.C.; Nourisson, C.; Clark, A.; Kellogg, M.E.; Bonde, R.K.; McGuire, P.M.

2007-01-01

Florida manatees (Trichechus manatus latirostris) are marine mammals that inhabit the coastal waters and rivers of the southeastern USA, primarily Florida. Previous studies have shown that Florida manatees have low mitochondrial DNA variability, suggesting that nuclear DNA loci are necessary for discriminatory analyses. Here we report 10 polymorphic microsatellite loci with an average of 4.2 alleles per locus, and average heterozygosity of 50.1%. These loci have been developed for use in population studies, parentage assignment, and individual identification. ?? 2007 Blackwell Publishing Ltd.

Characterization of 12 polymorphic microsatellite markers for a facultatively eusocial sweat bee (Megalopta genalis).

PubMed

Kapheim, Karen M; Pollinger, John P; Wcislo, William T; Wayne, Robert K

2009-11-01

We developed a library of twelve polymorphic di- and tri-nucleotide microsatellite markers for Megalopta genalis, a facultatively eusocial sweat bee. We tested each locus in a panel of 23 unrelated females and found 7-20 alleles per locus. Observed and expected heterozygosities ranged from 0.65 to 0.96 and from 0.69 to 0.95 respectively. None of the loci deviated from Hardy-Weinberg equilibrium proportions or was found to be in gametic disequilibrium. © 2009 Blackwell Publishing Ltd.

Association between HLA-E gene polymorphism and unexplained recurrent spontaneous abortion (RSA) in Iranian women.

PubMed

Fotoohi, Maryam; Ghasemi, Nasrin; Mirghanizadeh, Seyed Ali; Vakili, Mahmood; Samadi, Morteza

2016-07-01

Human leukocyte antigen-E (HLA-E)is a non-classical major histocompatibility complex (MHC) class I antigens which expressed on extra villous cytotrophoblast, which interacts with NKG2A, is an inhibitory receptor on natural killer (NK) cells and leading to down regulation of immune response in the maternal-fetal interface and provides maternal immune tolerance of the fetus. This study was designated to investigate the gene frequencies of E0101 and E0103 in HLA-E gene in Iranian women with recurrent spontaneous abortion (RSA). Amplification Refractory Mutation System (ARMS-PCR) technique was carried out to detect polymorphism in exon 3 of the HLA-E gene in women with RSA and controls (n=200). Differences between groups were analyzed by SPSS19 software using (2) test. There was no significant difference in the allele frequencies of the HLA-E polymorphism between RSA and fertile controls but HLA-E 0101/0103 heterozygous genotype was found to be significantly higher in RSA group (p=0.006, OR=1.73), so this genotype might confer susceptibility to RSA. Our results suggest that HLA-E 0101/0103 heterozygous genotype leads to increase of RSA risk. It seems that by genotyping of HLA-E polymorphism, we can predict the risk of RSA in infertile women.

Possible role of IL-6 and TIE2 gene polymorphisms in predicting the initial high transport status in patients with peritoneal dialysis: an observational study.

PubMed

Ding, Li; Shao, Xinghua; Cao, Liou; Fang, Wei; Yan, Hao; Huang, Jiaying; Gu, Aiping; Yu, Zanzhe; Qi, Chaojun; Chang, Xinbei; Ni, Zhaohui

2016-10-26

The aim of this study was to investigate the effect of interleukin (IL)-6 and TIE2 gene polymorphisms on baseline peritoneal transport property. An observational study. Renji Hospital in Shanghai, China. This study included 220 patients with continuous ambulatory peritoneal dialysis (PD). Patients were divided into 2 groups based on the results of an initial peritoneal equilibration test performed within 3 months of starting PD therapy: group 1 consisted of low/low average transporters (n=123), and group 2 consisted of high/high average transporters (n=97). We genotyped TIE2 and IL-6 polymorphisms and analysed their effects on baseline transport status. The genotype AT in IL-6 Rs13306435 and the genotype CC in TIE2 Rs639225 were both negatively associated with a higher initial peritoneal transport status (IL-6 Rs13306435: OR=0.408, 95% CI 0.227 to 0.736; TIE2 Rs639225: OR=0.188, 95% CI 0.044 to 0.806). IL-6 and TIE2 polymorphisms are associated with baseline peritoneal transport property. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/.

Polymorphisms and Tissue Expression of the Feline Leukocyte Antigen Class I Loci FLAI-E, -H and -K

PubMed Central

Holmes, Jennifer C.; Holmer, Savannah G.; Ross, Peter; Buntzman, Adam S.; Frelinger, Jeffrey A.; Hess, Paul R.

2013-01-01

Cytotoxic CD8+ T-cell immunosurveillance for intracellular pathogens, such as viruses, is controlled by classical major histocompatibility complex (MHC) class Ia molecules, and ideally, these antiviral T-cell populations are defined by the specific peptide and restricting MHC allele. Surprisingly, despite the utility of the cat in modeling human viral immunity, little is known about the Feline Leukocyte Antigen class I complex (FLAI). Only a few coding sequences with uncertain locus origin and expression patterns have been reported. Of 19 class I genes, 3 loci - FLAI-E, -H and -K – are predicted to encode classical molecules, and our objective was to evaluate their status by analyzing polymorphisms and tissue expression. Using locus-specific, PCR-based genotyping, we amplified 33 FLAI-E, -H, and -K alleles from 12 cats of various breeds, identifying, for the first time, alleles across 3 distinct loci in a feline species. Alleles shared the expected polymorphic and invariant sites in the α1/α2 domains, and full-length cDNA clones possessed all characteristic class Ia exons. Alleles could be assigned to a specific locus with reasonable confidence, although there was evidence of potentially confounding interlocus recombination between FLAI-E and -K. Only FLAI-E, -H and -K-origin alleles were amplified from cDNAs of multiple tissue types. We also defined hypervariable regions across these genes, which permitted the assignment of names to both novel and established alleles. As predicted, FLAI-E, -H, and -K fulfill the major criteria of class Ia genes. These data represent a necessary prerequisite for studying epitope-specific antiviral CD8+ T-cell responses in cats. PMID:23812210

Genetic variation in renin predicts the effects of thiazide diuretics.

PubMed

Huang, Chin-Chou; Chung, Chia-Min; Hung, Shuen-Iu; Leu, Hsin-Bang; Wu, Tao-Cheng; Huang, Po-Hsun; Lin, Shing-Jong; Pan, Wen-Harn; Chen, Jaw-Wen

2011-08-01

While genetic variants of renin-angiotensin-aldosterone system (RAAS) may modify the blood pressure (BP) response to thiazide diuretics, there was no evidence of genetic variations in renin (REN) playing a role. This study aimed to address the potential effects of genetic variations of RAAS on the response to initial treatment of hydrochlorothiazide (HCTZ). We enrolled nondiabetic hypertensive patients with a systolic blood pressure (SBP) ≥140 or a diastolic blood pressure (DBP) ≥90mmHg, who were either previously untreated or unsatisfactorily treated. After lifestyle modification and diet instruction for 2weeks, 90 patients with persistently elevated BP were given HCTZ 50 mg every morning for 2 weeks. Single nucleotide polymorphism markers were selected from genes involving in RAAS, including rs7079 and rs699 of angiotensinogen, rs4293 and rs4353 of angiotensin-converting enzyme and rs1464816 and rs11240688 of REN. The patients were divided into three groups according to the SBP response after HCTZ. The upper 1/3 responders had older age (P=0·035), higher SBP (P=0·039), higher pulse pressure (P=0·006) and lower plasma REN activity (PRA) (P=0·020) when compared with the lower 1/3 responders. Renin rs11240688 CC polymorphism (β=9·931, corrected P=0·012), Log PRA (β=7·451, P=0·004) and baseline SBP (β=0·299, P=0·006) were the independent predictors for the BP lowering response. In addition to PRA, renin rs11240688 CC polymorphism may also independently predict the effect of HCTZ. © 2011 The Authors. European Journal of Clinical Investigation © 2011 Stichting European Society for Clinical Investigation Journal Foundation.

Impact of CCL4 gene polymorphisms and environmental factors on oral cancer development and clinical characteristics

PubMed Central

Lien, Ming-Yu; Lin, Chiao-Wen; Tsai, Hsiao-Chi; Chen, Yng-Tay; Tsai, Ming-Hsui; Hua, Chun-Hung; Yang, Shun-Fa; Tang, Chih-Hsin

2017-01-01

In Taiwan, oral cancer has causally been associated with environmental carcinogens. CCL4 (C-C chemokine ligand 4), a macrophage inflammatory protein with a key role in inflammation and immune-regulation, was implicated in carcinogenesis by facilitating instability in the tumor environment. The purpose of this study was to identify gene polymorphisms of CCL4 specific to patients with oral squamous cell carcinoma (OSCC) susceptibility and clinicopathological characteristics. A total of 2,053 participants, including 1192 healthy people and 861 patients with oral cancer, were recruited for this study. Three single-nucleotide polymorphisms (SNPs) of the CCL4 gene were analyzed by a real-time PCR. We found that the T/T homozygotes of CCL4 rs1634507 G/T polymorphism and the GG haplotype of 2 CCL4 SNPs (rs1634507 and rs10491121) combined were associated with oral-cancer susceptibility. In addition, TA haplotype significantly decreased the risks for oral cancer by 0.118 fold. Among 1420 smokers, CCL4 polymorphisms carriers with the betel-nut chewing habit had a 15.476–20.247-fold greater risk of having oral cancer compared to CCL4 wild-type (WT) carriers without the betel-nut chewing habit. Finally, patients with oral cancer who had A/G heterozygotes of CCL4 rs10491121 A/G polymorphism showed a lower risk for an advanced tumor size (> T2) (p=0.046), compared to those patients with AA homozygotes. Our results suggest that the CCL4 rs1634507 SNP have potential predictive significance in oral carcinogenesis. Gene-environment interactions of CCL4 polymorphisms might influence oral-cancer susceptibility. CCL4 rs10491121 may be a factor to predict the tumor size in OSCC patients. PMID:28404909

Impact of CCL4 gene polymorphisms and environmental factors on oral cancer development and clinical characteristics.

PubMed

Lien, Ming-Yu; Lin, Chiao-Wen; Tsai, Hsiao-Chi; Chen, Yng-Tay; Tsai, Ming-Hsui; Hua, Chun-Hung; Yang, Shun-Fa; Tang, Chih-Hsin

2017-05-09

In Taiwan, oral cancer has causally been associated with environmental carcinogens. CCL4 (C-C chemokine ligand 4), a macrophage inflammatory protein with a key role in inflammation and immune-regulation, was implicated in carcinogenesis by facilitating instability in the tumor environment. The purpose of this study was to identify gene polymorphisms of CCL4 specific to patients with oral squamous cell carcinoma (OSCC) susceptibility and clinicopathological characteristics. A total of 2,053 participants, including 1192 healthy people and 861 patients with oral cancer, were recruited for this study. Three single-nucleotide polymorphisms (SNPs) of the CCL4 gene were analyzed by a real-time PCR. We found that the T/T homozygotes of CCL4 rs1634507 G/T polymorphism and the GG haplotype of 2 CCL4 SNPs (rs1634507 and rs10491121) combined were associated with oral-cancer susceptibility. In addition, TA haplotype significantly decreased the risks for oral cancer by 0.118 fold. Among 1420 smokers, CCL4 polymorphisms carriers with the betel-nut chewing habit had a 15.476-20.247-fold greater risk of having oral cancer compared to CCL4 wild-type (WT) carriers without the betel-nut chewing habit. Finally, patients with oral cancer who had A/G heterozygotes of CCL4 rs10491121 A/G polymorphism showed a lower risk for an advanced tumor size (> T2) (p=0.046), compared to those patients with AA homozygotes. Our results suggest that the CCL4 rs1634507 SNP have potential predictive significance in oral carcinogenesis. Gene-environment interactions of CCL4 polymorphisms might influence oral-cancer susceptibility. CCL4 rs10491121 may be a factor to predict the tumor size in OSCC patients.

Reduction of the allotropic transition temperature in nanocrystalline zirconium: Predicted by modified equation of state (MEOS) method and molecular dynamics simulation

NASA Astrophysics Data System (ADS)

Salati, Amin; Mokhtari, Esmail; Panjepour, Masoud; Aryanpour, Gholamreza

2013-04-01

The temperature at which polymorphic phase transformation occurs in nanocrystalline (NC) materials is different from that of coarse-grained specimens. This anomaly has been related to the role of grain boundary component in these materials and can be predicted by a dilated crystal model. In this study, based on this model, a modified equation of state (MEOS) method (instead of equation of state, EOS, method) is used to calculate the total Gibbs free energy of each phase (β-Zr or α-Zr) in NC Zr. Thereupon, the change in the total Gibbs free energy for β-Zr to α-Zr phase transformation (ΔGβ→α) via the grain size is calculated by this method. Similar to polymorphic transformation in other NC materials (Fe, Nb, Co, TiO2, Al2O3 and ZnS), it is found that the estimated transformation temperature in NC Zr (β→α) is reduced with decreasing grain size. Finally, a molecular dynamics (MD) simulation is employed to confirm the theoretical results.

Functional Analysis of a Novel Genome-Wide Association Study Signal in SMAD3 That Confers Protection From Coronary Artery Disease.

PubMed

Turner, Adam W; Martinuk, Amy; Silva, Anada; Lau, Paulina; Nikpay, Majid; Eriksson, Per; Folkersen, Lasse; Perisic, Ljubica; Hedin, Ulf; Soubeyrand, Sebastien; McPherson, Ruth

2016-05-01

A recent genome-wide association study meta-analysis identified an intronic single nucleotide polymorphism in SMAD3, rs56062135C>T, the minor allele (T) which associates with protection from coronary artery disease. Relevant to atherosclerosis, SMAD3 is a key contributor to transforming growth factor-β pathway signaling. Here, we seek to identify ≥1 causal coronary artery disease-associated single nucleotide polymorphisms at the SMAD3 locus and characterize mechanisms whereby the risk allele(s) contribute to coronary artery disease risk. By genetic and epigenetic fine mapping, we identified a candidate causal single nucleotide polymorphism rs17293632C>T (D', 0.97; r(2), 0.94 with rs56062135) in intron 1 of SMAD3 with predicted functional effects. We show that the sequence encompassing rs17293632 acts as a strong enhancer in human arterial smooth muscle cells. The common allele (C) preserves an activator protein (AP)-1 site and enhancer function, whereas the protective (T) allele disrupts the AP-1 site and significantly reduces enhancer activity (P<0.001). Pharmacological inhibition of AP-1 activity upstream demonstrates that this allele-specific enhancer effect is AP-1 dependent (P<0.001). Chromatin immunoprecipitation experiments reveal binding of several AP-1 component proteins with preferential binding to the (C) allele. We show that rs17293632 is an expression quantitative trait locus for SMAD3 in blood and atherosclerotic plaque with reduced expression of SMAD3 in carriers of the protective allele. Finally, siRNA knockdown of SMAD3 in human arterial smooth muscle cells increases cell viability, consistent with an antiproliferative role. The coronary artery disease-associated rs17293632C>T single nucleotide polymorphism represents a novel functional cis-acting element at the SMAD3 locus. The protective (T) allele of rs17293632 disrupts a consensus AP-1 binding site in a SMAD3 intron 1 enhancer, reduces enhancer activity and SMAD3 expression, altering human arterial smooth muscle cell proliferation. © 2016 American Heart Association, Inc.

PPARgamma gene polymorphism is associated with exercise-mediated changes of insulin resistance in healthy men.

PubMed

Kahara, Toshio; Takamura, Toshinari; Hayakawa, Tetsuo; Nagai, Yukihiro; Yamaguchi, Hiromi; Katsuki, Tatsuo; Katsuki, Ken-Ichi; Katsuki, Michio; Kobayashi, Ken-Ichi

2003-02-01

Exercise training improves insulin sensitivity, but individual responses vary greatly. Peroxisome proliferator-activated receptor-gamma (PPARgamma) is a regulator of adipose cell differentiation and plays an important role in systemic insulin action. We investigated whether PPARgamma gene polymorphism affects insulin resistance in response to exercise in Japanese healthy men. The exercise program at an individual intensity of 50% of the maximal heart rate was performed for 20 to 60 min/d, and 2 to 3 days per week to attain a level of physical activity of 700 kcal/wk. The program was conducted for 3 months without any dietary intervention, and the clinical and metabolic characteristics were examined before and after the exercise program. Body mass index (BMI) did not change significantly after the exercise program, whereas percentage of body fat (% body fat), fasting plasma glucose (FPG), and serum leptin levels decreased significantly. Pro12Ala polymorphism in PPARgamma gene was performed on genomic DNA isolated from human leukocytes and examined with polymerase chain reaction (PCR) and subsequent restriction enzyme analysis using BstU-I. In this study, the Ala allele did not correlate with fasting immunoreactive insulin (IRI) and homeostasis model assessment-insulin resistance index (HOMA-R) at baseline, but did so with the changes in IRI and HOMA-R after exercise (DeltaIRI, Pro/Pro 0.55 +/- 3.49 microU/mL v Pro/Ala -2.83 +/- 1.47 microU/mL, P <.05; DeltaHOMA-R, Pro/Pro 0.09 +/- 0.86 v Pro/Ala -0.61 +/- 0.32, P <.05). This result suggests that the Ala allele is associated with improvement in insulin resistance after exercise. We conclude that PPARgamma gene polymorphism may be a reliable indicator of whether exercise will have a beneficial effect as part of the treatment of insulin resistance syndrome. Copyright 2003, Elsevier Science (USA). All rights reserved.

Single nucleotide polymorphism discovery in bovine liver using RNA-seq technology.

PubMed

Pareek, Chandra Shekhar; Błaszczyk, Paweł; Dziuba, Piotr; Czarnik, Urszula; Fraser, Leyland; Sobiech, Przemysław; Pierzchała, Mariusz; Feng, Yaping; Kadarmideen, Haja N; Kumar, Dibyendu

2017-01-01

RNA-seq is a useful next-generation sequencing (NGS) technology that has been widely used to understand mammalian transcriptome architecture and function. In this study, a breed-specific RNA-seq experiment was utilized to detect putative single nucleotide polymorphisms (SNPs) in liver tissue of young bulls of the Polish Red, Polish Holstein-Friesian (HF) and Hereford breeds, and to understand the genomic variation in the three cattle breeds that may reflect differences in production traits. The RNA-seq experiment on bovine liver produced 107,114,4072 raw paired-end reads, with an average of approximately 60 million paired-end reads per library. Breed-wise, a total of 345.06, 290.04 and 436.03 million paired-end reads were obtained from the Polish Red, Polish HF, and Hereford breeds, respectively. Burrows-Wheeler Aligner (BWA) read alignments showed that 81.35%, 82.81% and 84.21% of the mapped sequencing reads were properly paired to the Polish Red, Polish HF, and Hereford breeds, respectively. This study identified 5,641,401 SNPs and insertion and deletion (indel) positions expressed in the bovine liver with an average of 313,411 SNPs and indel per young bull. Following the removal of the indel mutations, a total of 195,3804, 152,7120 and 205,3184 raw SNPs expressed in bovine liver were identified for the Polish Red, Polish HF, and Hereford breeds, respectively. Breed-wise, three highly reliable breed-specific SNP-databases (SNP-dbs) with 31,562, 24,945 and 28,194 SNP records were constructed for the Polish Red, Polish HF, and Hereford breeds, respectively. Using a combination of stringent parameters of a minimum depth of ≥10 mapping reads that support the polymorphic nucleotide base and 100% SNP ratio, 4,368, 3,780 and 3,800 SNP records were detected in the Polish Red, Polish HF, and Hereford breeds, respectively. The SNP detections using RNA-seq data were successfully validated by kompetitive allele-specific PCR (KASPTM) SNP genotyping assay. The comprehensive QTL/CG analysis of 110 QTL/CG with RNA-seq data identified 20 monomorphic SNP hit loci (CARTPT, GAD1, GDF5, GHRH, GHRL, GRB10, IGFBPL1, IGFL1, LEP, LHX4, MC4R, MSTN, NKAIN1, PLAG1, POU1F1, SDR16C5, SH2B2, TOX, UCP3 and WNT10B) in all three cattle breeds. However, six SNP loci (CCSER1, GHR, KCNIP4, MTSS1, EGFR and NSMCE2) were identified as highly polymorphic among the cattle breeds. This study identified breed-specific SNPs with greater SNP ratio and excellent mapping coverage, as well as monomorphic and highly polymorphic putative SNP loci within QTL/CGs of bovine liver tissue. A breed-specific SNP-db constructed for bovine liver yielded nearly six million SNPs. In addition, a KASPTM SNP genotyping assay, as a reliable cost-effective method, successfully validated the breed-specific putative SNPs originating from the RNA-seq experiments.

Cyclin D1 and epidermal growth factor polymorphisms associated with survival in patients with advanced colorectal cancer treated with Cetuximab.

PubMed

Zhang, Wu; Gordon, Michael; Press, Oliver A; Rhodes, Katrin; Vallböhmer, Daniel; Yang, Dong Yun; Park, David; Fazzone, William; Schultheis, Anne; Sherrod, Andy E; Iqbal, Syma; Groshen, Susan; Lenz, Heinz-Josef

2006-07-01

The study aimed to investigate whether polymorphisms in genes of the EGFR signaling pathway are associated with clinical outcome in advanced colorectal cancer (CRC) patients treated with single-agent Cetuximab. Polymorphisms of interest in the EGFR pathway include: cyclin D1 (CCND1) A870G, cyclooxygenase 2 (Cox-2) G-765C, epidermal growth factor (EGF) A61G, epidermal growth factor receptor (EGFR) codon R497 K, EGFR CA dinucleotide repeat in intron 1, interleukin (IL)-8 T-251A and vascular endothelial growth factor (VEGF) C936 T gene polymorphisms. Thirty-nine metastatic CRC patients were enrolled in the IMCL-0144 trial and treated with single-agent Cetuximab. Using the polymerase chain reaction-restriction fragment length polymorphism method, gene polymorphisms of CCND1, COX-2, EGF, EGFR, IL-8 and VEGF were assessed from genomic DNA extracted from blood samples. A significant association was found between the CCND1 A870G polymorphism and overall survival in our 39 CRC subjects. Patients with the AA homozygous genotype survived for a median of 2.3 months [95% confidence interval (CI)=2.1-5.7], whereas those with any G allele (AG, GG genotype) survived for a median of 8.7 months (95% CI=4.4-13.5) (P=0.019, log-rank test). When we analysed the cyclin D1 and EGF polymorphisms together, patients with favourable genotypes (EGF any A allele and CCND1 any G allele) showed a median survival time of 12 months (95% CI=4.8-15.2), whereas patients with any two unfavourable genotypes (EGF GG or CCND1 AA) showed a median survived time of 4.4 months (95% CI=2.1-5.7) (P=0.004, log-rank test). The findings of this pilot study suggest that the cyclin D1 A870G and the EGF A61G polymorphisms may be useful molecular markers for predicting clinical outcome in CRC patients treated with single-agent Cetuximab.

PCR-Restriction Fragment Length Polymorphism for Rapid, Low-Cost Identification of Isoniazid-Resistant Mycobacterium tuberculosis▿

PubMed Central

Caws, Maxine; Tho, Dau Quang; Duy, Phan Minh; Lan, Nguyen Thi Ngoc; Hoa, Dai Viet; Torok, Mili Estee; Chau, Tran Thi Hong; Van Vinh Chau, Nguyen; Chinh, Nguyen Tran; Farrar, Jeremy

2007-01-01

PCR-restriction fragment length poymorphism (PCR-RFLP) is a simple, robust technique for the rapid identification of isoniazid-resistant Mycobacterium tuberculosis. One hundred consecutive isolates from a Vietnamese tuberculosis hospital were tested by MspA1I PCR-RFLP for the detection of isoniazid-resistant katG_315 mutants. The test had a sensitivity of 80% and a specificity of 100% against conventional phenotypic drug susceptibility testing. The positive and negative predictive values were 1 and 0.86, respectively. None of the discrepant isolates had mutant katG_315 codons by sequencing. The test is cheap (less than $1.50 per test), specific, and suitable for the rapid identification of isoniazid resistance in regions with a high prevalence of katG_315 mutants among isoniazid-resistant M. tuberculosis isolates. PMID:17428939

Personality traits as an endophenotype in genetic studies on suicidality in bipolar disorder.

PubMed

Pawlak, J; Dmitrzak-Węglarz, M; Maciukiewicz, M; Kapelski, P; Czerski, P; Leszczyńska-Rodziewicz, A; Zaremba, D; Hauser, J

2017-04-01

Introduction The influence of personality traits on suicidal behaviour risk has been well documented. Personality traits and suicidal behaviour are partially genetically determined and personality has been described as an endophenotype of suicidal behaviour. The aim of this study was to investigate a possible association between personality traits with suicidal behaviour and selected serotonergic gene polymorphisms. In the study we included 156 patients meeting DSM-IV criteria for bipolar disorder (BP) and 93 healthy controls. The personality dimensions were assessed using the Temperament and Character Inventory (TCI). We genotyped two selected polymorphisms of the tryptophan hydroxylase 1 (TPH1) gene (rs1800532 218A>C and rs1799913 779A>C) and polymorphism in the promoter region of serotonin transporter gene (5-HTTLPR, rs25531) related to serotoninergic neurotransmission. Multiple poisson regression, logistic regression and Kruskal-Wallis tests were applied. We found numerous differences between the BP patients and the control group in terms of their TCI dimensions/subdimensions. Significant differences were found between patients with, and without, suicidal attempts in fatigability and asthenia (Ha4), as well as in harm avoidance (Ha). We also found that the interactions between TCI subdimensions (the interaction of disordiness (Ns4) and spiritual acceptance (St3), disordiness (Ns4) and integrated conscience (C5), extravagance (Ns3) and resourcefulness (Sd3)) were significantly contributing for suicidal behaviour risk. We found association between all studied genetic polymorphisms and several TCI dimensions and subdimensions. Our results confirm that personality traits are partially determined by genes. Both personality traits and the interactions between temperament and character traits, may be helpful in predicting suicidal behaviour.

AS3MT, GSTO, and PNP polymorphisms: impact on arsenic methylation and implications for disease susceptibility.

PubMed

Antonelli, Ray; Shao, Kan; Thomas, David J; Sams, Reeder; Cowden, John

2014-07-01

Oral exposure to inorganic arsenic (iAs) is associated with adverse health effects. Epidemiological studies suggest differences in susceptibility to these health effects, possibly due to genotypic variation. Genetic polymorphisms in iAs metabolism could lead to increased susceptibility by altering urinary iAs metabolite concentrations. To examine the impact of genotypic polymorphisms on iAs metabolism. We screened 360 publications from PubMed and Web of Science for data on urinary mono- and dimethylated arsenic (MMA and DMA) percentages and polymorphic genes encoding proteins that are hypothesized to play roles in arsenic metabolism. The genes we examined were arsenic (+3) methyltransferase (AS3MT), glutathione-s-transferase omega (GSTO), and purine nucleoside phosphorylase (PNP). Relevant data were pooled to determine which polymorphisms are associated across studies with changes in urinary metabolite concentration. In our review, AS3MT polymorphisms rs3740390, rs11191439, and rs11191453 were associated with statistically significant changes in percent urinary MMA. Studies of GSTO polymorphisms did not indicate statistically significant associations with methylation, and there are insufficient data on PNP polymorphisms to evaluate their impact on metabolism. Collectively, these data support the hypothesis that AS3MT polymorphisms alter in vivo metabolite concentrations. Preliminary evidence suggests that AS3MT genetic polymorphisms may impact disease susceptibility. GSTO polymorphisms were not associated with iAs-associated health outcomes. Additional data are needed to evaluate the association between PNP polymorphisms and iAs-associated health outcomes. Delineation of these relationships may inform iAs mode(s) of action and the approach for evaluating low-dose health effects for iAs. Genotype impacts urinary iAs metabolite concentrations and may be a potential mechanism for iAs-related disease susceptibility. Published by Elsevier Inc.

Meta-Prediction of MTHFR Gene Polymorphisms and Air Pollution on the Risk of Hypertensive Disorders in Pregnancy Worldwide.

PubMed

Yang, Ya-Ling; Yang, Hsiao-Ling; Shiao, S Pamela K

2018-02-13

Hypertensive disorders in pregnancy (HDP) are devastating health hazards for both women and children. Both methylenetetrahydrofolate reductase ( MTHFR ) gene polymorphisms and air pollution can affect health status and result in increased risk of HDP for women. The major objective of this study was to investigate the effect of MTHFR polymorphisms, air pollution, and their interaction on the risk of HDP by using meta-predictive analytics. We searched various databases comprehensively to access all available studies conducted for various ethnic populations from countries worldwide, from 1997 to 2017. Seventy-one studies with 8064 cases and 13,232 controls for MTHFR C677T and 11 studies with 1425 cases and 1859 controls for MTHFR A1298C were included. MTHFR C677T homozygous TT (risk ratio (RR) = 1.28, p < 0.0001) and CT plus TT (RR = 1.07, p = 0.0002) were the risk genotypes, while wild-type CC played a protective role (RR = 0.94, p = 0.0017) for HDP. The meta-predictive analysis found that the percentage of MTHFR C677T TT plus CT ( p = 0.044) and CT ( p = 0.043) genotypes in the HDP case group were significantly increased with elevated levels of air pollution worldwide. Additionally, in countries with higher air pollution levels, the pregnant women with wild-type CC MTHFR 677 had a protection effect against HDP ( p = 0.014), whereas, the homozygous TT of MTHFR C677T polymorphism was a risk genotype for developing HDP. Air pollution level is an environmental factor interacting with increased MTHFR C677T polymorphisms, impacting the susceptibility of HDP for women.

Meta-Prediction of MTHFR Gene Polymorphisms and Air Pollution on the Risk of Hypertensive Disorders in Pregnancy Worldwide

PubMed Central

Yang, Ya-Ling; Yang, Hsiao-Ling; Shiao, S. Pamela K.

2018-01-01

Hypertensive disorders in pregnancy (HDP) are devastating health hazards for both women and children. Both methylenetetrahydrofolate reductase (MTHFR) gene polymorphisms and air pollution can affect health status and result in increased risk of HDP for women. The major objective of this study was to investigate the effect of MTHFR polymorphisms, air pollution, and their interaction on the risk of HDP by using meta-predictive analytics. We searched various databases comprehensively to access all available studies conducted for various ethnic populations from countries worldwide, from 1997 to 2017. Seventy-one studies with 8064 cases and 13,232 controls for MTHFR C677T and 11 studies with 1425 cases and 1859 controls for MTHFR A1298C were included. MTHFR C677T homozygous TT (risk ratio (RR) = 1.28, p < 0.0001) and CT plus TT (RR = 1.07, p = 0.0002) were the risk genotypes, while wild-type CC played a protective role (RR = 0.94, p = 0.0017) for HDP. The meta-predictive analysis found that the percentage of MTHFR C677T TT plus CT (p = 0.044) and CT (p = 0.043) genotypes in the HDP case group were significantly increased with elevated levels of air pollution worldwide. Additionally, in countries with higher air pollution levels, the pregnant women with wild-type CC MTHFR 677 had a protection effect against HDP (p = 0.014), whereas, the homozygous TT of MTHFR C677T polymorphism was a risk genotype for developing HDP. Air pollution level is an environmental factor interacting with increased MTHFR C677T polymorphisms, impacting the susceptibility of HDP for women. PMID:29438331

Genetic polymorphisms in phase I and phase II enzymes and breast cancer risk associated with menopausal hormone therapy in postmenopausal women.

PubMed

2010-01-01

Recent findings indicate a greater risk of postmenopausal breast cancer with estrogen-progestagen therapy than estrogen monotherapy, and more so for current than past use. Few studies have examined individual genetic susceptibility to the effects of menopausal hormone therapy. We used two population-based case-control studies with 3,155 postmenopausal breast cancer patients and 5,496 controls to evaluate modification of breast cancer risk associated with duration of hormone use by genes involved in hormone metabolism and detoxification. Twenty-eight polymorphisms in eight genes of phase I (CYP1A1, CYP1A2, CYP1B1, CYP2C9, CYP2C19, CYP3A4, CYP3A5, CYP3A7) and nine genes of phase II enzymes (COMT, GSTM1, GSTM3, GSTP1, GSTT1, SULT1A1, UGT1A1, UGT1A6, UGT2B7) were genotyped. The risk associated with duration of use of combined estrogen-progestagen therapy was significantly modified by genetic polymorphisms located in CYP1B1, GSTP1, and GSTT1. In homozygote carriers of the CYP1B1_142_G and the CYP1B1_355 _T variant alleles, adjusted odds ratios (OR) per year of use were 1.06 (95% confidence interval (CI) = 1.02-1.09) and 1.06 (95% CI = 1.03-1.09), respectively, compared with 1.02 (95% CI = 1.01-1.03) in non-carriers of either polymorphism (p(interaction) = 0.01). Carriers of the functional GSTT1 allele and the GSTP1_341_T allele were at significantly higher risks associated with hormone use compared with non-carriers (p(interaction) = 0.0001 and 0.02). CYP1A1_2452_C>A significantly reduced the risk associated with duration of use of estrogen monotherapy (p(interaction) = 0.01). The finding regarding GSTT1 was still statistically significant after corrections for multiple comparisons. Postmenopausal breast cancer risk associated with hormone therapy may be modified by genetically determined variations in phase I and II enzymes involved in steroid hormone metabolism.

TP53 and MDM2 single nucleotide polymorphisms influence survival in non-del(5q) myelodysplastic syndromes

PubMed Central

Sallman, David A.; Basiorka, Ashley A.; Irvine, Brittany A.; Zhang, Ling; Epling-Burnette, P.K.; Rollison, Dana E.; Mallo, Mar; Sokol, Lubomir; Solé, Francesc; Maciejewski, Jaroslaw; List, Alan F.

2015-01-01

P53 is a key regulator of many cellular processes and is negatively regulated by the human homolog of murine double minute-2 (MDM2) E3 ubiquitin ligase. Single nucleotide polymorphisms (SNPs) of either gene alone, and in combination, are linked to cancer susceptibility, disease progression, and therapy response. We analyzed the interaction of TP53 R72P and MDM2 SNP309 SNPs in relationship to outcome in patients with myelodysplastic syndromes (MDS). Sanger sequencing was performed on DNA isolated from 208 MDS cases. Utilizing a novel functional SNP scoring system ranging from +2 to −2 based on predicted p53 activity, we found statistically significant differences in overall survival (OS) (p = 0.02) and progression-free survival (PFS) (p = 0.02) in non-del(5q) MDS patients with low functional scores. In univariate analysis, only IPSS and the functional SNP score predicted OS and PFS in non-del(5q) patients. In multivariate analysis, the functional SNP score was independent of IPSS for OS and PFS. These data underscore the importance of TP53 R72P and MDM2 SNP309 SNPs in MDS, and provide a novel scoring system independent of IPSS that is predictive for disease outcome. PMID:26416416

FcgammaRIIa genotype predicts progression of HIV infection.

PubMed

Forthal, Donald N; Landucci, Gary; Bream, Jay; Jacobson, Lisa P; Phan, Tran B; Montoya, Benjamin

2007-12-01

Polymorphisms in FcgammaR genes are associated with susceptibility to or severity of a number of autoimmune and infectious diseases. We found that HIV-infected men in the Multicenter AIDS Cohort Study with the FcgammaRIIa RR genotype progressed to a CD4(+) cell count of <200/mm(3) at a faster rate than individuals with the RH or HH genotypes (relative hazard = 1.6; p = 0.0001). However, progression to AIDS (using the broad definition of either a CD4(+) cell count <200/mm(3) or development of an AIDS-defining illness) was less impacted by FcgammaRIIa genotype, largely because HH homozygotes had an increased risk of Pneumocystis jiroveci pneumonia as an AIDS-defining illness. We also showed that chronically infected subjects develop a substantial anti-gp120-specific IgG2 response. Moreover, HIV-1 immune complexes are more efficiently internalized by monocytes from HH subjects compared with RR subjects, likely because of the presence of IgG2 in the complexes. Finally, the FcgammaRIIIa F/V gene polymorphism was not associated with progression of HIV infection, but, as demonstrated previously, did predict the risk of Kaposi's sarcoma. These results demonstrate the importance of FcgammaRs in AIDS pathogenesis and point toward a critical role for interactions between FcgammaRs and immune complexes in disease progression.

Polymorphic microsatellite loci for Haumania danckelmaniana and transferability to H. liebrechtsiana (Marantaceae).

PubMed

Ley, Alexandra C; Hardy, Olivier J

2016-03-01

Microsatellite markers were developed for the species Haumania danckelmaniana (Marantaceae) from central tropical Africa. Microsatellite isolation was performed simultaneously on three different species of Marantaceae through a procedure that combines multiplex microsatellite enrichment and next-generation sequencing. From 80 primers selected for initial screening, 20 markers positively amplified in H. danckelmaniana, of which 10 presented unambiguous amplification products within the expected size range and eight were polymorphic with four to nine alleles per locus. Positive transferability with the related species H. liebrechtsiana was observed for the same 10 markers. The polymorphic microsatellite markers are suitable for studies in genetic diversity and structure, mating system, and gene flow in H. danckelmaniana and the closely related species H. liebrechtsiana.

Characterization of 10 new nuclear microsatellite markers in Acca sellowiana (Myrtaceae).

PubMed

Klabunde, Gustavo H F; Olkoski, Denise; Vilperte, Vinicius; Zucchi, Maria I; Nodari, Rubens O

2014-06-01

Microsatellite primers were identified and characterized in Acca sellowiana in order to expand the limited number of pre-existing polymorphic markers for use in population genetic studies for conservation, phylogeography, breeding, and domestication. • A total of 10 polymorphic microsatellite primers were designed from clones obtained from a simple sequence repeat (SSR)-enriched genomic library. The primers amplified di- and trinucleotide repeats with four to 27 alleles per locus. In all tested populations, the observed heterozygosity ranged from 0.269 to 1.0. • These new polymorphic SSR markers will allow future genetic studies to be denser, either for genetic structure characterization of natural populations or for studies involving genetic breeding and domestication process in A. sellowiana.

SEAN: SNP prediction and display program utilizing EST sequence clusters.

PubMed

Huntley, Derek; Baldo, Angela; Johri, Saurabh; Sergot, Marek

2006-02-15

SEAN is an application that predicts single nucleotide polymorphisms (SNPs) using multiple sequence alignments produced from expressed sequence tag (EST) clusters. The algorithm uses rules of sequence identity and SNP abundance to determine the quality of the prediction. A Java viewer is provided to display the EST alignments and predicted SNPs.

Adult height is associated with increased risk of ovarian cancer: a Mendelian randomisation study.

PubMed

Dixon-Suen, Suzanne C; Nagle, Christina M; Thrift, Aaron P; Pharoah, Paul D P; Ewing, Ailith; Pearce, Celeste Leigh; Zheng, Wei; Chenevix-Trench, Georgia; Fasching, Peter A; Beckmann, Matthias W; Lambrechts, Diether; Vergote, Ignace; Lambrechts, Sandrina; Van Nieuwenhuysen, Els; Rossing, Mary Anne; Doherty, Jennifer A; Wicklund, Kristine G; Chang-Claude, Jenny; Jung, Audrey Y; Moysich, Kirsten B; Odunsi, Kunle; Goodman, Marc T; Wilkens, Lynne R; Thompson, Pamela J; Shvetsov, Yurii B; Dörk, Thilo; Park-Simon, Tjoung-Won; Hillemanns, Peter; Bogdanova, Natalia; Butzow, Ralf; Nevanlinna, Heli; Pelttari, Liisa M; Leminen, Arto; Modugno, Francesmary; Ness, Roberta B; Edwards, Robert P; Kelley, Joseph L; Heitz, Florian; du Bois, Andreas; Harter, Philipp; Schwaab, Ira; Karlan, Beth Y; Lester, Jenny; Orsulic, Sandra; Rimel, Bobbie J; Kjær, Susanne K; Høgdall, Estrid; Jensen, Allan; Goode, Ellen L; Fridley, Brooke L; Cunningham, Julie M; Winham, Stacey J; Giles, Graham G; Bruinsma, Fiona; Milne, Roger L; Southey, Melissa C; Hildebrandt, Michelle A T; Wu, Xifeng; Lu, Karen H; Liang, Dong; Levine, Douglas A; Bisogna, Maria; Schildkraut, Joellen M; Berchuck, Andrew; Cramer, Daniel W; Terry, Kathryn L; Bandera, Elisa V; Olson, Sara H; Salvesen, Helga B; Thomsen, Liv Cecilie Vestrheim; Kopperud, Reidun K; Bjorge, Line; Kiemeney, Lambertus A; Massuger, Leon F A G; Pejovic, Tanja; Bruegl, Amanda; Cook, Linda S; Le, Nhu D; Swenerton, Kenneth D; Brooks-Wilson, Angela; Kelemen, Linda E; Lubiński, Jan; Huzarski, Tomasz; Gronwald, Jacek; Menkiszak, Janusz; Wentzensen, Nicolas; Brinton, Louise; Yang, Hannah; Lissowska, Jolanta; Høgdall, Claus K; Lundvall, Lene; Song, Honglin; Tyrer, Jonathan P; Campbell, Ian; Eccles, Diana; Paul, James; Glasspool, Rosalind; Siddiqui, Nadeem; Whittemore, Alice S; Sieh, Weiva; McGuire, Valerie; Rothstein, Joseph H; Narod, Steven A; Phelan, Catherine; Risch, Harvey A; McLaughlin, John R; Anton-Culver, Hoda; Ziogas, Argyrios; Menon, Usha; Gayther, Simon A; Ramus, Susan J; Gentry-Maharaj, Aleksandra; Wu, Anna H; Pike, Malcolm C; Tseng, Chiu-Chen; Kupryjanczyk, Jolanta; Dansonka-Mieszkowska, Agnieszka; Budzilowska, Agnieszka; Rzepecka, Iwona K; Webb, Penelope M

2018-04-01

Observational studies suggest greater height is associated with increased ovarian cancer risk, but cannot exclude bias and/or confounding as explanations for this. Mendelian randomisation (MR) can provide evidence which may be less prone to bias. We pooled data from 39 Ovarian Cancer Association Consortium studies (16,395 cases; 23,003 controls). We applied two-stage predictor-substitution MR, using a weighted genetic risk score combining 609 single-nucleotide polymorphisms. Study-specific odds ratios (OR) and 95% confidence intervals (CI) for the association between genetically predicted height and risk were pooled using random-effects meta-analysis. Greater genetically predicted height was associated with increased ovarian cancer risk overall (pooled-OR (pOR) = 1.06; 95% CI: 1.01-1.11 per 5 cm increase in height), and separately for invasive (pOR = 1.06; 95% CI: 1.01-1.11) and borderline (pOR = 1.15; 95% CI: 1.02-1.29) tumours. Women with a genetic propensity to being taller have increased risk of ovarian cancer. This suggests genes influencing height are involved in pathways promoting ovarian carcinogenesis.

Association of IL-1β +3954 C/T and IL-10-1082 G/A cytokine gene polymorphisms with susceptibility to tuberculosis.

PubMed

Meenakshi, P; Ramya, S; Shruthi, T; Lavanya, J; Mohammed, H H; Mohammed, S A; Vijayalakshmi, V; Sumanlatha, G

2013-07-01

Tuberculosis (TB) constitutes the major cause of death due to infectious diseases. Cytokines play a major role in defence against Mycobacterium tuberculosis infection. Polymorphisms in the genes encoding various cytokines have been associated with tuberculosis susceptibility. Household contacts (HHC) are at increased risk of developing the disease. In this study, we examined the association of IL-1β and IL-10 cytokine gene polymorphisms with risk of developing tuberculosis in TB patients, their HHC and healthy controls (HC) using JavaStat and SPSS. Multifactor dimensionality reduction (MDR) analyses were performed to explore the potential gene-gene interactions. The genotype and allele frequencies of IL-1β +3954C/T polymorphism did not vary significantly between TB patients and HC. GG (P < 0.005, OR = 0.219 and 95% CI = 0.059-0.735) and GA (P < 0.0001, OR = 2.938 and 95% CI = 1.526-5.696) genotypes of IL-10-1082 G/A polymorphism were found to be significantly associated with patients versus HC. HHC with CC (P < 0.03, OR = 1.833 and 95% CI = 1.1-3.35) genotype in IL-1β and GA (P < 0.0001, OR = 4.612 and 95% CI = 2.225-9.702) genotype in IL-10 were at increased risk of developing tuberculosis. MDR tests revealed high-risk genotypes in IL-1β and IL-10 based on the association model. Our results demonstrate that the polymorphisms of IL-1β and IL-10 genes may be valuable markers to predict the risk for the development of TB in household contacts. © 2013 John Wiley & Sons Ltd.

E2 allele of the apolipoprotein E gene polymorphism is predictive for obesity status in Roma minority population of Croatia.

PubMed

Zeljko, Hrvojka Marija; Škarić-Jurić, Tatjana; Narančić, Nina Smolej; Tomas, Željka; Barešić, Ana; Salihović, Marijana Peričić; Starčević, Boris; Janićijević, Branka

2011-01-18

The Roma (Gypsies) are a transnational minority, founder population characterized by unique genetic background modeled by culturally determined endogamy. The present study explores whether the widely found cardiovascular diseases (CVD) risk effects of ACE I/D, APOE (ε2, ε3, ε4), eNOS-VNTR and LEP G2548A polymorphisms can be replicated in this specific population. The community-based study was carried on 208 adult Bayash Roma living in rural settlements of eastern and northern Croatia. Risk effect of four CVD candidate polymorphisms are related to the most prominent classical CVD risk phenotypes: obesity indicators (body mass index and waist circumference), hypertension and hyperlipidemia (triglycerides, HDL and LDL cholesterol). For all of them the standard risk cut-offs were applied. The extent to which the phenotypic status is related to genotype was assessed by logistic regression analysis. The strongest associations were found for ε2 allele of the APOE as a predictor of waist circumference (OR 3.301; 95%CI 1.254-8.688; p = 0.016) as well as for BMI (OR 3.547; 95%CI 1.471-8.557; p = 0.005). It is notable that ε3 allele of APOE gene turned out to be a protective genetic factor determining low lipid levels. The strength of the relation and the similarity of the results obtained for both tested indicators of obesity provide firm evidence that APOE plays an important role in obesity development in the Roma population.

Ab initio prediction of superdense tetragonal and monoclinic polymorphs of carbon

DOE PAGES

Li, Zhen -Zhen; Wang, Jian -Tao; Xu, Li -Fang; ...

2016-11-02

The design and synthesis of three-dimensional denser carbons are one of the hot issues in condensed matter physics because of their fascinating properties. Here we identify by ab initio calculations several tetragonal and monoclinic polymorphs of carbon that adopt the t32, t32*, m32, and m32* structures in P4¯2 1c, P4 32 12, P2 1/c, and C2 symmetry, respectively. These carbon polymorphs have large 32-atom unit cells in all-sp 3 bonding networks comprising five- and six-membered rings that are dynamically stable, as verified by a phonon mode analysis. Electronic band structure calculations show that they are insulators with band gaps inmore » the range of 5.19–5.41 eV, close to the calculated band gap of 5.34 eV for diamond. Remarkably, these carbon phases possess an extremely high atom number density exceeding that of diamond. Lastly, the present results establish different types of carbon phases and offer insights into their outstanding structural and electronic properties.« less

Telomerase reverse transcriptase locus polymorphisms and cancer risk: a field synopsis and meta-analysis.

PubMed

Mocellin, Simone; Verdi, Daunia; Pooley, Karen A; Landi, Maria T; Egan, Kathleen M; Baird, Duncan M; Prescott, Jennifer; De Vivo, Immaculata; Nitti, Donato

2012-06-06

Several recent studies have provided evidence that polymorphisms in the telomerase reverse transcriptase (TERT) gene sequence are associated with cancer development, but a comprehensive synopsis is not available. We conducted a systematic review and meta-analysis of the available molecular epidemiology data regarding the association between TERT locus polymorphisms and predisposition to cancer. A systematic review of the English literature was conducted by searching PubMed, Embase, Cancerlit, Google Scholar, and ISI Web of Knowledge databases for studies on associations between TERT locus polymorphisms and cancer risk. Random-effects meta-analysis was performed to pool per-allele odds ratios for TERT locus polymorphisms and risk of cancer, and between-study heterogeneity and potential bias sources (eg, publication and chasing bias) were assessed. Because the TERT locus includes the cleft lip and palate transmembrane 1-like (CLPTM1L) gene, which is in linkage disequilibrium with TERT, CLPTM1L polymorphisms were also analyzed. Cumulative evidence for polymorphisms with statistically significant associations was graded as "strong," "moderate," and "weak" according to the Venice criteria. The joint population attributable risk was calculated for polymorphisms with strong evidence of association. Eighty-five studies enrolling 490 901 subjects and reporting on 494 allelic contrasts were retrieved. Data were available on 67 TERT locus polymorphisms and 24 tumor types, for a total of 221 unique combinations of polymorphisms and cancer types. Upon meta-analysis, a statistically significant association with the risk of any cancer type was found for 22 polymorphisms. Strong, moderate, and weak cumulative evidence for association with at least one tumor type was demonstrated for 11, 9, and 14 polymorphisms, respectively. For lung cancer, which was the most studied tumor type, the estimated joint population attributable risk for three polymorphisms (TERT rs2736100, intergenic rs4635969, and CLPTM1L rs402710) was 41%. Strong evidence for lack of association was identified for five polymorphisms in three tumor types. To our knowledge, this is the largest collection of data for associations between TERT locus polymorphisms and cancer risk. Our findings support the hypothesis that genetic variability in this genomic region can modulate cancer susceptibility in humans.

9β Polymorphism of the Glucocorticoid Receptor Gene Appears to Have Limited Impact in Patients with Addison’s Disease

PubMed Central

Ross, Ian Louis; Dandara, Collet; Swart, Marelize; Lacerda, Miguel; Schatz, Desmond; Blom, Dirk Jacobus

2014-01-01

Background Addison’s disease (AD) has been associated with an increased risk of cardiovascular disease. Glucocorticoid receptor polymorphisms that alter glucocorticoid sensitivity may influence metabolic and cardiovascular risk factors in patients with AD. The 9β polymorphism of the glucocorticoid receptor gene is associated with relative glucocorticoid resistance and has been reported to increase the risk of myocardial infarction in the elderly. We explored the impact of this polymorphism in patients with AD. Materials and Methods 147 patients with AD and 147 age, gender and ethnicity matched healthy controls were recruited. Blood was taken in a non-fasted state for plasma lipid determination, measurement of cardiovascular risk factors and DNA extraction. Results Genotype data for the 9β polymorphism was available for 139 patients and 146 controls. AD patients had a more atherogenic lipid profile characterized by an increase in the prevalence of small dense LDL (p = 0.003), increased triglycerides (p = 0.002), reduced HDLC (p<0.001) an elevated highly sensitive C-reactive protein (p = 0.01), compared with controls. The 9β polymorphism (at least one G allele) was found in 28% of patients and controls respectively. After adjusting for age, gender, ethnicity, BMI and hydrocortisone dose per metre square of body surface area in patients, there were no significant metabolic associations with this polymorphism and hydrocortisone doses were not higher in patients with the polymorphism. Conclusions This study did not identify any associations between the 9β polymorphism and cardiovascular risk factors or hydrocortisone dose and determination of this polymorphism is therefore unlikely to be of clinical benefit in the management of patients with AD. PMID:24466047

9β Polymorphism of the glucocorticoid receptor gene appears to have limited impact in patients with Addison's disease.

PubMed

Ross, Ian Louis; Dandara, Collet; Swart, Marelize; Lacerda, Miguel; Schatz, Desmond; Blom, Dirk Jacobus

2014-01-01

Addison's disease (AD) has been associated with an increased risk of cardiovascular disease. Glucocorticoid receptor polymorphisms that alter glucocorticoid sensitivity may influence metabolic and cardiovascular risk factors in patients with AD. The 9β polymorphism of the glucocorticoid receptor gene is associated with relative glucocorticoid resistance and has been reported to increase the risk of myocardial infarction in the elderly. We explored the impact of this polymorphism in patients with AD. 147 patients with AD and 147 age, gender and ethnicity matched healthy controls were recruited. Blood was taken in a non-fasted state for plasma lipid determination, measurement of cardiovascular risk factors and DNA extraction. Genotype data for the 9β polymorphism was available for 139 patients and 146 controls. AD patients had a more atherogenic lipid profile characterized by an increase in the prevalence of small dense LDL (p = 0.003), increased triglycerides (p = 0.002), reduced HDLC (p<0.001) an elevated highly sensitive C-reactive protein (p = 0.01), compared with controls. The 9β polymorphism (at least one G allele) was found in 28% of patients and controls respectively. After adjusting for age, gender, ethnicity, BMI and hydrocortisone dose per metre square of body surface area in patients, there were no significant metabolic associations with this polymorphism and hydrocortisone doses were not higher in patients with the polymorphism. This study did not identify any associations between the 9β polymorphism and cardiovascular risk factors or hydrocortisone dose and determination of this polymorphism is therefore unlikely to be of clinical benefit in the management of patients with AD.

Microsatellite markers for the native Texas perennial grass, Panicum hallii (Poaceae).

PubMed

Lowry, David B; Purmal, Colin T; Meyer, Eli; Juenger, Thomas E

2012-03-01

We developed microsatellites for Panicum hallii for studies of gene flow, population structure, breeding experiments, and genetic mapping. Next-generation (454) genomic sequence data were used to design markers. Eighteen robust markers were discovered, 15 of which were polymorphic across six accessions of P. hallii var. hallii. Fourteen of the markers cross-amplified in a P. capillare accession. For the 15 polymorphic markers, the total number of alleles per locus ranged from two to 26 (mean: 11.0) across six populations (11-19 individuals per population). Observed heterozygosity (mean: 0.031) was 13.7 times lower than the expected heterozygosity (mean: 0.426). The deficit of heterozygous individuals is consistent with P. hallii having a high rate of self-fertilization. These markers will be useful for studies in P. hallii and related species.

Controlling the crystal polymorph by exploiting the time dependence of nucleation rates.

PubMed

Little, Laurie J; King, Alice A K; Sear, Richard P; Keddie, Joseph L

2017-10-14

Most substances can crystallise into two or more different crystal lattices called polymorphs. Despite this, there are no systems in which we can quantitatively predict the probability of one competing polymorph forming instead of the other. We address this problem using large scale (hundreds of events) studies of the competing nucleation of the alpha and gamma polymorphs of glycine. In situ Raman spectroscopy is used to identify the polymorph of each crystal. We find that the nucleation kinetics of the two polymorphs is very different. Nucleation of the alpha polymorph starts off slowly but accelerates, while nucleation of the gamma polymorph starts off fast but then slows. We exploit this difference to increase the purity with which we obtain the gamma polymorph by a factor of ten. The statistics of the nucleation of crystals is analogous to that of human mortality, and using a result from medical statistics, we show that conventional nucleation data can say nothing about what, if any, are the correlations between competing nucleation processes. Thus we can show that with data of our form it is impossible to disentangle the competing nucleation processes. We also find that the growth rate and the shape of a crystal depend on it when nucleated. This is new evidence that nucleation and growth are linked.

Epigenetic variation predicts regional and local intraspecific functional diversity in a perennial herb.

PubMed

Medrano, Mónica; Herrera, Carlos M; Bazaga, Pilar

2014-10-01

The ecological significance of epigenetic variation has been generally inferred from studies on model plants under artificial conditions, but the importance of epigenetic differences between individuals as a source of intraspecific diversity in natural plant populations remains essentially unknown. This study investigates the relationship between epigenetic variation and functional plant diversity by conducting epigenetic (methylation-sensitive amplified fragment length polymorphisms, MSAP) and genetic (amplified fragment length polymorphisms, AFLP) marker-trait association analyses for 20 whole-plant, leaf and regenerative functional traits in a large sample of wild-growing plants of the perennial herb Helleborus foetidus from ten sampling sites in south-eastern Spain. Plants differed widely in functional characteristics, and exhibited greater epigenetic than genetic diversity, as shown by per cent polymorphism of MSAP fragments (92%) or markers (69%) greatly exceeding that for AFLP ones (41%). After controlling for genetic structuring and possible cryptic relatedness, every functional trait considered exhibited a significant association with at least one AFLP or MSAP marker. A total of 27 MSAP (13.0% of total) and 12 AFLP (4.4%) markers were involved in significant associations, which explained on average 8.2% and 8.0% of trait variance, respectively. Individual MSAP markers were more likely to be associated with functional traits than AFLP markers. Between-site differences in multivariate functional diversity were directly related to variation in multilocus epigenetic diversity after multilocus genetic diversity was statistically accounted for. Results suggest that epigenetic variation can be an important source of intraspecific functional diversity in H. foetidus, possibly endowing this species with the capacity to exploit a broad range of ecological conditions despite its modest genetic diversity. © 2014 John Wiley & Sons Ltd.

Angiotensin-Converting Enzyme I/D Polymorphism and Preeclampsia Risk: Evidence of Small-Study Bias

PubMed Central

Serrano, Norma C; Díaz, Luis A; Páez, Maria C; Mesa, Clara M; Cifuentes, Rodrigo; Monterrosa, Alvaro; González, Adriana; Smeeth, Liam; Hingorani, Aroon D; Casas, Juan P

2006-01-01

Background Inappropriate activation of the renin–angiotensin system may play a part in the development of preeclampsia. An insertion/deletion polymorphism within the angiotensin-I converting enzyme gene (ACE-I/D) has shown to be reliably associated with differences in angiotensin-converting enzyme (ACE) activity. However, previous studies of the ACE-I/D variant and preeclampsia have been individually underpowered to detect plausible genotypic risks. Methods and Findings A prospective case-control study was conducted in 1,711 unrelated young pregnant women (665 preeclamptic and 1,046 healthy pregnant controls) recruited from five Colombian cities. Maternal blood was obtained to genotype for the ACE-I/D polymorphism. Crude and adjusted odds ratio (OR) and 95% confidence interval (CI) using logistic regression models were obtained to evaluate the strength of the association between ACE-I/D variant and preeclampsia risk. A meta-analysis was then undertaken of all published studies to February 2006 evaluating the ACE-I/D variant in preeclampsia. An additive model (per-D-allele) revealed a null association between the ACE-I/D variant and preeclampsia risk (crude OR = 0.95 [95% CI, 0.81–1.10]) in the new case-control study. Similar results were obtained after adjusting for confounders (adjusted per-allele OR = 0.90 [95% CI, 0.77–1.06]) and using other genetic models of inheritance. A meta-analysis (2,596 cases and 3,828 controls from 22 studies) showed a per-allele OR of 1.26 (95% CI, 1.07–1.49). An analysis stratified by study size showed an attenuated OR toward the null as study size increased. Conclusions It is highly likely that the observed small nominal increase in risk of preeclampsia associated with the ACE D-allele is due to small-study bias, similar to that observed in cardiovascular disease. Reliable assessment of the origins of preeclampsia using a genetic approach may require the establishment of a collaborating consortium to generate a dataset of adequate size. PMID:17194198

Tumor necrosis factor-308 polymorphism increases the embryo implantation rate in women undergoing in vitro fertilization.

PubMed

Vialard, F; El Sirkasi, M; Tronchon, V; Boudjenah, R; Molina-Gomes, D; Bergere, M; Mauduit, C; Wainer, R; Selva, J; Benahmed, M

2013-10-01

Do TNF-308 and -238 polymorphisms impact the embryo implantation rate after in vitro fertilization (IVF) in women without female infertility factor? The presence of the TNF-308A allele is associated with high implantation and multiple pregnancy rates in women without known infertility factors after ovarian hyperstimulation with exogenous FSH. Multiple pregnancies are frequent after the use of Assisted Reproductive Technologies. Single embryo transfer (SET) has been proposed as a simple way to prevent these risks. However, the extension of SET indications to patients not selected based on specific criteria is controversial because of reduced pregnancy rates. To date, the predictive value of the parameters used for SET (age, gynecological history of the patient and uterine characteristics) allows a pregnancy rate of ~30%. The potential predictive value of TNF polymorphisms (-308, rs1800629 and -238, rs361525) on implantation rate was evaluated in 424 women requiring IVF due to male fertility factors. This cohort retrospective study was conducted over 4 years in University-affiliated hospitals. The entire patient group included 424 women undergoing intracytoplasmic sperm injection (ICSI) due to male fertility factors without the contribution of any female factor. From among this group, a selected patient group included 120 women with a normal karyotype, age under 38 years, serum follicle-stimulating hormone (Day-3 FSH) levels below 10 IU/l, a long agonist desensitization protocol associated with recombinant FSH treatment and a Caucasian background. The TNF-238 polymorphism was not associated with implantation rate. In contrast, the presence of the TNF-308A allele was associated with increased Day 3-E2 levels as well as higher implantation and multiple pregnancy rates after fresh embryo transfer in women from the entire and selected patient groups. Moreover, in the selected patient group, the presence of the TNF-308A allele was also associated with a decrease in the miscarriage rate. The benefit of the TNF-308A allele in predicting implantation rates was not observed after the use of frozen embryos. Future studies are needed to evaluate whether the TNF-308A allele might also be a biomarker in women with infertility factors. The TNF-308A allele may represent a good candidate for a potential predictive, non-invasive biomarker in the SET strategy. However, its impact should be evaluated in prospective studies. This study was conducted with financial support from the French Institute for Health and Medical Research (INSERM), Organon France for a FARO (Fond d'Aide à la Recherche Organon) fellowship (to V.T.) and CHU Nice PHRC (PHRC 09-279).There are no competing interests.

Assessment of genetic relationship in Persea spp by traditional molecular markers.

PubMed

Reyes-Alemán, J C; Valadez-Moctezuma, E; Barrientos-Priego, A F

2016-04-04

Currently, the reclassification of the genus Persea is under discussion with molecular techniques for DNA analysis representing an alternative for inter- and intra-specific differentiation. In the present study, the traditional random-amplified polymorphic DNA (RAPD) and the inter simple sequence repeat (ISSR) markers were used to determine the genomic relationship of different species and hybrids representative of the subgenera Eriodaphne and Persea in a population conserved in a germplasm bank. The data were analyzed statistically using multivariate methods. In the RAPD analysis, a total of 190 polymorphic bands were produced, with an average of 23.7 bands per primer, the percentage contribution of each primer was from 7.66 to 19.63; the polymorphic information content (PIC) ranged from 0.23 to 0.45, with an average of 0.35. In the ISSR analysis, a total of 111 polymorphic bands were considered, with an average of 18.5 bands per primer, the percentage contribution of each was from 11.83 to 19.57; the PIC ranged from 0.35 to 0.48, with an average of 0.42. The phenograms obtained in each technique showed the relationship among the accessions through the clusters formed. In general, both the techniques grouped representatives of the Persea americana races (P. americana var. drymifolia, P. americana var. guatemalensis, and P. americana var. americana). However, it was not possible to separate the species of Persea used as reference into independent clades. In addition, they tended to separate the representatives of subgenera Eriodaphne and Persea.

Influence of IFNL3 and HLA-DPB1 genotype on postpartum control of hepatitis C virus replication and T-cell recovery.

PubMed

Honegger, Jonathan R; Tedesco, Dana; Kohout, Jennifer A; Prasad, Mona R; Price, Aryn A; Lindquist, Tera; Ohmer, Samantha; Moore-Clingenpeel, Melissa; Grakoui, Arash; Walker, Christopher M

2016-09-20

Chronic hepatitis C virus (HCV) infection is characterized by exhaustion of virus-specific T-cells and stable viremia. Pregnancy is an exception. Viremia gradually climbs during gestation but sometimes declines sharply in the months following delivery. Here, we demonstrated that postpartum HCV control was associated with enhanced virus-specific T-cell immunity. Women with viral load declines of at least 1 log10 between the third trimester and 3-mo postpartum exhibited HCV-specific T-cell responses of greater breadth (P = 0.0052) and magnitude (P = 0.026) at 3-mo postpartum than women who failed to control viremia. Moreover, viral dynamics were consistent in women after consecutive pregnancies, suggesting genetic underpinnings. We therefore searched for genetic associations with human leukocyte antigen (HLA) alleles and IFN-λ3 gene (IFNL3) polymorphisms that influence HCV infection outcome. Postpartum viral control was associated with the IFNL3 rs12979860 genotype CC (P = 0.045 at 6 mo) that predicts a positive response to IFN-based therapy. Suppression of virus replication after pregnancy was also strongly influenced by the HLA class II DPB1 locus. HLA-DPB1 alleles are classified by high and low patterns of expression. Carriage of at least one high-expression HLA-DPB1 allele predicted resurgent virus-specific T-cell immunity and viral control at 3-mo postpartum (P = 0.0002). When considered together in multivariable analysis, IFNL3 and HLA-DPB1 independently affected viral control at 3- and 6-mo postpartum. Together, these findings support a model where spontaneous control of HCV such as sometimes follows pregnancy is governed by genetic polymorphisms that affect type III IFN signaling and virus-specific cellular immune responses.

The carriers of the A/G-G/G allelic combination of the c.2039 A>G and c.-29 G>A FSH receptor polymorphisms retrieve the highest number of oocytes in IVF/ICSI cycles.

PubMed

Allegra, Adolfo; Marino, Angelo; Raimondo, Stefania; Maiorana, Antonio; Gullo, Salvatore; Scaglione, Piero; Volpes, Aldo; Alessandro, Riccardo

2017-02-01

The objective of this study was the elucidation of the possible role of the single-nucleotide polymorphisms (SNP) at position -29 and 2039 of the FSH receptor gene (FSHR) as independent predictive markers of ovarian response. Indeed, the tailoring of reproductive treatments is crucial for both maximizing the success of IVF patients and obtaining a reduction in hypo- or hyper-response rates. This prospective, observational study analyzed the association of -29 and 2039 FSHR polymorphisms with the number of retrieved oocytes in 140 patients attending an IVF/ICSI cycle for severe male factors (≤5,000,000 spermatozoa/mL) or tubal factors at the ANDROS Day Surgery Clinic, Palermo, Italy. The results of this study demonstrate that the genetic combination of A/G for polymorphism c.2039 A>G with G/G for polymorphism c.-29 G>A is significantly associated with the highest number of collected oocytes (p = 0.03). This association was significant even after controlling for the effect of other clinical variables. The A/G-G/G allelic variant, identified as an independent variable, if confirmed in a larger number of patients, could be considered as a new genetic biomarker, which could increase the efficacy of prediction models for ovarian stimulation.

Methylenetetrahydrofolate reductase C677T polymorphism predicts response and time to progression to gemcitabine-based chemotherapy for advanced non-small cell lung cancer in a Chinese Han population*

PubMed Central

Hong, Wei; Wang, Kai; Zhang, Yi-ping; Kou, Jun-yan; Hong, Dan; Su, Dan; Mao, Wei-min; Yu, Xin-min; Xie, Fa-jun; Wang, Xiao-jian

2013-01-01

Objective: The aim of this study was to evaluate the association between the methylenetetrahydrofolate reductase (MTHFR) C677T excision repair cross-complementation group 1 (ERCC1) genetic polymorphisms and the clinical efficacy of gemcitabine-based chemotherapy in advanced non-small cell lung cancer (NSCLC). Methods: A total of 135 chemonaive patients with unresectable advanced NSCLC were treated with gemcitabine/platinum regimens. The polymorphisms of MTHFR C677T, ERCC1 C8092A, and ERCC1 C118T were genotyped using the TaqMan methods. Results: The overall response rate was 28.9%. Patients with MTHFR CC genotype had a higher rate of objective response than patients with variant genotype (TT or CT) (41.2% versus 19.1%, P=0.01). Median time to progression (TTP) of patients with MTHFR CC genotype was longer than that of patients with variant genotype (7.6 months versus 5.0 months, P=0.003). No significant associations were obtained between ERCC1 C118T and C8092A polymorphisms and both response and survival. Conclusions: Our data suggest the value of MTHFR C677T polymorphism as a possible predictive marker of response and TTP in advanced NSCLC patients treated with gemcitabine/platinum. PMID:23463763

Association of donor and recipient SUMO4 rs237025 genetic variant with new-onset diabetes mellitus after liver transplantation in a Chinese population.

PubMed

Zhang, Tao; Liu, Yuan; Hu, Yibo; Zhang, Xiaoqing; Zhong, Lin; Fan, Junwei; Peng, Zhihai

2017-09-05

New-onset diabetes mellitus (NODM) is a common complication after liver transplantation (LT). The small ubiquitin-like modifier 4 (SUMO4) rs237025 polymorphism has been reported to be associated with type 2 diabetes mellitus (T2DM). In this study, we aimed to evaluate the association of donor and recipient SUMO4 rs237025 polymorphisms with NODM and the long-term consequences of NODM after LT. A total of 126 liver transplant patients were enrolled in the study. One single nucleotide polymorphism, SUMO4 rs237025, was genotyped in both donors and recipients. Both donor and recipient SUMO4 rs237025 polymorphisms were found to be significantly associated with NODM after LT. In multivariate analysis, recipient age>50 years, tacrolimus trough concentrations>10ng/mL at 1month after LT, donor and recipient rs237025 genetic variant, and the combined donor and recipient rs237025 genetic variant were independent predictive factors of NODM. Area under the receiver operating characteristic curve (AUROC) analysis indicated the higher predictive ability of the model containing combined donor and recipient rs237025 polymorphisms than the clinical model (p=0.046). Furthermore, Kaplan-Meier survival analysis demonstrated that NODM was related to significantly poorer patient survival in comparison with non-NODM patients (p=0.041). Both donor and recipient SUMO4 rs237025 polymorphisms contribute to the development of NODM after LT and NODM is a frequent complication that negatively affects patient survival. Copyright © 2017. Published by Elsevier B.V.

Identification and characterization of transcript polymorphisms in soybean lines varying in oil composition and content

PubMed Central

2014-01-01

Background Variation in seed oil composition and content among soybean varieties is largely attributed to differences in transcript sequences and/or transcript accumulation of oil production related genes in seeds. Discovery and analysis of sequence and expression variations in these genes will accelerate soybean oil quality improvement. Results In an effort to identify these variations, we sequenced the transcriptomes of soybean seeds from nine lines varying in oil composition and/or total oil content. Our results showed that 69,338 distinct transcripts from 32,885 annotated genes were expressed in seeds. A total of 8,037 transcript expression polymorphisms and 50,485 transcript sequence polymorphisms (48,792 SNPs and 1,693 small Indels) were identified among the lines. Effects of the transcript polymorphisms on their encoded protein sequences and functions were predicted. The studies also provided independent evidence that the lack of FAD2-1A gene activity and a non-synonymous SNP in the coding sequence of FAB2C caused elevated oleic acid and stearic acid levels in soybean lines M23 and FAM94-41, respectively. Conclusions As a proof-of-concept, we developed an integrated RNA-seq and bioinformatics approach to identify and functionally annotate transcript polymorphisms, and demonstrated its high effectiveness for discovery of genetic and transcript variations that result in altered oil quality traits. The collection of transcript polymorphisms coupled with their predicted functional effects will be a valuable asset for further discovery of genes, gene variants, and functional markers to improve soybean oil quality. PMID:24755115

Is colour polymorphism advantageous to populations and species?

PubMed

Forsman, Anders

2016-06-01

I am writing in response to an article by Bolton, Rollins and Griffith (2015) entitled 'The danger within: the role of genetic, behavioural and ecological factors in population persistence of colour polymorphic species' that was recently published as an Opinion under the NEWS AND VIEWS section in Molecular Ecology. Bolton et al. (Molecular Ecology, 2015, 24, 2907) argue that colour polymorphism may reduce population fitness and increase extinction risk and emphasize that this is contrary to predictions put forward by Forsman et al. (Ecology, 89, 2008, 34) and Wennersten & Forsman (Biological Reviews 87, 2012, 756) that the existence of multiple colour morphs with co-adapted gene complexes and associated trait values may increase the ecological and evolutionary success of polymorphic populations and species. Bolton et al. (Molecular Ecology, 2015, 24, 2907) further state that there is no clear evidence from studies of 'true polymorphic species' that polymorphism promotes population persistence. In response, I (i) challenge their classifications of polymorphisms and revisit the traditional definitions recognizing the dynamic nature of polymorphisms, (ii) review empirical studies that have examined whether and how polymorphism is associated with extinction risk, (iii) discuss the roles of trait correlations between colour pattern and other phenotypic dimensions for population fitness and (iv) highlight that the causes and mechanisms that influence the composition and maintenance of polymorphisms are different from the consequences of the polymorphic condition and how it may impact on aspects of ecological success and long-term persistence of populations and species. © 2016 John Wiley & Sons Ltd.

Association of the TYMS 3G/3G genotype with poor response and GGH 354GG genotype with the bone marrow toxicity of the methotrexate in RA patients.

PubMed

Jekic, Biljana; Lukovic, Ljiljana; Bunjevacki, Vera; Milic, Vera; Novakovic, Ivana; Damnjanovic, Tatjana; Milasin, Jelena; Popovic, Branka; Maksimovic, Nela; Damjanov, Nemanja; Radunovic, Goran; Kovacevic, Ljiljana; Krajinovic, Maja

2013-03-01

Gamma-glutamyl hydrolase (GGH), cyclin D1 (CCND1) and thymidylate synthase (TS) genes encode enzymes that are involved in methotrexate (MTX) action. In a group of 184 RA patients treated with MTX, we have investigated whether selected polymorphisms in these genes modulate MTX efficacy and/or have impact on adverse drug effects (ADEs). The efficacy of the MTX therapy has been estimated using the disease activity score in 28 joints (DAS28-ESR) based on EULAR criteria and relative DAS28 values (rDAS28). All adverse drug events were recorded. Patients were genotyped for selected polymorphisms of the GGH (-354 G > T and 452 C > T), CCND1 (870 A > G) and TYMS (variable number of tandem repeats, VNTR, and G to C substitution of triple repeat, 3R allele) gene. Association studies have been performed between obtained genotypes and the efficacy and toxicity of MTX. According to the EULAR response criteria, 146 RA patients (79.3 %) were classified as responders (good/moderate response) and 38 (20.7 %) as non-responders (poor response). Higher frequency of the TYMS 3 G/3 G genotype has been found among non-responders as compared to individuals with remaining genotypes (p = 0.02). ADEs were recorded in 53 patients. Among those patients eight experienced bone marrow toxicity, all of them carried GGH -354GG genotype (p = 0.003). No other significant association were observed. The 3 G/3 G genotype of the TYMS gene may indicate predisposition of poor response to MTX and GG genotype of GGH -354 T > G polymorphism may have high predictive value for myelosuppression in RA patients.

Interaction of TLR-IFN and HLA polymorphisms on susceptibility of chronic HBV infection in Southwest Han Chinese.

PubMed

He, Dengming; Tao, Shiqi; Guo, Shimin; Li, Maoshi; Wu, Junqiu; Huang, Hongfei; Guo, Xinwu; Yan, Guohua; Zhu, Peng; Wang, Yuming

2015-08-01

The toll-like receptor-interferon (TLR-IFN) signalling pathway plays a crucial role in HBV infection. Human leucocyte antigen (HLA) polymorphisms are associated with chronic HBV infection by genome wide association study (GWAS). We aimed to explore interaction between TLR-IFN and HLA gene polymorphisms in susceptibility of chronic HBV infection. In the Chinese Southwest Han population, 1191 chronic HBV infection patients and 273 HBV clearance were selected. A total of 39 single nucleotide polymorphism loci in 23 genes of the TLR-IFN pathway and four HLA polymorphism loci associated with chronic HBV infection identified by GWAS were selected for genotyping. SNPStats, QVALUE, and multifactor dimensionality reduction were used for statistical analysis. A significant association was seen in several of the TLR-IFN pathway genes, TLR9 rs352140 (OR = 0.70, P = 0.0088), IL1B rs16944 (OR = 0.67, P = 0.016), IL12B rs3212227 (OR = 1.38, P = 0.021), IFNGR1 rs3799488 (OR = 1.48, P = 0.0048), IFNGR2 rs1059293 (OR = 0.27, P = 0.011), MX1 rs467960 (OR = 0.68, P = 0.022), as well as four loci in HLA, rs3077 (OR = 0.55, P < 0.0001), rs2856718 (OR = 0.60, P = 4e-04), rs9277535 (OR = 0.54, P < 0.0001) and rs7453920 (OR = 0.43, P < 0.0001). A synergistic relationship was seen between rs9277535 and rs16944 (0.13%), rs1143623 and rs6613 (0.10%). The combination of rs9277535 in HLA and rs16944 in IL1B was the best model to predict chronic HBV infection (testing accuracy = 0.6040, P = 0.0010, cross-validation consistency = 10/10). TLR-IFN pathway gene polymorphisms are associated with chronic HBV infection. Interactions with polymorphisms in these genes may be one mechanism by which HLA polymorphisms influence susceptibility to chronic HBV infection, as specific single nucleotide polymorphism combinations are highly predictive of chronic HBV infection. © 2014 The Authors. Liver International Published by John Wiley & Sons Ltd.

The Nominal/Generic Specific Heat per Average Atom Concept for CHNO Energetic Materials

DTIC Science & Technology

2006-07-01

Heat Per Average Atom for TATB. RDX . TNT. HMX . and HNS... HMX can exist in different solid polymorphic forms. At a certain temperature, TT, one form may change to another form if the heat energy of...densities ( p. ) up to, and including, crystals at TMD for TNT, RDX , HMX , and TATB. The presently proposed N/G CP magnitude, in certain temperature

ATM Polymorphisms Predict Severe Radiation Pneumonitis in Patients With Non-Small Cell Lung Cancer Treated With Definitive Radiation Therapy

DOE Office of Scientific and Technical Information (OSTI.GOV)

Xiong, Huihua; Department of Epidemiology, The University of Texas MD Anderson Cancer Center, Houston, Texas; Liao, Zhongxing, E-mail: zliao@mdanderson.org

2013-03-15

Purpose: The ataxia telangiectasia mutated (ATM) gene mediates detection and repair of DNA damage. We investigated associations between ATM polymorphisms and severe radiation-induced pneumonitis (RP). Methods and Materials: We genotyped 3 potentially functional single nucleotide polymorphisms (SNPs) of ATM (rs1801516 [D1853N/5557G>A], rs189037 [-111G>A] and rs228590) in 362 patients with non-small cell lung cancer (NSCLC), who received definitive (chemo)radiation therapy. The cumulative severe RP probabilities by genotypes were evaluated using the Kaplan-Meier analysis. The associations between severe RP risk and genotypes were assessed by both logistic regression analysis and Cox proportional hazard model with time to event considered. Results: Of 362more » patients (72.4% of non-Hispanic whites), 56 (15.5%) experienced grade ≥3 RP. Patients carrying ATM rs189037 AG/GG or rs228590 TT/CT genotypes or rs189037G/rs228590T/rs1801516G (G-T-G) haplotype had a lower risk of severe RP (rs189037: GG/AG vs AA, adjusted hazard ratio [HR] = 0.49, 95% confidence interval [CI], 0.29-0.83, P=.009; rs228590: TT/CT vs CC, HR=0.57, 95% CI, 0.33-0.97, P=.036; haplotype: G-T-G vs A-C-G, HR=0.52, 95% CI, 0.35-0.79, P=.002). Such positive findings remained in non-Hispanic whites. Conclusions: ATM polymorphisms may serve as biomarkers for susceptibility to severe RP in non-Hispanic whites. Large prospective studies are required to confirm our findings.« less

Associations of interleukin-1 gene cluster polymorphisms with C-reactive protein concentration and lung function decline in smoking-induced chronic obstructive pulmonary disease

PubMed Central

Wang, Yu; Shumansky, Karey; Sin, Don D; Man, SF Paul; Akhabir, Loubna; Connett, John E; Anthonisen, Nicholas R; Paré, Peter D; Sandford, Andrew J; He, Jian-Qing

2015-01-01

Objective: We reported association of haplotypes formed by IL-1b (IL1B)-511C/T (rs16944) and a variable number of tandem repeats (rs2234663) in intron 3 of IL-1 receptor antagonist (IL1RN) with rate of lung function decline in smoking-induced COPD. The aim of current study was to further investigate this association. Methods: We genotyped an additional 19 polymorphisms in IL1 cluster (including IL1A, IL1B and IL1RN) in non-Hispanic whites who had the fastest (n = 268) and the slowest (n = 292) decline of FEV1% predicted in the same study. We also analyzed the association of all 21 polymorphisms with serum CRP levels. Results: None of 21 polymorphisms showed significant association with rate of decline of lung function or CRP levels after adjusting for multiple comparisons. Before adjusting for multiple comparisons, only IL1RN_19327 (rs315949) showed significant association with lung function decline (P = 0.03, additive model). The frequencies of genotypes containing the IL1RN_19327A allele were 71.9% and 62.2%, respectively in the fast and slow decline groups (P = 0.02, odds ratio = 1.6, 95% confidence interval = 1.1-2.3); the IL1B_5200 (rs1143633) and rs2234663 in IL1RN were associated with serum CRP levels (P=0.04 and 0.03, respectively). Conclusions: No single marker was significantly associated with either rate of lung function decline or serum CRP levels. PMID:26722511

[Genetic diversity of wild Cynodon dactylon germplasm detected by SRAP markers].

PubMed

Yi, Yang-Jie; Zhang, Xin-Quan; Huang, Lin-Kai; Ling, Yao; Ma, Xiao; Liu, Wei

2008-01-01

Sequence-related amplified polymorphism (SRAP) molecular markers were used to detect the genetic diversity of 32 wild accessions of Cynodon dactylon collected from Sichuan, Chongqing, Guizhou and Tibet, China. The following results were obtained. (1) Fourteen primer pairs produced 132 polymorphic bands, averaged 9.4 bands per primer pair. The percentage of polymorphic bands in average was 79.8%. The Nei's genetic similarity coefficient of the tested accessions ranged from 0.591 to 0.957, and the average Nei's coefficient was 0.759. These results suggested that there was rich genetic diversity among the wild resources of Cynodon dactylon tested. (2) Thirty two wild accessions were clustered into four groups. Moreover, the accessions from the same origin frequently clustered into one group. The findings implied that a correlation among the wild resources, geographical and ecological environment. (3) Genetic differentiation between and within six eco-geographical groups of C. dactylon was estimated by Shannon's diversity index, which showed that 65.56% genetic variance existed within group, and 34.44% genetic variance was among groups. (4) Based on Nei's unbiased measures of genetic identity, UPGMA cluster analysis measures of six eco-geographical groups of Cynodon dactylon, indicated that there was a correlation between genetic differentiation and eco-geographical habits among the groups.

A novel MALDI–TOF based methodology for genotyping single nucleotide polymorphisms

PubMed Central

Blondal, Thorarinn; Waage, Benedikt G.; Smarason, Sigurdur V.; Jonsson, Frosti; Fjalldal, Sigridur B.; Stefansson, Kari; Gulcher, Jeffery; Smith, Albert V.

2003-01-01

A new MALDI–TOF based detection assay was developed for analysis of single nucleotide polymorphisms (SNPs). It is a significant modification on the classic three-step minisequencing method, which includes a polymerase chain reaction (PCR), removal of excess nucleotides and primers, followed by primer extension in the presence of dideoxynucleotides using modified thermostable DNA polymerase. The key feature of this novel assay is reliance upon deoxynucleotide mixes, lacking one of the nucleotides at the polymorphic position. During primer extension in the presence of depleted nucleotide mixes, standard thermostable DNA polymerases dissociate from the template at positions requiring a depleted nucleotide; this principal was harnessed to create a genotyping assay. The assay design requires a primer- extension primer having its 3′-end one nucleotide upstream from the interrogated site. The assay further utilizes the same DNA polymerase in both PCR and the primer extension step. This not only simplifies the assay but also greatly reduces the cost per genotype compared to minisequencing methodology. We demonstrate accurate genotyping using this methodology for two SNPs run in both singleplex and duplex reactions. We term this assay nucleotide depletion genotyping (NUDGE). Nucleotide depletion genotyping could be extended to other genotyping assays based on primer extension such as detection by gel or capillary electrophoresis. PMID:14654708

Genetic variability of citrinin-producing Penicillium citrinum strains as occupational health hazards in northern Iran.

PubMed

Khosravi, Ali Reza; Sheikhkarami, Mojgan; Shokri, Hojjatollah; Sabokbar, Azar

2012-12-01

We evaluated the ability of randomly amplified polymorphic DNA (RAPD) to type citrinin-producing Penicillium citrinum (P. citrinum) strains recovered from the forest's air in northern Iran. A total of 12 P. citrinum strains (P1-P12) were characterised by citrinin production and random amplification of polymorphic DNA (RAPD) technique. All the strains produced citrinin with levels ranging from 1.5 μg mL(-1) to 39.6 μg mL(-1) (average value: 12.68 μg mL(-1)). Of 11 primers tested, eight primers produced polymorphic amplification patterns. These primers generated a total of 105 reproducible RAPD bands, averaging to 13.1 bands per primer. Dendrogram for each primer indicating the distance of the strains to each other was constructed. RAPD results showed that the collected strains constituted four different clusters. The first cluster included two isolates (P1 and P3). The second cluster included seven isolates (P2, P4, P5, P6, P7, P8, and P10). The third and fourth clusters included one isolate (P9) and two isolates (P11 and P12), respectively. We concluded that RAPD analysis might be used in providing genotypic characters for toxigenic P. citrinum strains typing in epidemiological investigations and public health related risk assessment.