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Sample records for promoter polymorphisms common

  1. TERT promoter mutations and rs2853669 polymorphism: prognostic impact and interactions with common alterations in glioblastomas.

    PubMed

    Nencha, Umberto; Rahimian, Amithys; Giry, Marine; Sechi, Andrea; Mokhtari, Karima; Polivka, Marc; Schmitt, Yohann; Di Stefano, Anna-Luisa; Alentorn, Agusti; Labussière, Marianne; Sanson, Marc

    2016-02-01

    TERT promoter (TERTp) mutation is the most common mutation in glioblastomas. It creates a putative binding site for Ets/TCF transcription factors, enhancing telomerase expression and activity, whereas the rs2853669 variant disrupts another Ets/TCF binding. We explore here the interaction between these two alterations, tumor genomic profile and the impact on prognosis. The TERTp and rs2853669 statuses were determined and confronted with the outcome and molecular profile, i.e., loss of chromosome 10q, CDKN2A deletion, IDH mutation, EGFR amplification, MGMT promoter methylation. 651 glioblastomas were selected (sex ratio = 1.35, median age 60.4 years, median survival 13.5 months). The TERTp mutation found in 481 patients (74 %) was independent from rs2853669 genotypes. TERTp mutation, but not rs2853669 status, was associated with older age (61.4 vs. 52.8 years). rs2853669 status had no impact on overall survival (OS) either in mutated TERTp or wild-type TERTp. Neither rs2736100 (TERT, 5q15.33) nor rs192011116 (TERC, 3q26.2) status had any impact on survival or showed any association with a TERTp mutation. The TERTp mutation was associated with EGFR amplification chromosome 10q loss, CDKN2A deletion and IDH wt. EGFR amplification was associated with a better outcome in TERTp mutated GBM, and a worse outcome in TERTp WT. This study-the largest analyzing the TERTp mutation and the rs2853669 polymorphism-fails to find any prognostic impact of rs2853669. It confirms the dual prognostic impact of EGFR amplification depending on TERTp status. PMID:26608520

  2. TERT promoter mutations in bladder cancer affect patient survival and disease recurrence through modification by a common polymorphism.

    PubMed

    Rachakonda, P Sivaramakrishna; Hosen, Ismail; de Verdier, Petra J; Fallah, Mahdi; Heidenreich, Barbara; Ryk, Charlotta; Wiklund, N Peter; Steineck, Gunnar; Schadendorf, Dirk; Hemminki, Kari; Kumar, Rajiv

    2013-10-22

    The telomerase reverse transcriptase (TERT) promoter, an important element of telomerase expression, has emerged as a target of cancer-specific mutations. Originally described in melanoma, the mutations in TERT promoter have been shown to be common in certain other tumor types that include glioblastoma, hepatocellular carcinoma, and bladder cancer. To fully define the occurrence and effect of the TERT promoter mutations, we investigated tumors from a well-characterized series of 327 patients with urothelial cell carcinoma of bladder. The somatic mutations, mainly at positions -124 and -146 bp from ATG start site that create binding motifs for E-twenty six/ternary complex factors (Ets/TCF), affected 65.4% of the tumors, with even distribution across different stages and grades. Our data showed that a common polymorphism rs2853669, within a preexisting Ets2 binding site in the TERT promoter, acts as a modifier of the effect of the mutations on survival and tumor recurrence. The patients with the mutations showed poor survival in the absence [hazard ratio (HR) 2.19, 95% confidence interval (CI) 1.02-4.70] but not in the presence (HR 0.42, 95% CI 0.18-1.01) of the variant allele of the polymorphism. The mutations in the absence of the variant allele were highly associated with the disease recurrence in patients with Tis, Ta, and T1 tumors (HR 1.85, 95% CI 1.11-3.08). The TERT promoter mutations are the most common somatic lesions in bladder cancer with clinical implications. The association of the mutations with patient survival and disease recurrence, subject to modification by a common polymorphism, can be a unique putative marker with individualized prognostic potential. PMID:24101484

  3. Habitat-based polymorphism is common in stream fishes.

    PubMed

    Senay, Caroline; Boisclair, Daniel; Peres-Neto, Pedro R

    2015-01-01

    Morphological differences (size and shape) across habitats are common in lake fish where differences relate to two dominant contrasting habitats: the pelagic and littoral habitat. Repeated occurrence of littoral and pelagic morphs across multiple populations of several lake fish species has been considered as important evidence that polymorphism is adaptive in these systems. It has been suggested that these habitat-based polymorphic differences are due to the temporal stability of the differences between littoral and pelagic habitats. Although streams are spatially heterogeneous, they are also more temporally dynamic than lakes and it is still an open question whether streams provide the environmental conditions that promote habitat-based polymorphism. We tested whether fish from riffle, run and pool habitats, respectively, differed consistently in their morphology. Our test compared patterns of morphological variation (size and shape) in 10 fish species from the three stream habitat types in 36 separate streams distributed across three watersheds. For most species, body size and shape (after controlling for body size) differed across riffle, run and pool habitats. Unlike many lake species, the nature of these differences was not consistent across species, possibly because these species use these habitat types in different ways. Our results suggest that habitat-based polymorphism is an important feature also in stream fishes despite the fact that streams are temporally variable in contrast to lake systems. Future research is required to assess whether the patterns of habitat-based polymorphism encountered in streams have a genetic basis or they are simply the result of within generation phenotypic plasticity. PMID:25041645

  4. Data describing the effect of DRD4 promoter polymorphisms on promoter activity.

    PubMed

    Tei, Shoin; Mitsuhashi, Hiroaki; Ishiura, Shoichi

    2016-06-01

    This data article tested whether polymorphisms within the dopamine D4 receptor (DRD4) gene promoter can lead to differences in the promoter activity. The variants, a 120-bp variable number tandem repeat (VNTR), -906 T/C, -809 G/A, -616G/C, and -521C/T, were introduced into the DRD4 promoter and the promoter activity was measured in a neural cell line using the luciferase assay. However, no differences were detected among the haplotypes investigated, and the in vitro data obtained from our protocol could not support the involvement of DRD4 promoter polymorphisms in heritable human traits. PMID:27115024

  5. [The β-amylase polymorphism of winter common wheat grains].

    PubMed

    Netsvetaev, V P; Akinshina, O V; Bondarenko, L S; Motorina, I P

    2012-02-01

    The polymorphism of winter common wheat with respect to β-amylase isoenzymes has been analyzed using electrophoresis in polyacrylamide gel (PAAG) buffered with a Tris-glycine system (pH 8.3). Seven β-amylase isoenzymes have been found in wheat cultivars and the breeding stock. Isoenzymes A, B, and C are the most frequent in Russian and Ukrainian cultivars (51.7 4.7, 30.7 3.8, and 11.9 2.5%, respectively). Two alleles of the β-Amy-D1 locus of the long arm of chromosome 4D have been identified. The substrate-enzyme affine effect can be used to locate the zones of activity of this enzyme by means of staining for proteins. It has been determined that β-amylase zymotypes may play a role in the aggregating capacity of the grain protein complex via the formation of S-S bonds. PMID:22567995

  6. Promoter polymorphisms regulating corticotrophin-releasing hormone transcription in vitro.

    PubMed

    Wagner, U; Wahle, M; Moritz, F; Wagner, U; Häntzschel, H; Baerwald, C G O

    2006-02-01

    To investigate whether polymorphisms in the corticotrophin-releasing hormone (CRH) promoter are associated with altered CRH gene regulation, we studied the reactivity of three recently described promoter variants in vitro. The 3625 bp variants A1B1, A2B1 and A2B2 of the human CRH promoter were cloned in the 5' region to a luciferase reporter gene and transiently transfected into both mouse anterior pituitary cells AtT-20D16vF2 and pheochromocytoma cells PC12. Incubation with 8-Br-cAMP alone or in combination with cytokines significantly enhanced the promoter activity in both cell lines studied by up to 22-fold. However, dexamethasone antagonised cAMP effects on CRH expression in AtT-20 cells while showing no effect on PC12 cells, indicating that tissue-specific factors play a crucial role. Among the haplotypes studied, A1B1 exhibited the greatest reactivity on various stimuli. Electric mobility shift assay (EMSA) was performed to study whether the described polymorphic nucleotide sequences in the 5' region of the hCRH gene interfere with binding of nuclear proteins. A specific DNA protein complex was detected at position -2353 bp for the wild type sequence only, possibly interfering with a binding site for the activating transcription factor 6 (ATF6). Taken together, this is the first study to demonstrate that CRH promoter reactivity varies between the compound promoter alleles. PMID:16523405

  7. Single nucleotide polymorphisms in common bean: their discovery and genotyping using a multiplex detection system

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Single-nucleotide Polymorphism (SNP) markers are by far the most common form of DNA polymorphism in a genome. The objectives of this study were to discover SNPs in common bean comparing sequences from coding and non-coding regions obtained from Genbank and genomic DNA and to compare sequencing resu...

  8. Common genetic polymorphisms affect the human requirement for the nutrient choline

    PubMed Central

    da Costa, Kerry-Ann; Kozyreva, Olga G.; Song, Jiannan; Galanko, Joseph A.; Fischer, Leslie M.; Zeisel, Steven H.

    2006-01-01

    Humans eating diets deficient in the essential nutrient choline can develop organ dysfunction. We hypothesized that common single nucleotide polymorphisms (SNPs) in genes involved in choline metabolism influence the dietary requirement of this nutrient. Fifty-seven humans were fed a low choline diet until they developed organ dysfunction or for up to 42 days. We tested DNA SNPs for allelic association with susceptibility to developing organ dysfunction associated with choline deficiency. We identified an SNP in the promoter region of the phosphatidylethanolamine N-methyltransferase gene (PEMT; −744 G→C; rs12325817) for which 18 of 23 carriers of the C allele (78%) developed organ dysfunction when fed a low choline diet (odds ratio 25, P=0.002). The first of two SNPs in the coding region of the choline dehydrogenase gene (CHDH; +318 A→C; rs9001) had a protective effect on susceptibility to choline deficiency, while a second CHDH variant (+432 G→T; rs12676) was associated with increased susceptibility to choline deficiency. A SNP in the PEMT coding region (+5465 G→A; rs7946) and a betaine:homocysteine methyl-transferase (BHMT) SNP (+742 G→A; rs3733890) were not associated with susceptibility to choline deficiency. Identification of common polymorphisms that affect dietary requirements for choline could enable us to identify individuals for whom we need to assure adequate dietary choline intake.—da Costa, K.-A., Kozyreva, O. G., Song, J., Galanko, J. A., Fischer, L. M., Zeisel, S. H. Common genetic polymorphisms affect the human requirement for the nutrient choline. PMID:16816108

  9. Common Genetic Polymorphisms Influence Blood Biomarker Measurements in COPD

    PubMed Central

    Drummond, M. Bradley; Hawkins, Gregory A.; Yang, Jenny; Chen, Ting-huei; Quibrera, Pedro Miguel; Anderson, Wayne; Barr, R. Graham; Bleecker, Eugene R.; Beaty, Terri; Casaburi, Richard; Castaldi, Peter; Cho, Michael H.; Comellas, Alejandro; Crapo, James D.; Criner, Gerard; Demeo, Dawn; Christenson, Stephanie A.; Couper, David J.; Doerschuk, Claire M.; Freeman, Christine M.; Gouskova, Natalia A.; Han, MeiLan K.; Hanania, Nicola A.; Hansel, Nadia N.; Hersh, Craig P.; Hoffman, Eric A.; Kaner, Robert J.; Kanner, Richard E.; Kleerup, Eric C.; Lutz, Sharon; Martinez, Fernando J.; Meyers, Deborah A.; Peters, Stephen P.; Regan, Elizabeth A.; Rennard, Stephen I.; Scholand, Mary Beth; Silverman, Edwin K.; Woodruff, Prescott G.; O’Neal, Wanda K.; Bowler, Russell P.

    2016-01-01

    Implementing precision medicine for complex diseases such as chronic obstructive lung disease (COPD) will require extensive use of biomarkers and an in-depth understanding of how genetic, epigenetic, and environmental variations contribute to phenotypic diversity and disease progression. A meta-analysis from two large cohorts of current and former smokers with and without COPD [SPIROMICS (N = 750); COPDGene (N = 590)] was used to identify single nucleotide polymorphisms (SNPs) associated with measurement of 88 blood proteins (protein quantitative trait loci; pQTLs). PQTLs consistently replicated between the two cohorts. Features of pQTLs were compared to previously reported expression QTLs (eQTLs). Inference of causal relations of pQTL genotypes, biomarker measurements, and four clinical COPD phenotypes (airflow obstruction, emphysema, exacerbation history, and chronic bronchitis) were explored using conditional independence tests. We identified 527 highly significant (p < 8 X 10−10) pQTLs in 38 (43%) of blood proteins tested. Most pQTL SNPs were novel with low overlap to eQTL SNPs. The pQTL SNPs explained >10% of measured variation in 13 protein biomarkers, with a single SNP (rs7041; p = 10−392) explaining 71%-75% of the measured variation in vitamin D binding protein (gene = GC). Some of these pQTLs [e.g., pQTLs for VDBP, sRAGE (gene = AGER), surfactant protein D (gene = SFTPD), and TNFRSF10C] have been previously associated with COPD phenotypes. Most pQTLs were local (cis), but distant (trans) pQTL SNPs in the ABO blood group locus were the top pQTL SNPs for five proteins. The inclusion of pQTL SNPs improved the clinical predictive value for the established association of sRAGE and emphysema, and the explanation of variance (R2) for emphysema improved from 0.3 to 0.4 when the pQTL SNP was included in the model along with clinical covariates. Causal modeling provided insight into specific pQTL-disease relationships for airflow obstruction and emphysema. In

  10. Common Genetic Polymorphisms Influence Blood Biomarker Measurements in COPD.

    PubMed

    Sun, Wei; Kechris, Katerina; Jacobson, Sean; Drummond, M Bradley; Hawkins, Gregory A; Yang, Jenny; Chen, Ting-Huei; Quibrera, Pedro Miguel; Anderson, Wayne; Barr, R Graham; Basta, Patricia V; Bleecker, Eugene R; Beaty, Terri; Casaburi, Richard; Castaldi, Peter; Cho, Michael H; Comellas, Alejandro; Crapo, James D; Criner, Gerard; Demeo, Dawn; Christenson, Stephanie A; Couper, David J; Curtis, Jeffrey L; Doerschuk, Claire M; Freeman, Christine M; Gouskova, Natalia A; Han, MeiLan K; Hanania, Nicola A; Hansel, Nadia N; Hersh, Craig P; Hoffman, Eric A; Kaner, Robert J; Kanner, Richard E; Kleerup, Eric C; Lutz, Sharon; Martinez, Fernando J; Meyers, Deborah A; Peters, Stephen P; Regan, Elizabeth A; Rennard, Stephen I; Scholand, Mary Beth; Silverman, Edwin K; Woodruff, Prescott G; O'Neal, Wanda K; Bowler, Russell P

    2016-08-01

    Implementing precision medicine for complex diseases such as chronic obstructive lung disease (COPD) will require extensive use of biomarkers and an in-depth understanding of how genetic, epigenetic, and environmental variations contribute to phenotypic diversity and disease progression. A meta-analysis from two large cohorts of current and former smokers with and without COPD [SPIROMICS (N = 750); COPDGene (N = 590)] was used to identify single nucleotide polymorphisms (SNPs) associated with measurement of 88 blood proteins (protein quantitative trait loci; pQTLs). PQTLs consistently replicated between the two cohorts. Features of pQTLs were compared to previously reported expression QTLs (eQTLs). Inference of causal relations of pQTL genotypes, biomarker measurements, and four clinical COPD phenotypes (airflow obstruction, emphysema, exacerbation history, and chronic bronchitis) were explored using conditional independence tests. We identified 527 highly significant (p < 8 X 10-10) pQTLs in 38 (43%) of blood proteins tested. Most pQTL SNPs were novel with low overlap to eQTL SNPs. The pQTL SNPs explained >10% of measured variation in 13 protein biomarkers, with a single SNP (rs7041; p = 10-392) explaining 71%-75% of the measured variation in vitamin D binding protein (gene = GC). Some of these pQTLs [e.g., pQTLs for VDBP, sRAGE (gene = AGER), surfactant protein D (gene = SFTPD), and TNFRSF10C] have been previously associated with COPD phenotypes. Most pQTLs were local (cis), but distant (trans) pQTL SNPs in the ABO blood group locus were the top pQTL SNPs for five proteins. The inclusion of pQTL SNPs improved the clinical predictive value for the established association of sRAGE and emphysema, and the explanation of variance (R2) for emphysema improved from 0.3 to 0.4 when the pQTL SNP was included in the model along with clinical covariates. Causal modeling provided insight into specific pQTL-disease relationships for airflow obstruction and emphysema. In

  11. Transcriptional Regulation of the Human P450 Oxidoreductase Gene: Hormonal Regulation and Influence of Promoter Polymorphisms

    PubMed Central

    Tee, Meng Kian; Huang, Ningwu; Damm, Izabella

    2011-01-01

    P450 oxidoreductase (POR) is the flavoprotein that acts as the obligatory electron donor to all microsomal P450 enzymes, including those involved in hepatic drug metabolism as well as three steroidogenic P450 enzymes. The untranslated first exon of human POR was located recently, permitting analysis of human POR transcription. Expression of deletional mutants containing up to 3193 bp of the human POR promoter in human adrenal NCI-H295A and liver Hep-G2 cells located the proximal promoter at −325/−1 bp from the untranslated exon. Common human POR polymorphisms at −208 and −173 had little influence on transcription, but the polymorphism at −152 reduced transcription significantly in both cell lines. EMSA and supershift assays identified binding of Smad3/Smad4 between −249 and −261 and binding of thyroid hormone receptor-β (TRβ) at −240/−245. Chromatin immunoprecipitation showed that Smad3, Smad4, TRα, TRβ, and estrogen receptor-α were bound between −374 and −149. Cotransfection of vectors for these transcription factors and POR promoter-reporter constructs into both cell types followed by hormonal treatment showed that T3 exerts major tropic effects via TRβ, with TRα, estrogen receptor-α, Smad3, and Smad4 exerting lesser, modulatory effects. T3 also increased POR mRNA in both cell lines. Thyroid hormone also is essential for rat liver POR expression but acts via different transcription factor complexes. These are the first data on human POR gene transcription, establishing roles for TRβ and Smad3/4 in its expression and indicating that the common polymorphism at −152 may play a role in genetic variation in steroid biosynthesis and drug metabolism. PMID:21393444

  12. [Genetic polymorphisms commonly influencing efficacy of diverse addictive substances].

    PubMed

    Nishizawa, Daisuke; Ikeda, Kazutaka

    2014-04-01

    Opioids, such as morphine and fentanyl, are widely used as effective analgesics for the treatment of acute and chronic pain. In addition, the opioid system has a key role in the rewarding effects of morphine, ethanol, cocaine and various other drugs. The authors have focused on G-protein-activated inwardly rectifying potassium (GIRK) channel subunits, GIRK2 and GIRK3, that are important molecules in opioid transmission, and found that the single-nucleotide polymorphisms (SNPs) within the GIRK2 and GIRK3 gene regions were significantly associated with postoperative requirements of analgesics including opioids in patients who underwent abdominal surgery and mRNA expression of these genes in postmortem specimens, one of which was also associated with vulnerability to methamphetamine (METH) dependence. Further, by conducting a multistage genome-wide association study (GWAS) in healthy subjects, the authors found that genetic polymorphisms within a linkage disequilibrium block that spans 2q33.3-2q34 were strongly associated with the requirements for postoperative opioid analgesics after painful cosmetic surgery. The C allele of the best candidate SNP, rs2952768, was associated with more analgesic requirements, and consistent results were obtained in patients who underwent abdominal surgery. In addition, carriers of the C allele in this SNP exhibited less vulnerability to severe drug dependence in patients with methamphetamine dependence, alcohol dependence, and eating disorders and a lower 'Reward Dependence score on a personality questionnaire in healthy subjects. Furthermore, the C/C genotype of this SNP was significantly associated with the elevated expression of a neighboring gene, CREB1. The results show that SNPs in this locus are the most potent genetic factors associated with human opioid sensitivity known to date, affecting both the efficacy of opioid analgesics and liability to severe substance dependence. These outcomes provide valuable information for the

  13. Interleukin 10 gene promoter polymorphisms in women with early-onset pre-eclampsia.

    PubMed

    Sowmya, S; Sri Manjari, K; Ramaiah, A; Sunitha, T; Nallari, P; Jyothy, A; Venkateshwari, A

    2014-11-01

    Pre-eclampsia is one of the most serious disorders of human pregnancy and T helper type 1 (Th1)/Th2 imbalance plays a major role in its aetiology. The Th2 cytokine, interleukin (IL)-10, plays a significant role in the maintenance of pregnancy. The present study is aimed at understanding the role of IL-10 promoter polymorphisms (-1082 G/A; -592 A/C and -819 C/T) and their haplotypes in early-onset pre-eclampsia. A total of 120 patients and an equal number of women with normal pregnancy, from Government Maternity Hospital, Petlaburz, Hyderabad, India, were considered for the present study. A standard amplification refractory mutation system-polymerase chain reaction (ARMS-PCR) was carried out for genotyping followed by agarose gel electrophoresis. Appropriate statistical methods were applied to test for the significance of the results. It was found that the IL-10 -819 C allele (P = 0·003) and -592 A (P = 0·005) allele frequencies increased significantly in patients compared to controls. No significant difference was found with regard to -1082 promoter polymorphism. Haplotype analysis of the IL-10 single nucleotide polymorphisms (SNPs) revealed a significant association with ACC haplotype with a twofold increased risk in patients compared to controls. The frequencies of two common IL-10 haplotypes (GCC and ATA) did not show any significant difference. Further, the diplotype analysis revealed five genotypes: -1082A with -819C (P = 0·0016); -1082G with -819C (P = 0·0018); -819C with -592C (P = 0·001); -1082A with -592C (P = 0·032); and -1082G with -592C (P = 0·005) associated with the disease. These findings support the concept of contribution of IL-10 gene polymorphisms in the pathogenesis of early-onset pre-eclampsia. PMID:24962617

  14. Interleukin 10 gene promoter polymorphisms in women with early-onset pre-eclampsia

    PubMed Central

    Sowmya, S; Sri Manjari, K; Ramaiah, A; Sunitha, T; Nallari, P; Jyothy, A; Venkateshwari, A

    2014-01-01

    Pre-eclampsia is one of the most serious disorders of human pregnancy and T helper type 1 (Th1)/Th2 imbalance plays a major role in its aetiology. The Th2 cytokine, interleukin (IL)-10, plays a significant role in the maintenance of pregnancy. The present study is aimed at understanding the role of IL-10 promoter polymorphisms (−1082 G/A; −592 A/C and −819 C/T) and their haplotypes in early-onset pre-eclampsia. A total of 120 patients and an equal number of women with normal pregnancy, from Government Maternity Hospital, Petlaburz, Hyderabad, India, were considered for the present study. A standard amplification refractory mutation system–polymerase chain reaction (ARMS–PCR) was carried out for genotyping followed by agarose gel electrophoresis. Appropriate statistical methods were applied to test for the significance of the results. It was found that the IL-10 −819 C allele (P = 0·003) and −592 A (P = 0·005) allele frequencies increased significantly in patients compared to controls. No significant difference was found with regard to −1082 promoter polymorphism. Haplotype analysis of the IL-10 single nucleotide polymorphisms (SNPs) revealed a significant association with ACC haplotype with a twofold increased risk in patients compared to controls. The frequencies of two common IL-10 haplotypes (GCC and ATA) did not show any significant difference. Further, the diplotype analysis revealed five genotypes: −1082A with −819C (P = 0·0016); −1082G with −819C (P = 0·0018); −819C with −592C (P = 0·001); −1082A with −592C (P = 0·032); and −1082G with −592C (P = 0·005) associated with the disease. These findings support the concept of contribution of IL-10 gene polymorphisms in the pathogenesis of early-onset pre-eclampsia. PMID:24962617

  15. Detection of prion gene promoter and intron1 indel polymorphisms in Anatolian water buffalo (Bubalus bubalis).

    PubMed

    Oztabak, K; Ozkan, E; Soysal, I; Paya, I; Un, C

    2009-12-01

    Bovine spongiform encephalopathy (BSE) is a fatal disease caused by miss folded prion protein. Studies in the cattle, comparing genetic data from BSE diseased and healthy animals have shown that indel polymorphisms in the promoter and intron 1 of PRNP gene were associated with disease susceptibility. Several studies were conducted to find out allele and genotypic frequencies of indel polymorphisms in promoter and intron 1 of the cattle PRNP gene. Unlike domestic cattle and bison, no indel polymorphisms of the PRNP promoter and intron 1 were examined in any population of the water buffalo (Bubalus bubalis). Aim of this study was to analyse frequencies of allele, genotype, and haplotype of the indel polymorphisms (23 bp indel in promoter and 12 bp indel in intron 1) in prion protein coding gene (PRNP) of water buffalo. Therefore a PCR based procedure, previously used in cattle to detect indel polymorphisms of PRNP promoter and intron 1 locus, was applied to 106 Anatolian water buffalo DNAs. Our results have revealed high frequency of in variants and in23/in12 haplotype for PRNP promoter and intron 1 indel polymorphisms in water buffalo. The results of the study have demonstrated that frequencies of allele, genotype, and haplotype of the indel polymorphisms in PRNP gene of the Anatolian water buffalo are significantly different those from cattle and bison PRNP indel polymorphisms. PMID:19912420

  16. [Genetic polymorphisms commonly associated with sensitivity to various addictive substances].

    PubMed

    Nishizawa, Daisuke; Ikeda, Kazutaka

    2013-11-01

    Opioids, such as morphine and fentanyl, are widely used as effective analgesics for the treatment of acute and chronic pain. In addition, the opioid system has a key role in the rewarding effects of morphine, ethanol, cocaine and various other drugs. The authors have focused on G-protein-activated inwardly rectifying potassium (GIRK) channel subunits, GIRK2 and GIRK3, which are important molecules in opioid transmission, and found that the SNPs within the GIRK2 and GIRK3 gene region were significantly associated with postoperative analgesic requirements, one of which was also associated with vulnerability to methamphetamine (METH) dependence. Further, by conducting a multistage genome-wide association study (GWAS) in healthy subjects, the authors found that the rs2952768 single-nucleotide polymorphism (SNP) was strongly associated with the requirements for postoperative opioid analgesics after painful cosmetic surgery and consistent results were obtained in patients who underwent abdominal surgery. In addition, the SNP also showed significant association with vulnerability to severe drug dependence in patients with METH dependence, alcohol dependence, and eating disorders and a lower 'Reward Dependence' score on a personality questionnaire in healthy subjects. These outcomes provide valuable information for the personalized treatment of pain and drug dependence. PMID:25069259

  17. Polymorphism in the promoter region of the Toll-like receptor 9 gene and cervical human papillomavirus infection

    PubMed Central

    Oliveira, Lucas Boeno; Louvanto, Karolina; Ramanakumar, Agnihotram V.; Franco, Eduardo L.

    2013-01-01

    Polymorphism in the Toll-like receptor (TLR) 9 gene has been shown to have a significant role in some diseases; however, little is known about its possible role in the natural history of human papillomavirus (HPV) infections. We investigated the association between a single-nucleotide polymorphism (SNP) (rs5743836) in the promoter region of TLR9 (T1237C) and type-specific HPV infections. Specimens were derived from a cohort of 2462 women enrolled in the Ludwig–McGill Cohort Study. We randomly selected 500 women who had a cervical HPV infection detected at least once during the study as cases. We defined two control groups: (i) a random sample of 300 women who always tested HPV negative, and (ii) a sample of 234 women who were always HPV negative but had a minimum of ten visits during the study. TLR9 genotyping was performed using bidirectional PCR amplification of specific alleles. Irrespective of group, the WT homozygous TLR9 genotype (TT) was the most common form, followed by the heterozygous (TC) and the mutant homozygous (CC) forms. There were no consistent associations between polymorphism and infection risk, either overall or by type or species. Likewise, there were no consistently significant associations between polymorphism and HPV clearance or persistence. We concluded that this polymorphism in the promoter region of TLR9 gene does not seem to have a mediating role in the natural history of the HPV infection. PMID:23677790

  18. Copy number polymorphisms are not a common feature of innate immune genes.

    PubMed

    Linzmeier, Rose M; Ganz, Tomas

    2006-07-01

    Extensive copy number polymorphism was recently reported for innate immunity-related alpha-defensin genes DEFA1 and DEFA3 and beta-defensin genes DEFB4, DEFB103, and DEFB104. To establish whether such polymorphisms are a common feature of innate immune genes we used quantitative real-time PCR to determine the copy numbers of seven genes whose products have important innate immune functions. The genes encoding lysozyme, lactoferrin, cathelicidin antimicrobial peptide (hCAP18/LL-37), cathepsin G, bactericidal/permeability-increasing protein, azurocidin (CAP37/heparin-binding protein), and neutrophil elastase were each found to be single copy per haploid genome. These findings, along with the recent observation that defensin genes DEFA4, DEFA5, DEFA6, and DEFB1 are single copy, suggest that copy number polymorphisms are not a common feature of the innate immune genome but are restricted to a small subset of innate immunity-related genes. PMID:16617005

  19. Common interleukin-6 promoter variants associate with the more severe forms of distal interphalangeal osteoarthritis

    PubMed Central

    Kämäräinen, Olli-Pekka; Solovieva, Svetlana; Vehmas, Tapio; Luoma, Katariina; Riihimäki, Hilkka; Ala-Kokko, Leena; Männikkö, Minna; Leino-Arjas, Päivi

    2008-01-01

    Introduction The objective of this study was to investigate the relationship of the IL-6 promoter variants G-597A, G-572C and G-174C (rs1800797, rs1800796 and rs1800795, respectively), which have been shown to affect both the transcription and secretion of IL-6, to symptomatic distal interphalangeal (DIP) osteoarthritis (OA). Methods A total of 535 women aged 45 to 63 years were included. Radiographs of both hands were taken and each DIP joint was evaluated (grade 0 to 4) for the presence of OA. Information on symptoms (pain, tenderness) in each joint was collected by using a self-administered questionnaire. Symptomatic DIP OA was defined by the presence of both radiographic findings of grade 2 or more and symptoms in at least two DIP joints, and symmetrical DIP OA by the presence of radiographic findings of grade 2 or more in at least one symmetrical pair of DIP joints. Common polymorphic loci in the IL-6 gene were amplified and the promoter haplotypes were reconstructed from genotype data with the PHASE program. Logistic regression analysis was used to examine the association between the IL-6 genotypes/diplotypes and the DIP OA outcome. Results The G alleles of two promoter single nucleotide polymorphisms (SNPs) G-597A and G-174C were more common among the subjects with symptomatic DIP OA than among those with no disease (P = 0.020 and 0.024, corrected for multiple testing). In addition, the carriage of at least one G allele in these positions increased the risk of disease (P = 0.006 and P = 0.008, respectively). Carrying a haplotype with the G allele in all three promoter SNPs increased the risk of symptomatic DIP OA more than fourfold (odds ratio (OR) 4.45, P = 0.001). Carriage of the G-G diplotype indicated an increased risk of both symmetrical DIP OA (OR 1.52, 95% confidence interval 1.01 to 2.28) and symptomatic DIP OA (OR 3.67, 95% confidence interval 1.50 to 9.00). Conclusion The present study showed that the presence of G alleles at common IL-6

  20. Common MIR146A Polymorphisms in Chinese Ankylosing Spondylitis Subjects and Controls.

    PubMed

    Niu, Zhenmin; Wang, Jiucun; Zou, Hejian; Yang, Chengde; Huang, Wei; Jin, Li

    2015-01-01

    Common polymorphisms of microRNA gene MIR146A were reported as associated with different autoimmune diseases, include systemic lupus erythematosus, psoriatic arthritis, asthma and ankylosing spondylitis. In this study we investigated MIR146A SNPs in Chinese people with ankylosing spondylitis. Three common SNPs: rs2910164, rs2431697 and rs57095329 were selected and genotyped in 611 patients and 617 controls. We found no association between these SNPs and ankylosing spondylitis in our samples. PMID:26366721

  1. Common MIR146A Polymorphisms in Chinese Ankylosing Spondylitis Subjects and Controls

    PubMed Central

    Niu, Zhenmin; Wang, Jiucun; Zou, Hejian; Yang, Chengde; Huang, Wei; Jin, Li

    2015-01-01

    Common polymorphisms of microRNA gene MIR146A were reported as associated with different autoimmune diseases, include systemic lupus erythematosus, psoriatic arthritis, asthma and ankylosing spondylitis. In this study we investigated MIR146A SNPs in Chinese people with ankylosing spondylitis. Three common SNPs: rs2910164, rs2431697 and rs57095329 were selected and genotyped in 611 patients and 617 controls. We found no association between these SNPs and ankylosing spondylitis in our samples. PMID:26366721

  2. Inaccurate Color Discrimination by Pollinators Promotes Evolution of Discrete Color Polymorphism in Food-Deceptive Flowers.

    PubMed

    Kagawa, Kotaro; Takimoto, Gaku

    2016-02-01

    Many plant species employing a food-deceptive pollination strategy show discrete or continuous floral polymorphism within their populations. Previous studies have suggested that negative frequency-dependent selection (NFDS) caused by the learning behavior of pollinators was responsible for the maintenance of floral polymorphism. However, NFDS alone does not explain why and when discrete or continuous polymorphism evolves. In this study, we use an evolutionary simulation model to propose that inaccurate discrimination of flower colors by pollinators results in evolution of discrete flower color polymorphism. Simulations showed that associative learning based on inaccurate discrimination in pollinators caused disruptive selection of flower colors. The degree of inaccuracy determined the number of discrete flower colors that evolved. Our results suggest that animal behavior based on inaccurate discrimination may be a general cause of disruptive selection that promotes discrete trait polymorphism. PMID:26807747

  3. Polymorphisms of the ELANE Gene Promoter Region in End-Stage Chronic Kidney Disease Patients

    PubMed Central

    Fernandes, Rafael; Freitas, Bruno; Miranda, Vasco; Costa, Elísio; Santos-Silva, Alice; Bronze-da-Rocha, Elsa

    2016-01-01

    End-stage renal disease (ESRD) patients have a high mortality rate that exceeds that of non-ESRD population. The hemodialysis procedure induces neutrophil activation and elastase release, which might have a role in the inflammatory process and in the development of oxidative stress. The ELANE gene encodes the neutrophil elastase. We analyzed the effect of ELANE promoter region polymorphisms and its relation with the circulating levels of elastase, as well as several clinical, biochemical and inflammatory markers in 123 ESRD patients. We found two duplications in heterozygosity in the promoter region and a new polymorphism, the c.-801G>A. ESRD patients heterozygous for the c.-903T>G polymorphism had no changes in the circulating levels of elastase or other evaluated variables, and those homozygous for the c.-741G>A polymorphism showed significant effects on neutrophils count, as well as in neutrophils/lymphocytes ratio, which might be associated with an increased inflammatory process. PMID:27136588

  4. Understanding TERT Promoter Mutations: A Common Path to Immortality.

    PubMed

    Bell, Robert J A; Rube, H Tomas; Xavier-Magalhães, Ana; Costa, Bruno M; Mancini, Andrew; Song, Jun S; Costello, Joseph F

    2016-04-01

    Telomerase (TERT) activation is a fundamental step in tumorigenesis. By maintaining telomere length, telomerase relieves a main barrier on cellular lifespan, enabling limitless proliferation driven by oncogenes. The recently discovered, highly recurrent mutations in the promoter ofTERTare found in over 50 cancer types, and are the most common mutation in many cancers. Transcriptional activation ofTERT, via promoter mutation or other mechanisms, is the rate-limiting step in production of active telomerase. AlthoughTERTis expressed in stem cells, it is naturally silenced upon differentiation. Thus, the presence ofTERTpromoter mutations may shed light on whether a particular tumor arose from a stem cell or more differentiated cell type. It is becoming clear thatTERTmutations occur early during cellular transformation, and activate theTERTpromoter by recruiting transcription factors that do not normally regulateTERTgene expression. This review highlights the fundamental and widespread role ofTERTpromoter mutations in tumorigenesis, including recent progress on their mechanism of transcriptional activation. These somatic promoter mutations, along with germline variation in theTERTlocus also appear to have significant value as biomarkers of patient outcome. Understanding the precise molecular mechanism ofTERTactivation by promoter mutation and germline variation may inspire novel cancer cell-specific targeted therapies for a large number of cancer patients.Mol Cancer Res; 14(4); 315-23. ©2016 AACR. PMID:26941407

  5. Association between seven common OPG genetic polymorphisms and osteoporosis risk: a meta-analysis.

    PubMed

    Guo, Liang; Tang, Ke; Quan, Zhengxue; Zhao, Zenghui; Jiang, Dianming

    2014-01-01

    Functional polymorphisms of the osteoprotegerin (OPG) gene are known to be involved in bone mineral density and the development of osteoporosis; however, some conflicting results have been reported. The aim of this meta-analysis is to provide a relatively comprehensive assessment of the relationship between seven common OPG genetic polymorphisms (T149C, A163G, G209A, T245G, T950C, G1181C, and C1217T) and osteoporosis risk. A literature search for eligible studies published before August 1st, 2013 was conducted in PubMed, Embase, Web of Science, Cochrane Library, and CNKI (China National Knowledge Infrastructure) databases. Pooled odds ratios and their corresponding 95% confidence intervals were used to evaluate the strength of the association under fixed- or random-effect models according to a heterogeneity test. All analyses were performed using the STATA software, version 12.0. Fourteen case-control studies with a total of 2383 osteoporosis cases and 2280 healthy controls were included in this meta-analysis. Among the seven polymorphisms, A163G and G1181C revealed significant associations with osteoporosis risk. For A163G (rs3102735), the combined results showed that the G allele of the A163G polymorphism may be associated with an increased risk of osteoporosis. Stratified analyses showed that the magnitude of the effect was similar in Caucasian and postmenopausal woman subgroups. For G1181C (rs2073618), however, we found that individuals with the C allele of the G1181C polymorphism had a decreased risk of osteoporosis, especially in Asian and postmenopausal woman subgroups. In summary, this meta-analysis indicated that the G allele of the OPG A163G polymorphism might increase osteoporosis risk in Caucasians, whereas individuals with the C allele of the G1181C polymorphism had a decreased risk of osteoporosis, especially in Asians. Both of these effects were observed in postmenopausal women. These polymorphisms could probably be used with other genetic markers

  6. Myeloperoxidase promoter region polymorphism and lung cancer risk.

    PubMed

    Wu, Xifeng; Schabath, Matthew B; Spitz, Margaret R

    2003-01-01

    Historically, myeloperoxidase activity and subsequent production of hypochlorous acid has been associated with the killing of host-invading microorganisms (bacteria, viruses, and fungi). Currently, there is a wealth of evidence that the MPO polymorphism and enzyme activity is associated with a wide range of pathological and biological processes, including lung cancer carcinogenesis. Although the molecular epidemiology reports reviewed in this chapter are not in complete agreement on all aspects of their findings, it is evident that the MPO polymorphism contributes to the modulation of overall lung cancer risk. Four of the five molecular epidemiologic studies reviewed in this chapter utilized similar case-control study designs with quite different sources of populations. These studies all demonstrate that the MPO variant genotype modulates overall lung cancer risk. However, these studies are not in agreement regarding age and gender effects, and gene-environmental interactions. The nested case control study designed utilized by Misra et al. (35) is a valid and sound approach, but their results found no evidence of an association. Certainly, heterogeneity in study populations can contribute to the variability between these studies. Additionally, epidemiologic issues such as case-control matching and sources of control populations may contribute to the conflicting findings. Thus, the publication of inconsistent or null studies as well as other positive findings is certainly encouraged to elucidate the range of effects associated with the MPO polymorphism and lung cancer risk. PMID:12407737

  7. A synonymous polymorphism in a common MDR1 (ABCB1) haplotype shapes protein function

    PubMed Central

    Fung, King Leung; Gottesman, Michael M.

    2009-01-01

    The MDR1 (ABCB1) gene encodes a membrane-bound transporter that actively effluxes a wide range of compounds from cells. The overexpression of MDR1 by multidrug-resistant cancer cells is a serious impediment to chemotherapy. MDR1 is expressed in various tissues to protect them from the adverse effect of toxins. The pharmacokinetics of drugs that are also MDR1 substrates also influence disease outcome and treatment efficacy. Although MDR1 is a well conserved gene, there is increasing evidence that its polymorphisms affect substrate specificity. Three single nucleotide polymorphisms (SNPs) occur frequently and have strong linkage, creating a common haplotype at positions 1236C>T (G412G), 2677G>T (A893S) and 3435C>T (I1145I). The frequency of the synonymous 3435C>T polymorphism has been shown to vary significantly according to ethnicity. Existing literature suggests that the haplotype plays a role in response to drugs and disease susceptibility. This review summarizes recent findings on the 3435C>T polymorphism of MDR1 and the haplotype to which it belongs. A possible molecular mechanism of action by ribosome stalling that can change protein structure and function by altering protein folding is discussed. PMID:19285158

  8. Functional Prostacyclin Synthase Promoter Polymorphisms. Impact in Pulmonary Arterial Hypertension

    PubMed Central

    Cornelius, Amber R.; Lu, Xiao; Conklin, David S.; Del Rosario, Mark J.; Lowe, Anita M.; Elos, Mihret T.; Fettig, Lynsey M.; Wong, Randall E.; Hara, Naoko; Cogan, Joy D.; Phillips, John A.; Taylor, Matthew R.; Graham, Brian B.; Tuder, Rubin M.; Loyd, James E.; Geraci, Mark W.

    2014-01-01

    Rationale: Pulmonary arterial hypertension (PAH) is a progressive disease characterized by elevated pulmonary artery pressure, vascular remodeling, and ultimately right ventricular heart failure. PAH can have a genetic component (heritable PAH), most often through mutations of bone morphogenetic protein receptor 2, and idiopathic and associated forms. Heritable PAH is not completely penetrant within families, with approximately 20% concurrence of inactivating bone morphogenetic protein receptor 2 mutations and delayed onset of PAH disease. Because one of the treatment options is using prostacyclin analogs, we hypothesized that prostacyclin synthase promoter sequence variants associated with increased mRNA expression may play a protective role in the bone morphogenetic protein receptor 2 unaffected carriers. Objectives: To characterize the range of prostacyclin synthase promoter variants and assess their transcriptional activities in PAH-relevant cell types. To determine the distribution of prostacyclin synthase promoter variants in PAH, unaffected carriers in heritable PAH families, and control populations. Methods: Polymerase chain reaction approaches were used to genotype prostacyclin synthase promoter variants in more than 300 individuals. Prostacyclin synthase promoter haplotypes’ transcriptional activities were determined with luciferase reporter assays. Measurements and Main Results: We identified a comprehensive set of prostacyclin synthase promoter variants and tested their transcriptional activities in PAH-relevant cell types. We demonstrated differences of prostacyclin synthase promoter activities dependent on their haplotype. Conclusions: Prostacyclin synthase promoter sequence variants exhibit a range of transcriptional activities. We discovered a significant bias for more active prostacyclin synthase promoter variants in unaffected carriers as compared with affected patients with PAH. PMID:24605778

  9. Matrix metalloproteinase-3 gene promoter polymorphisms: A potential risk factor for pelvic organ prolapse

    PubMed Central

    Karachalios, Charalampos; Bakas, Panagiotis; Kaparos, Georgios; Demeridou, Styliani; Liapis, Ilias; Grigoriadis, Charalampos; Liapis, Aggelos

    2016-01-01

    Pelvic organ prolapse (POP) is a common multifactorial condition. Matrix metalloproteinases (MMPs) are enzymes capable of breaking down various connective tissue elements. Single-nucleotide polymorphisms (SNPs) in regulatory areas of MMP-encoding genes can alter their transcription rate, and therefore the possible effect on pelvic floor supporting structures. The insertion of an adenine (A) base in the promoter of the MMP-3 gene at position −1612/−1617 produces a sequence of six adenines (6A), whereas the other allele has five (5A). The aim of the present study was to investigate the possible association of MMP-3 gene promoter SNPs with the risk of POP. The patient group comprised 80 women with clinically significant POP [Stage II, III or IV; POP quantification (POP-Q) system]. The control group consisted of 80 females without any or important pelvic floor support defects (Stages 0 or I; POP-Q system). All the participants underwent the same preoperative evaluation. SNP detection was determined with whole blood sample DNA analysis by quantitative polymerase chain reaction (PCR) in LightCycler® PCR platforms, using the technique of sequence-specific hybridization probe-binding assays and melting temperature curve analysis. The results showed there was no statistically significant difference between 5A/5A, 5A/6A and 6A/6A MMP-3 gene promoter variants in the two study groups (P=0.4758). Therefore, MMP-3 gene promoter SNPs alone is insufficient to increase the genetic susceptibility to POP development. PMID:27588175

  10. Tumor necrosis factor alpha -308 gene locus promoter polymorphism: an analysis of association with health and disease.

    PubMed

    Elahi, Maqsood M; Asotra, Kamlesh; Matata, Bashir M; Mastana, Sarabjit S

    2009-03-01

    Tumor necrosis factor-alpha (TNF-alpha) is a potent immunomediator and proinflammatory cytokine that has been implicated in the pathogenesis of a large number of human diseases. The location of its gene within major histocompatibility complex and biological activities has raised the possibility that polymorphisms within this locus may contribute to the pathogenesis of wide range of autoimmune and infectious diseases. For example, a bi-allelic single nucleotide substitution of G (TNFA1 allele) with A (TNFA2 allele) polymorphism at -308 nucleotides upstream from the transcription initiation site in the TNF-alpha promoter is associated with elevated TNF-alpha levels and disease susceptibilities. However, it is still unclear whether TNF-alpha -308 polymorphism plays a part in the disease process, in particular whether it could affect transcription factor binding and in turn influence TNF-alpha transcription and synthesis. Several studies have suggested that TNFA2 allele is significantly linked with the high TNF-alpha-producing autoimmune MHC haplotype HLA-A1, B8, DR3, with elevated serum TNF-alpha levels and a more severe outcome in diseases. This review discusses the genetics of the TNF-alpha -308 polymorphism in selected major diseases and evaluates its common role in health and disease. PMID:19708125

  11. Gene-Based Single Nucleotide Polymorphism Markers for Genetic and Association Mapping in Common Bean

    PubMed Central

    2012-01-01

    Background In common bean, expressed sequence tags (ESTs) are an underestimated source of gene-based markers such as insertion-deletions (Indels) or single-nucleotide polymorphisms (SNPs). However, due to the nature of these conserved sequences, detection of markers is difficult and portrays low levels of polymorphism. Therefore, development of intron-spanning EST-SNP markers can be a valuable resource for genetic experiments such as genetic mapping and association studies. Results In this study, a total of 313 new gene-based markers were developed at target genes. Intronic variation was deeply explored in order to capture more polymorphism. Introns were putatively identified after comparing the common bean ESTs with the soybean genome, and the primers were designed over intron-flanking regions. The intronic regions were evaluated for parental polymorphisms using the single strand conformational polymorphism (SSCP) technique and Sequenom MassARRAY system. A total of 53 new marker loci were placed on an integrated molecular map in the DOR364 × G19833 recombinant inbred line (RIL) population. The new linkage map was used to build a consensus map, merging the linkage maps of the BAT93 × JALO EEP558 and DOR364 × BAT477 populations. A total of 1,060 markers were mapped, with a total map length of 2,041 cM across 11 linkage groups. As a second application of the generated resource, a diversity panel with 93 genotypes was evaluated with 173 SNP markers using the MassARRAY-platform and KASPar technology. These results were coupled with previous SSR evaluations and drought tolerance assays carried out on the same individuals. This agglomerative dataset was examined, in order to discover marker-trait associations, using general linear model (GLM) and mixed linear model (MLM). Some significant associations with yield components were identified, and were consistent with previous findings. Conclusions In short, this study illustrates the power of intron

  12. Tumor necrosis factor (TNF)-alpha promoter polymorphisms in ankylosing spondylitis: comment on the article by Ji et al.

    PubMed

    Chen, Zhongwen; Ge, Rui

    2014-09-01

    TNF-α promoter polymorphisms may be associated with the severity rather than the susceptibility of AS. Further studies with a large sample size and precise methodology are needed. Interactions may already exist between gene and environment. All of these are helpful to determine the exact mechanisms of TNF-α promoter polymorphisms in AS. PMID:24643503

  13. Combining Information from Common Type 2 Diabetes Risk Polymorphisms Improves Disease Prediction

    PubMed Central

    Weedon, Michael N; McCarthy, Mark I; Hitman, Graham; Walker, Mark; Groves, Christopher J; Zeggini, Eleftheria; Rayner, N. William; Shields, Beverley; Owen, Katharine R; Hattersley, Andrew T; Frayling, Timothy M

    2006-01-01

    Background A limited number of studies have assessed the risk of common diseases when combining information from several predisposing polymorphisms. In most cases, individual polymorphisms only moderately increase risk (~20%), and they are thought to be unhelpful in assessing individuals' risk clinically. The value of analyzing multiple alleles simultaneously is not well studied. This is often because, for any given disease, very few common risk alleles have been confirmed. Methods and Findings Three common variants (Lys23 of KCNJ11, Pro12 of PPARG, and the T allele at rs7903146 of TCF7L2) have been shown to predispose to type 2 diabetes mellitus across many large studies. Risk allele frequencies ranged from 0.30 to 0.88 in controls. To assess the combined effect of multiple susceptibility alleles, we genotyped these variants in a large case-control study (3,668 controls versus 2,409 cases). Individual allele odds ratios (ORs) ranged from 1.14 (95% confidence interval [CI], 1.05 to 1.23) to 1.48 (95% CI, 1.36 to 1.60). We found no evidence of gene-gene interaction, and the risks of multiple alleles were consistent with a multiplicative model. Each additional risk allele increased the odds of type 2 diabetes by 1.28 (95% CI, 1.21 to 1.35) times. Participants with all six risk alleles had an OR of 5.71 (95% CI, 1.15 to 28.3) compared to those with no risk alleles. The 8.1% of participants that were double-homozygous for the risk alleles at TCF7L2 and Pro12Ala had an OR of 3.16 (95% CI, 2.22 to 4.50), compared to 4.3% with no TCF7L2 risk alleles and either no or one Glu23Lys or Pro12Ala risk alleles. Conclusions Combining information from several known common risk polymorphisms allows the identification of population subgroups with markedly differing risks of developing type 2 diabetes compared to those obtained using single polymorphisms. This approach may have a role in future preventative measures for common, polygenic diseases. PMID:17020404

  14. A polymorphic repeat in the IGF1 promoter influences the risk of endometrial cancer

    PubMed Central

    Bolton, Katherine A; Avery-Kiejda, Kelly A; Holliday, Elizabeth G; Attia, John; Bowden, Nikola A

    2016-01-01

    Due to the lack of high-throughput genetic assays for tandem repeats, there is a paucity of knowledge about the role they may play in disease. A polymorphic CA repeat in the promoter region of the insulin-like growth factor 1 gene (IGF1 has been studied extensively over the past 10 years for association with the risk of developing breast cancer, among other cancers, with variable results. The aim of this study was to determine if this CA repeat is associated with the risk of developing breast cancer and endometrial cancer. Using a case–control design, we analysed the length of this CA repeat in a series of breast cancer and endometrial cancer cases and compared this with a control population. Our results showed an association when both alleles were considered in breast and endometrial cancers (P=0.029 and 0.011, respectively), but this did not pass our corrected threshold for significance due to multiple testing. When the allele lengths were analysed categorically against the most common allele length of 19 CA repeats, an association was observed with the risk of endometrial cancer due to a reduction in the number of long alleles (P=0.013). This was confirmed in an analysis of the long alleles separately for endometrial cancer risk (P=0.0012). Our study found no association between the length of this polymorphic CA repeat and breast cancer risk. The significant association observed between the CA repeat length and the risk of developing endometrial cancer has not been previously reported. PMID:27090263

  15. A polymorphic repeat in the IGF1 promoter influences the risk of endometrial cancer.

    PubMed

    Bolton, Katherine A; Avery-Kiejda, Kelly A; Holliday, Elizabeth G; Attia, John; Bowden, Nikola A; Scott, Rodney J

    2016-05-01

    Due to the lack of high-throughput genetic assays for tandem repeats, there is a paucity of knowledge about the role they may play in disease. A polymorphic CA repeat in the promoter region of the insulin-like growth factor 1 gene (IGF1 has been studied extensively over the past 10 years for association with the risk of developing breast cancer, among other cancers, with variable results. The aim of this study was to determine if this CA repeat is associated with the risk of developing breast cancer and endometrial cancer. Using a case-control design, we analysed the length of this CA repeat in a series of breast cancer and endometrial cancer cases and compared this with a control population. Our results showed an association when both alleles were considered in breast and endometrial cancers (P=0.029 and 0.011, respectively), but this did not pass our corrected threshold for significance due to multiple testing. When the allele lengths were analysed categorically against the most common allele length of 19 CA repeats, an association was observed with the risk of endometrial cancer due to a reduction in the number of long alleles (P=0.013). This was confirmed in an analysis of the long alleles separately for endometrial cancer risk (P=0.0012). Our study found no association between the length of this polymorphic CA repeat and breast cancer risk. The significant association observed between the CA repeat length and the risk of developing endometrial cancer has not been previously reported. PMID:27090263

  16. Characterization of 5' promoter and exon 1-3 polymorphism of the RAET1E gene.

    PubMed

    Cox, Steven T; Pearson, Hayley; Laza-Briviesca, Raquel; Pesoa, Susanna; Vullo, Carlos; Madrigal, J Alejandro; Saudemont, Aurore

    2016-01-01

    NKG2D is an activating receptor utilized by natural killer (NK) cells that recognizes upregulated ligands on infected, tumorigenic and damaged cells, leading to their cytolysis. However, the NKG2D ligand (NKG2DL) system is very complex with eight known gene loci encoding slightly different molecules. Furthermore, most NKG2DL gene loci such as MICA and MICB are highly polymorphic with potential for functional differences. NKG2DL expression on tumors varies depending on the malignancy and tumors can also release soluble NKG2DL that exert anergic effects on NK cells when engagement with NKG2D occurs, allowing escape from NK cell immunosurveillance. We carried out RAET1E typing of IHW cell line DNA, including a 580 bp proximal promoter fragment and exons 1-3 identifying 13 of 15 known RAET1E alleles. We determined 7 polymorphisms within the promoter region, including 2 already known that contributed to 9 promoter types. RAET1E alleles with variability in the extracellular region also differed with respect to promoter type and one allele, RAET1E(∗)003, associated with 5 promoter types. We then identified putative transcription factor binding sites for RAET1E, and found 5 of the 7 promoter polymorphisms may disrupt these sites, abrogating binding of transcription factors and varying the potential level of expression. PMID:26519211

  17. Microsatellite polymorphism in the P1 promoter region of the IGF‑1 gene is associated with endometrial cancer.

    PubMed

    Kwasniewski, Wojciech; Gozdzicka-Jozefiak, Anna; Wolun-Cholewa, Maria; Polak, Grzegorz; Sierocinska-Sawa, Jadwiga; Kwasniewska, Anna; Kotarski, Jan

    2016-06-01

    Endometrial carcinoma (EC) is the most common type of gynecological malignancy. Studies have demonstrated that the insulin growth factor (IGF) pathway is implicated in the development of endometrial tumors and that the serum levels of IGF‑1 are affected by estrogen. Most EC cells with high microsatellite instability (MSI‑H) accumulate mutations at a microsatellite sequence in the IGF‑1 gene. The present study investigated the CA repeat polymorphism in the P1 promoter region of the IGF‑1 gene among Caucasian females with endometrial hyperplasia, EC and healthy control subjects, whose blood serum and surgical tissue specimens were analyzed. Differences or correlations between the analyzed parameters [serum levels of IGF-1 and IGF binding protein (IGFBP)‑1 and IGFBP‑3 as well as estrogens among the polymorphisms] were verified using the χ2, Mann-Whitney U, Kruskal-Wallis or Spearman's rank correlation tests. A PCR amplification and DNA sequencing analysis was used for identification of (CA)n repeats in the P1 region of IGF‑1. ELISA was used to determine the blood serum levels of IGF‑1, IGFBP‑1, IGFBP‑3 and estrogens. Furthermore, IGF-1 was assessed in endometrial tissues by immunohistochemical analysis. The present study indicated no statistically significant differences between serum levels of IGF‑1, IGFBP‑1, IGFBP‑3 and estrone, estriol and estradiol in the control and study groups. A significant correlation was identified between the IGF-1 levels and estrone levels in the MSI-H polymorphism (r=-0.41, P=0.012) as well as a highly negative correlation between IGF-1 levels and the estradiol levels in the MSI-H polymorphism (r=-0.6, P=0.002). Genotypes without the 19 CA allele were predominantly found in EC. Furthermore, statistical analysis indicated that the number of IGF-1-expressing cells was significantly elevated in MSI-H type 18-20 (P=0.0072), MSI-L type 19-20 (P=0.025) and microsatellite-stable MSS type 19-19 (P=0.024) compared with

  18. Microsatellite polymorphism in the P1 promoter region of the IGF-1 gene is associated with endometrial cancer

    PubMed Central

    KWASNIEWSKI, WOJCIECH; GOZDZICKA-JOZEFIAK, ANNA; WOLUN-CHOLEWA, MARIA; POLAK, GRZEGORZ; SIEROCINSKA-SAWA, JADWIGA; KWASNIEWSKA, ANNA; KOTARSKI, JAN

    2016-01-01

    Endometrial carcinoma (EC) is the most common type of gynecological malignancy. Studies have demonstrated that the insulin growth factor (IGF) pathway is implicated in the development of endometrial tumors and that the serum levels of IGF-1 are affected by estrogen. Most EC cells with high microsatellite instability (MSI-H) accumulate mutations at a microsatellite sequence in the IGF-1 gene. The present study investigated the CA repeat polymorphism in the P1 promoter region of the IGF-1 gene among Caucasian females with endometrial hyperplasia, EC and healthy control subjects, whose blood serum and surgical tissue specimens were analyzed. Differences or correlations between the analyzed parameters [serum levels of IGF-1 and IGF binding protein (IGFBP)-1 and IGFBP-3 as well as estrogens among the polymorphisms] were verified using the χ2, Mann-Whitney U, Kruskal-Wallis or Spearman's rank correlation tests. A PCR amplification and DNA sequencing analysis was used for identification of (CA)n repeats in the P1 region of IGF-1. ELISA was used to determine the blood serum levels of IGF-1, IGFBP-1, IGFBP-3 and estrogens. Furthermore, IGF-1 was assessed in endometrial tissues by immunohistochemical analysis. The present study indicated no statistically significant differences between serum levels of IGF-1, IGFBP-1, IGFBP-3 and estrone, estriol and estradiol in the control and study groups. A significant correlation was identified between the IGF-1 levels and estrone levels in the MSI-H polymorphism (r=−0.41, P=0.012) as well as a highly negative correlation between IGF-1 levels and the estradiol levels in the MSI-H polymorphism (r=−0.6, P=0.002). Genotypes without the 19 CA allele were predominantly found in EC. Furthermore, statistical analysis indicated that the number of IGF-1-expressing cells was significantly elevated in MSI-H type 18-20 (P= 0.0072), MSI-L type 19-20 (P=0.025) and microsatellite-stable MSS type 19-19 (P=0.024) compared with those in the MSI-H 20

  19. Promoter polymorphisms and transcript levels of nicotinic receptor CHRNA5.

    PubMed

    Falvella, Felicia S; Galvan, Antonella; Colombo, Francesca; Frullanti, Elisa; Pastorino, Ugo; Dragani, Tommaso A

    2010-09-01

    Chromosomal locus 15q25, implicated in lung cancer risk and nicotine dependence, shows extensive linkage disequilibrium that complicates identification of causal variation. Cholinergic receptor nicotinic alpha5 (CHRNA5) has been identified as a lung cancer risk factor. We identified by sequence analysis three haplotypes (delTTC, insATC, and insTGG) in the 5' promoter region and three at the 3'-untranslated region of CHRNA5. Linkage disequilibrium analysis of the 5' variants showed that the insTGG haplotype is associated with three tightly linked risk alleles (nicotine dependence, lung cancer, and chronic obstructive pulmonary disease). The three CHRNA5 promoter haplotypes were statistically significantly associated with lung CHRNA5 transcript levels, determined by real-time polymerase chain reaction. In nontumor lung parenchyma from 68 patients who underwent lung lobectomy, the delTTC haplotype was associated with the highest CHRNA5 transcript levels (relative quantification units = 1.82), whereas the insTGG haplotype was associated with the lowest (0.88 units, P(diff) < .001, Welch t test; all statistical tests were two-sided). Luciferase reporter assays in human lung cancer cell lines A549, H460, H520, and H596 also showed that the 5' region haplotypes were statistically significantly associated with changes in CHRNA5 promoter activity, whereas the 3'-untranslated region variants were not. PMID:20733116

  20. Polymorphism, Genetic Effect and Association with Egg Production Traits of Chicken Matrix Metalloproteinases 9 Promoter

    PubMed Central

    Zhu, Guiyu; Jiang, Yunliang

    2014-01-01

    Matrix metalloproteinases (MMP) are key enzymes involved in cell and tissue remodeling during ovarian follicle development and ovulation. The control of MMP9 transcription in ovarian follicles occurs through a core promoter region (−2,400 to −1,700 bp). The aim of this study was to screen genetic variations in the core promoter region and examine MMP9 transcription regulation and reproduction performance. A single cytosine deletion/insertion polymorphism was found at −1954 C+/C−. Genetic association analysis indicated significant correlation between the deletion genotype (C−) with total egg numbers at 28 weeks (p = 0.031). Furthermore, luciferase-reporter assay showed the deletion genotype (C−) had significantly lower promoter activity than the insertion genotype (C+) in primary granulosa cells (p<0.01). Therefore, the identified polymorphism could be used for marker-assisted selection to improve chicken laying performance. PMID:25358310

  1. Association between PIN1 promoter polymorphisms and risk of nasopharyngeal carcinoma.

    PubMed

    Lu, Yan; Huang, Guo-Liang; Pu, Xing-Xiang; He, Yu-Xiang; Li, Bin-Bin; Liu, Xing-Yan; Dong, Zigang; He, Zhiwei

    2013-05-01

    Peptidylprolyl cis/trans isomerase, NIMA-interacting 1 (PIN1) plays an important role in cell transformation and oncogenesis. Association between PIN1 promoter polymorphisms and cancer risk was reported in several cancers. This study aimed to evaluate the association between two single nucleotide polymorphisms (SNPs, -667T>C, rs2233679 and -842G>C, rs2233678) on PIN1 promoter and risk of nasopharyngeal carcinoma (NPC). The two SNPs were genotyped using polymerase chain reaction-restriction fragment length polymorphism in a total of 334 native Chinese subjects consisting of 178 cases and 156 controls. The results indicated that the -667CT heterozygote and -667CC homozygote exhibited a significantly decreased risk of nasopharyngeal carcinoma when compared with -667TT homozygote (OR = 0.639, 95% CI = 0.452-0.903, p = 0.011 for -667CT; and OR = 0.441, 95% CI = 0.213-0.915, p = 0.038 for -667CC, respectively). In the -842G>C polymorphism, compared with -842GG homozygote, only -842CG heterozygote but not -842CC homozygote had a significantly decreased risk of nasopharyngeal carcinoma (OR = 0.465, 95% CI = 0.249-0.871, p = 0.010). Genotype in the two SNPs in patients showed no significant associations with the clinicopathologic features examined. Our study showed that the minor genotypes of PIN1 promoter (-667CT, -667CC and -842CG) were associated with decreased risk of NPC in a Chinese population, suggested that PIN1 promoter polymorphisms might play an important role in NPC carcinogenesis. PMID:23269625

  2. Expression of the Alpha Tocopherol Transfer Protein gene is regulated by Oxidative Stress and Common Single Nucleotide Polymorphisms

    PubMed Central

    Ulatowski, Lynn; Dreussi, Cara; Noy, Noa; Barnholtz-Sloan, Jill; Klein, Eric; Manor, Danny

    2012-01-01

    Vitamin E (α-tocopherol) is the major lipid soluble antioxidant in most animal species. By controlling the secretion of vitamin E from the liver, the α-tocopherol transfer protein (αTTP) regulates whole-body distribution and levels of this vital nutrient. However, the mechanism(s) that regulate the expression of this protein are poorly understood. Here we report that transcription of the TTPA gene in immortalized human hepatocytes (IHH) is induced by oxidative stress and by hypoxia, by agonists of the nuclear receptors PPARα and RXR, and by increased cAMP levels. The data show further that induction of TTPA transcription by oxidative stress is mediated by an already-present transcription factor, and does not require de novo protein synthesis. Silencing of the cAMP response element binding (CREB) transcription factor attenuated transcriptional responses of the TTPA gene to added peroxide, suggesting that CREB mediates responses of this gene to oxidative stress. Using a 1.9 Kb proximal segment of the human TTPA promoter together with site-directed mutagenesis approach, we found that single nucleotide polymorphisms (SNPs) that are commonly found in healthy humans dramatically affect promoter activity. These observations suggest that oxidative stress and individual genetic makeup contribute to vitamin E homeostasis in humans. These findings may explain the variable responses to vitamin E supplementation observed in human clinical trials. PMID:23079030

  3. Expression of the α-tocopherol transfer protein gene is regulated by oxidative stress and common single-nucleotide polymorphisms.

    PubMed

    Ulatowski, Lynn; Dreussi, Cara; Noy, Noa; Barnholtz-Sloan, Jill; Klein, Eric; Manor, Danny

    2012-12-15

    Vitamin E (α-tocopherol) is the major lipid-soluble antioxidant in most animal species. By controlling the secretion of vitamin E from the liver, the α-tocopherol transfer protein regulates whole-body distribution and levels of this vital nutrient. However, the mechanism(s) that regulates the expression of this protein is poorly understood. Here we report that transcription of the TTPA gene in immortalized human hepatocytes is induced by oxidative stress and by hypoxia, by agonists of the nuclear receptors PPARα and RXR, and by increased cAMP levels. The data show further that induction of TTPA transcription by oxidative stress is mediated by an already-present transcription factor and does not require de novo protein synthesis. Silencing of the cAMP response element-binding (CREB) transcription factor attenuated transcriptional responses of the TTPA gene to added peroxide, suggesting that CREB mediates responses of this gene to oxidative stress. Using a 1.9-kb proximal segment of the human TTPA promoter together with a site-directed mutagenesis approach, we found that single-nucleotide polymorphisms that are commonly found in healthy humans dramatically affect promoter activity. These observations suggest that oxidative stress and individual genetic makeup contribute to vitamin E homeostasis in humans. These findings may explain the variable responses to vitamin E supplementation observed in human clinical trials. PMID:23079030

  4. Analysis of Polymorphisms in the Lactotransferrin Gene Promoter and Dental Caries

    PubMed Central

    Brancher, João Armando; Pecharki, Giovana Daniela; Doetzer, Andrea Duarte; Medeiros, Kamilla Gabriella dos Santos; Cordeiro Júnior, Carlos Alberto; Sotomaior, Vanessa Santos; Bauer, Peter; Trevilatto, Paula Cristina

    2011-01-01

    Regarding host aspects, there has been strong evidence for a genetic component in the etiology of caries. The salivary protein lactotransferrin (LTF) exhibits antibacterial activity, but there is no study investigating the association of polymorphisms in the promoter region of LTF gene with caries. The objective of this study was firstly to search the promoter region of the human LTF gene for variations and, if existent, to investigate the association of the identified polymorphisms with dental caries in 12-year-old students. From 687 unrelated, 12-year-old, both sex students, 50 individuals were selected and divided into two groups of extreme phenotypes according to caries experience: 25 students without (DMFT = 0) and 25 with caries experience (DMFT ≥ 4). The selection of individuals with extreme phenotypes augments the chances to find gene variations which could be associated with such phenotypes. LTF gene-putative promoter region (+39 to −1143) of the selected 50 individuals was analyzed by high-resolution melting technique. Fifteen students, 8 without (DMFT = 0) and 7 with caries experience (mean DMFT = 6.28), presented deviations of the pattern curve suggestive of gene variations and were sequenced. However, no polymorphisms were identified in the putative promoter region of the LTF gene. PMID:22190933

  5. IL10 Promoter Polymorphisms are Associated with Rheumatic Heart Disease in Saudi Arabian Patients.

    PubMed

    Abdallah, Atiyeh M; Alnuzha, Aisha; Al-Mazroea, Abdulhadi H; Eldardear, Amr E; AlSamman, Ala Y; Almohammadi, Yousef; Al-Harbi, Khalid M

    2016-01-01

    Rheumatic heart disease (RHD) is an inflammatory disease that develops following streptococcal infections. IL10 helps to balance immune responses to pathogens. IL10 polymorphisms have been associated with RHD, although results remain inconclusive. Our aim was to investigate the association between IL10 polymorphisms and RHD in Saudi Arabian patients. IL10 promoter polymorphisms (-1082A/G, -829C/T, and -592C/A) were genotyped in 118 RHD patients and 200 matched controls using the TaqMan allelic discrimination assay. There was a significant difference in IL10-1082 genotype frequency between patients and controls (p = 0.01). -1082G allele carriage (GG+GA vs AA) and the (-1082, -819, -592) GCC haplotype carriage were associated with an increased risk of RHD (p = 0.004, OR 2.1, 95% CIs 1.7-3.4 and p = 0.004, OR 2, 95% CIs 1.3-3.4, respectively). The ACC haplotype was associated with a decrease in RHD risk (p = 0.015, OR 0.6, 95% CIs 0.4-0.9). IL10 promoter polymorphisms may play an important role in the development of RHD and provide an opportunity for therapeutic stratification. PMID:26255050

  6. Functional characterization of a promoter polymorphism that drives ACSL5 gene expression in skeletal muscle and associates with diet-induced weight loss.

    PubMed

    Teng, Allen C T; Adamo, Kristi; Tesson, Frédérique; Stewart, Alexandre F R

    2009-06-01

    Diet-induced weight loss is affected by a wide range of factors, including genetic variation. Identifying functional polymorphisms will help to elucidate mechanisms that account for variation in dietary metabolism. Previously, we reported a strong association between a common single nucleotide polymorphism (SNP) rs2419621 (C>T) in the promoter of acyl-CoA synthetase long chain 5 (ACSL5), rapid weight loss in obese Caucasian females, and elevated ACSL5 mRNA levels in skeletal muscle biopsies. Here, we showed by electrophoretic mobility shift assay (EMSA) that the T allele creates a functional cis-regulatory E-box element (CANNTG) that is recognized by the myogenic regulatory factor MyoD. The T allele promoted MyoD-dependent activation of a 1089-base pair ACSL5 promoter fragment in nonmuscle CV1 cells. Differentiation of skeletal myoblasts significantly elevated expression of the ACSL5 promoter. The T allele sustained promoter activity 48 h after differentiation, whereas the C allele showed a significant decline. These results reveal a mechanism for elevated transcription of ACSL5 in skeletal muscle of carriers of the rs2419621(T) allele, associated with more rapid diet-induced weight loss. Natural selection favoring promoter polymorphisms that reduced expression of catabolic genes in skeletal muscle likely accounts for the resistance of obese individuals to dietary intervention. PMID:19218499

  7. Association of endothelial nitric oxide synthase gene T-786C promoter polymorphism with gastric cancer

    PubMed Central

    Krishnaveni, Devulapalli; Amar Chand, Bhayal; Shravan Kumar, Porika; Uma Devi, Malladi; Ramanna, Macherla; Jyothy, Akka; Pratibha, Nallari; Balakrishna, N; Venkateshwari, Ananthapur

    2015-01-01

    AIM: To investigate the role of endothelial nitric oxide synthase -786T > C promoter polymorphism in the etiology of gastric cancer (GC). METHODS: A total of 150 GC patients and 150 control subjects were included in the study. The information on demographic features was elicited with an informed consent from all the patients and control subjects using a structured questionnaire. Helicobacter pylori (H. pylori) infectivity status was tested in antral biopsies from all the subjects by rapid urease test following the method of Vaira et al. Genomic DNA was isolated from whole blood samples following the salting out method of Lahiri et al. Genotype analysis of the rs2070744 polymorphism was carried out by allele-specific polymerase chain reaction method. The genotypes were determined based on the appearance of bands on an agarose gel stained with ethidium bromide under ultraviolet gel documentation with the help of 100 bp ladder. Odds ratios and corresponding 95%CIs were determined using java stat online software. RESULTS: There was a significant difference in the distribution of C allele (C vs T; P = 0.000, OR = 5.038) in patient group compared to the control subjects exhibiting a fivefold increased risk for GC. When the T/T and C/C genotypes were compared, there was an enhanced GC risk for individuals with C/C genotype (T/T vs C/C; P = 0.000). Among the demographic factors, smoking and alcoholism were the common risk factors in patients compared to the control subjects (P < 0.05). Patients with smoking and alcoholism developed cancer even in heterozygous T/C condition (smoking: P = 0.020 and alcoholism: P = 0.005). Individuals with H. pylori infection showed seven fold increased risk for cancer. All the patients with C/C genotype revealed a significant association between H. pylori infection and GC. Among the patients 2.4% of them revealed familial incidence of GC. No significant difference was noticed between cases and controls with regard to consanguinity (P = 0

  8. Interleukin-18 gene promoter 607A polymorphism, but not 137C polymorphism, is a protective factor for ischemic stroke in the Chinese population: A meta-analysis.

    PubMed

    Zhang, Ming-Jie; Zhou, Yi; Wang, Xu; Chen, Xue; Pi, Yan; Guo, Lu; Gao, Chang-Yue; Li, Jing-Cheng; Zhang, Li-Li

    2016-09-01

    Some epidemiological studies have evaluated the association between interleukin (IL)-18 promoter polymorphisms and the risk of ischemic stroke (IS), but the results were inconsistent. The present meta-analysis was therefore performed to investigate the relationship between IL-18 promoter 137G/C and 607C/A polymorphisms and the risk of IS in the Chinese population. Related studies from PubMed, Embase, Web of Science, CBMdisc and CNKI databases up to November 1, 2014 were systematically searched, also the reference lists of identified articles were manually searched. Information was extracted to calculate for the allelic, genotypic, dominant and recessive models using the pooled odds ratios (ORs) along with 95% confidence intervals (CIs). Evidence of significant association between 607C/A polymorphism and risk of IS was found in four genetic models based on the overall population. However, no significant association between 137G/C polymorphism and risk of IS was found in four genetic models. In summary, the present study suggests that IL-18 gene promoter 607A polymorphism is a protective factor for IS in the Chinese population, while 137C polymorphism has weaker or no protective properties. Still, a larger number of studies with large scale and sufficient original information are required to further confirm our findings. PMID:27419078

  9. Common Polymorphism in Interleukin 6 Influences Survival of Women with Ovarian and Peritoneal Carcinoma.

    PubMed Central

    Garg, Ruchi; Wollan, Melissa; Galic, Vijaya; Garcia, Rochelle; Goff, Barbara A.; Gray, Heidi J.; Swisher, Elizabeth

    2007-01-01

    Objectives The IL6 -174 promoter polymorphism impacts serum cytokine levels through transcriptional regulation. The objective of our study was to determine if -174 IL6 genotype influences survival in ovarian cancer. Methods The IL6 -174 polymorphism was assessed by direct DNA sequencing in lymphocyte DNA from 160 women with invasive ovarian, or peritoneal cancer patients. IL6 levels were measured in ascites and plasma in a subset of cases using colorimetric sandwich ELISA procedure. Overall survival was calculated according to the method of Kaplan and Meier. Cox regression analysis was used to evaluate the significance of individual variables in multivariate analysis. Chi-square or Fishers Exact was used to assess the significance of contingency tables. Results The IL6 -174 genotype frequencies of CC (19%), CG (50%), and GG (31%) were in Hardy-Weinberg equilibrium and were similar to published frequencies in Caucasian controls. There were no associations with IL6 -174 genotype and age, stage or optimal cytoreduction. Stage had a significant impact on survival (p=0.003). The IL6 -174 GG genotype was significantly associated with longer overall survival (median 131 months) compared to CC or CG (median 28 months, p=0.0007). In cox regression analysis using the covariates genotype (p=0.006) and stage (p=0.02), both were independently significant. Furthermore, there was no association found between IL6 levels in ascites or plasma, and genotype, stage, or overall survival. Conclusions The IL6 -174 GG genotype has a strong, independent, and favorable impact on survival for women with ovarian, and peritoneal carcinoma. PMID:17023036

  10. Polymorphisms in the promoter region of catalase gene and essential hypertension.

    PubMed

    Zhou, Xiao Feng; Cui, Jing; DeStefano, Anita L; Chazaro, Irmarie; Farrer, Lindsay A; Manolis, Athanasios J; Gavras, Haralambos; Baldwin, Clinton T

    2005-01-01

    Genetic variations that predispose individuals to complex disorders, such as essential hypertension, may be found in gene coding regions, intronic regions or in gene promoter regions. Most studies have focused on gene variations that result in amino acid substitutions because they result in different isoforms of the protein, presumably resulting in differences in protein properties. Less attention has been placed on the role of intronic or promoter mutations. In this report, we examined two single nucleotide polymorphisms (SNPs) in the catalase (CAT) gene prompter region in a cohort of hypertensive Caucasians and African Americans with a Mass Spec based Homogenous MassEXTEND assay. We found an association when a specific combination of the two promoter SNPs was examined in Caucasians. No association was observed in African Americans. Our data suggest that genetic variations in the promoter region of catalase gene influence the susceptibility to essential hypertension. In addition, the genetic factors that contribute to hypertension maybe different between ethnic groups. PMID:15735318

  11. Correlations of polymorphisms in matrix metalloproteinase-1, -2, and -7 promoters to susceptibility to malignant gliomas

    PubMed Central

    Kawal, Priyanka; Chandra, Anil; Rajkumar; Dhole, Tapan N.; Ojha, Balkrishna

    2016-01-01

    Background: Oligodendrogliomas are infiltrative astrocytic tumors. They constitute about 1-5% of intracranial tumors. These have been graded into benign and malignant grades. The single nucleotide polymorphisms (SNPs) in the promoter regions of MMP genes may influence tumor development and progression. This study was done to explore the correlations of the promoter SNPs in MMP-1, MMP-2 and MMP-7 genes susceptibility in development and progression of oligodendrogliomas. Objectives: We aimed to investigate the association of MMP1 (−1607A > G), MMP-2 (−1306 C/T) and MMP-7(−181A > G) gene polymorphism in oligodendrogliomas (grade I, II, III). Materials and Methods: In the present case control study, we enrolled a total of 30 cases of oligodendrogliomas (grade I to III) confirmed by histopathology and 30 healthy cases as control. Polymorphism for MMP-1 gene (−1607A > G), MMP-2 (−1306 C/T), MMP-7(−181A > G) were genotyped by restriction fragment length polymorphism. Results: Frequencies of MMP-1 (−1607A > G) genotypes and 2G alleles were significantly associated with the cases of oligodendrogliomas (30%) in relation to healthy controls (13%). [OR = 6.89; P = 0.02; 95%CI= (1.33-35.62)] and [OR = 2.66; P =0.01; 95% CI= (1.26-5.64)]. A significant association of MMP-2 (−1306C/T) polymorphism with oligodendroglioma (P = 0.54) was not found, suggesting that MMP-2 (−1306C/T) polymorphism is not associated with increased oligodendroglioma susceptibility. Frequencies of MMP-7(−181A > G) genotypes and 2G alleles were significantly associated with the cases of oligodendrogliomas (33.33%) in relation to healthy controls (13.33%). [OR = 5.65; P = 0.02; 95%CI= (1.26-25.36)] and [OR = 2.49; P =0.01; 95% CI= (1.17-5.27)]. Conclusions: MMP-1 (−1607 A > G), MMP-7(−181A > G) genotypes and 2G alleles were significantly associated with oligodendroglioma (grade I, II, III), but MMP-2 (−1306C/T) polymorphism is not associated with increased oligodendroglioma

  12. DNase I hypersensitivity mapping and promoter polymorphism analysis of human C4

    SciTech Connect

    Vaishnaw, A.K.; Hargreaves, R.; Morley, B.J.

    1995-04-01

    Human complement component C4 is encoded by two structurally distinct loci in the major histocompatibility complex (MHC) class III region. The two isotypes, C4A and C4B, differ at only four residues in the C4d fragment, but C4 constitutes the most polymorphic of the complement components. It is not known, however, whether the regions involved in the regulation of C4 expression also display polymorphic variation. By using the technique of DNase I hypersensitivity mapping, we established that the only area of transcriptional activity for C4 in the hepatocyte cell line, HepG2, occurs approximately 500 base pairs upstream of the transcriptional start site. This region was found to be remarkably constant in sequence when analyzed in the context of differing MHC haplotypes including HLA B57, C4A6, C4B1, DR7, which has been correlated with reduced expression of the C4A isotype. Similarly, polymerase chain reaction followed by single-strand conformation polymorphism analysis failed to demonstrate any promoter polymorphisms in 103 individuals comprising 52 systemic lupus erythermatosus patients and 51 healthy controls. 36 refs., 3 figs., 2 tabs.

  13. Common polymorphism in the oxytocin receptor gene (OXTR) is associated with human social recognition skills

    PubMed Central

    Skuse, David H.; Lori, Adriana; Cubells, Joseph F.; Lee, Irene; Conneely, Karen N.; Puura, Kaija; Lehtimäki, Terho; Binder, Elisabeth B.; Young, Larry J.

    2014-01-01

    The neuropeptides oxytocin and vasopressin are evolutionarily conserved regulators of social perception and behavior. Evidence is building that they are critically involved in the development of social recognition skills within rodent species, primates, and humans. We investigated whether common polymorphisms in the genes encoding the oxytocin and vasopressin 1a receptors influence social memory for faces. Our sample comprised 198 families, from the United Kingdom and Finland, in whom a single child had been diagnosed with high-functioning autism. Previous research has shown that impaired social perception, characteristic of autism, extends to the first-degree relatives of autistic individuals, implying heritable risk. Assessments of face recognition memory, discrimination of facial emotions, and direction of gaze detection were standardized for age (7–60 y) and sex. A common SNP in the oxytocin receptor (rs237887) was strongly associated with recognition memory in combined probands, parents, and siblings after correction for multiple comparisons. Homozygotes for the ancestral A allele had impairments in the range −0.6 to −1.15 SD scores, irrespective of their diagnostic status. Our findings imply that a critical role for the oxytocin system in social recognition has been conserved across perceptual boundaries through evolution, from olfaction in rodents to visual memory in humans. PMID:24367110

  14. Association between VNTR Polymorphism in Promoter Region of Prodynorphin (PDYN) Gene and Methamphetamine Dependence

    PubMed Central

    Saify, Khyber; Saadat, Mostafa

    2015-01-01

    AIM: Prodynorphin (PDYN; OMIM: 131340) is the precursor of the dynorphin related peptides which plays an important role in drug abuse. Previous studies have been shown that the expression of PDYN is regulated by a genetic polymorphism of VNTR in the promoter region of the gene. MATERIALS AND METHODS: The present case-control study was performed on 52 (41 males, 11 females) methamphetamine dependence patients and 635 (525 males, 110 females) healthy blood donors frequency matched with the patients according to age and gender, as a control group was participated in the study. RESULTS: The genotypes of VNTR PDYN polymorphism were determined using PCR method. The HL (OR = 1.22, 95%CI: 0.67-2.20, P = 0.500) and LL (OR = 0.86, 95%CI: 0.28-2.57, P = 0.792) genotypes does not alter the risk of methamphetamine dependence, in comparison with the HH genotypes. CONCLUSION: The present study revealed no association between the VNTR polymorphism in the promoter region of the PDYN gene and methamphetamine dependence risk.

  15. Association Study between Promoter Polymorphism of TPH1 and Progression of Idiopathic Scoliosis

    PubMed Central

    Yablanski, Vasil; Nikolova, Svetla; Vlaev, Evgeni; Savov, Alexey; Kremensky, Ivo

    2016-01-01

    The concept of disease-modifier genes as an element of genetic heterogeneity has been widely accepted and reported. The aim of the current study is to investigate the association between the promoter polymorphism TPH1 (rs10488682) and progression of idiopathic scoliosis (IS) in Eastern European population sample. A total of 105 patients and 210 healthy gender-matched controls were enrolled in this study. The TPH1 promoter polymorphism was genotyped by amplification followed by restriction. The statistical analysis was performed by Fisher's Exact Test. The results indicated that the genotypes and alleles of TPH1 (rs10488682) are not correlated with curve severity, curve pattern, or bracing. Therefore, the examined polymorphic variant could not be considered as a genetic factor with modifying effect of IS. In conclusion, this case-control study revealed no statistically significant association between TPH1 (rs10488682) and progression of IS in Eastern European population sample. These preliminary results should be replicated in extended population studies including larger sample sizes. The identification of molecular markers for IS could be useful for a more accurate prognosis of the risk for a rapid progression of the curve. That would permit early stage treatment of the patient with the least invasive procedures. PMID:27293961

  16. TERT promoter mutations and polymorphisms as prognostic factors in primary glioblastoma.

    PubMed

    Mosrati, Mohamed Ali; Malmström, Annika; Lysiak, Malgorzata; Krysztofiak, Adam; Hallbeck, Martin; Milos, Peter; Hallbeck, Anna-Lotta; Bratthäll, Charlotte; Strandéus, Michael; Stenmark-Askmalm, Marie; Söderkvist, Peter

    2015-06-30

    Telomerase reverse transcriptase (TERT) activity is up-regulated in several types of tumors including glioblastoma (GBM). In the present study, 128 primary glioblastoma patients were examined for single nucleotide polymorphisms of TERT in blood and in 92 cases for TERT promoter mutations in tumors. TERT promoter mutations were observed in 86% of the tumors and of these, C228T (-124 bp upstream start codon) was detected in 75% and C250T (-146 bp) in 25% of cases. TERT promoter mutations were associated with shorter overall survival (11 vs. 20 months p = 0.002 and 12 vs. 20, p = 0.04 for C228T and C250T, respectively). The minor alleles of rs2736100 and rs10069690 SNP's, located in intron 2 and the promotor regions, respectively, were associated with an increased risk of developing GBM (p = 0.004 and 0.001). GBM patients having both TERT promoter mutations and being homozygous carriers of the rs2853669 C-allele displayed significantly shorter overall survival than those with the wild type allele. The rs2853669 SNP is located in a putative Ets2 binding site in the promoter (-246 bp upstream start codon) close to the C228T and C250T mutation hot spots. Interleukin-6 (IL-6) expression regulated by TERT promoter status and polymorphism, what leads us to think that TERT and IL-6 plays a significant role in GBM, where specific SNPs increase the risk of developing GBM while the rs2853669 SNP and specific mutations in the TERT promoter of the tumor lead to shorter survival. PMID:26143636

  17. Interleukin 10 promoter region polymorphisms and susceptibility to advanced alcoholic liver disease

    PubMed Central

    Grove, J; Daly, A; Bassendine, M; Gilvarry, E; Day, C

    2000-01-01

    BACKGROUND—The factors determining why less than 10% of heavy drinkers develop advanced alcoholic liver disease (ALD) remain elusive, although genetic factors may be important. Interleukin 10 (IL-10) is an important cytokine with anti-inflammatory, anti-immune, and antifibrotic functions. Several polymorphisms have been identified in the IL-10 promoter and recent evidence suggests that some of these may have functional effects on IL-10 secretion.
AIMS—To test the hypothesis that IL-10 promoter region polymorphisms are associated with susceptibility to ALD.
METHODS—The allele frequencies for the two single base pair substitutions at positions −627 (C→A) and −1117 (A→G) in the IL-10 promoter were determined in 287 heavy drinkers with biopsy proved advanced ALD, 107 heavy drinkers with no evidence of liver disease or steatosis only on biopsy, and 227 local healthy volunteers.
RESULTS—At position −627, 50% of patients with advanced ALD had a least one A allele compared with 33% of controls (p<0.0001) and 34% of drinkers with no or mild disease (p=0.017). At position −1117, the slight excess of the A allele in drinkers with advanced disease was because of linkage disequilibrium between the A alleles at the two sites.
CONCLUSIONS—Among heavy drinkers, possession of the A allele at position −627 in the IL-10 promoter is associated with an increased risk of advanced liver disease. This is consistent with recent functional data that the −627*A allele is associated with low IL-10 expression which will favour inflammatory, immune mediated, and profibrotic mechanisms of alcohol related liver injury.


Keywords: ethyl alcohol; cirrhosis; interleukin 10; genetic polymorphism PMID:10716685

  18. Interleukin-6 promoter polymorphism interacts with pain and life stress influencing depression phenotypes.

    PubMed

    Kovacs, David; Eszlari, Nora; Petschner, Peter; Pap, Dorottya; Vas, Szilvia; Kovacs, Peter; Gonda, Xenia; Bagdy, Gyorgy; Juhasz, Gabriella

    2016-05-01

    Interleukin-6 (IL-6) has emerged as a potent biomarker for depression as its elevated plasma levels in patients with clinical depression have been confirmed by meta-analyses. Increased plasma IL-6 concentration was associated with various psychological stress factors and physical disorders accompanied by pain. Another modulator of the IL-6 level is rs1800795, a promoter polymorphism in the IL-6 gene which is able to influence its expression rate. Therefore, we examined in a Hungarian population sample of 1053 volunteers with European origins if rs1800795 polymorphism can affect depression symptoms measured by Zung Self-rating Depression Scale (ZSDS), and Brief Symptom Inventory (BSI). We also investigated the interactions of the polymorphism with reported painful physical conditions and Recent Negative Life Events (RLE) measured by the List of Life Threatening Experiences. Rs1800795 significantly interacted with both RLE and painful condition on depressive symptoms measured by ZSDS and BSI using different heritability models, while no main effects of the polymorphism were identified. After correction for multiple testing only the rs1800795 × RLE interaction effect (recessive model) remained significant on the BSI score, while both RLE and painful conditions significantly interacted on the ZSDS. In conclusion, the functional IL-6 rs1800795 polymorphism in interaction with various stress factors increases the risk of depression and has a greater impact on symptoms measured by the ZSDS. Thus, IL-6 and other cytokines may be more relevant in the development of somatic symptoms compared to affective signs of depression, delineating a specific genotype-phenotype relationship in this heterogeneous disorder. PMID:26821321

  19. Methylenetetrahydrofolate reductase (MTHFR) polymorphisms and promoter methylation in cervical oncogenic lesions and cancer

    PubMed Central

    Botezatu, Anca; Socolov, Demetra; Iancu, Iulia V; Huica, Irina; Plesa, Adriana; Ungureanu, Carmen; Anton, Gabriela

    2013-01-01

    The aim of this study was to investigate the role of methylenetetrahydrofolate reductase (MTHFR) polymorphisms and MTHFR methylation pattern in cervical lesions development among women from Romania, a country with high prevalence of human papillomavirus (HPV) cervical infections. To achieve this goal, blood samples and cervical cytology specimens (n = 77)/tumour tissue specimens (n = 23) were investigated. As control, blood and negative cytological smears (n = 50) were used. A statistically significant association was found between T allele of C677T polymorphism and cervical lesions, heterozygote women presenting a threefold increased risk (normal/cervical lesions and tumours: wild homozygote 34/41 (0.68/0.41), heterozygote 14/51 (0.28/0.51), mutant homozygote 2/8 (0.04/0.08); OR = 3.081, P = 0.0035). Using χ square test for the control group, the HPV-negative and HPV-positive patients with cervix lesions, a significant correlation between viral infection and T allele of C677T polymorphism (P = 0.0287) was found. The MTHFR promoter was methylated in all HGSIL and tumour samples, significant differences being noted between HPV-positive samples, control group and cases of cervical dysplastic lesions without HPV DNA (P < 0. 0001) and between samples from patients with high-risk (hr)HPV versus low-risk (lr)HPV (P = 0.0026). No correlations between polymorphisms and methylation were observed. In Romania, individuals carrying T allele are susceptible for cervical lesions. MTHFR promoter methylation is associated with cervical severity lesions and with hrHPV. PMID:23444906

  20. Role of IL-10 -819(t/c) promoter polymorphism in preeclampsia.

    PubMed

    Sowmya, Sabnavis; Ramaiah, Aruna; Sunitha, Tella; Nallari, Pratibha; Jyothy, Akka; Venkateshwari, Ananthapur

    2014-08-01

    Preeclampsia is a severe complication of pregnancy characterized by an excessive maternal systemic inflammatory response with activation of both the innate and adaptive immune system. Interleukin-10 affects maternal intravascular inflammation, as well as endothelial dysfunction. The aim of the study was to investigate the association between IL-10 T-819 C polymorphism and preeclampsia. A total of 120 pregnant women with preeclampsia and 120 women with normal pregnancy attending the Gynecological Unit of Government Maternity Hospital, Petlaburz, Hyderabad, India, were considered for the present study. A standard amplification refractory mutation system (ARMS) PCR was carried out for genotyping of IL-10 T-819 C promoter polymorphism in all the participants. Genotypic distribution of the control and patient groups was compared with values predicted by the Hardy-Weinberg equilibrium using χ2 test. Odds ratios (OR) and their respective 95 % confidence intervals were used to measure the strength of association between IL-10 gene polymorphism and preeclampsia. The frequencies of IL-10 T-819 C genotypes, CC, CT, and TT, were 47.5, 28.3, and 24.2 % in women with preeclampsia and 20.8, 48.3, and 30.8 % in the controls, respectively. There is a significant difference in the distribution of genotypes and alleles of IL-10 T-819 C between the two groups (test power = 0.66). The present study suggests that the IL-10 T-819 C gene promoter polymorphism can be a major genetic regulator in the etiology of preeclampsia. PMID:24477695

  1. Neanderthal and Denisova genetic affinities with contemporary humans: introgression versus common ancestral polymorphisms.

    PubMed

    Lowery, Robert K; Uribe, Gabriel; Jimenez, Eric B; Weiss, Mark A; Herrera, Kristian J; Regueiro, Maria; Herrera, Rene J

    2013-11-01

    Analyses of the genetic relationships among modern humans, Neanderthals and Denisovans have suggested that 1-4% of the non-Sub-Saharan African gene pool may be Neanderthal derived, while 6-8% of the Melanesian gene pool may be the product of admixture between the Denisovans and the direct ancestors of Melanesians. In the present study, we analyzed single nucleotide polymorphism (SNP) diversity among a worldwide collection of contemporary human populations with respect to the genetic constitution of these two archaic hominins and Pan troglodytes (chimpanzee). We partitioned SNPs into subsets, including those that are derived in both archaic lineages, those that are ancestral in both archaic lineages and those that are only derived in one archaic lineage. By doing this, we have conducted separate examinations of subsets of mutations with higher probabilities of divergent phylogenetic origins. While previous investigations have excluded SNPs from common ancestors in principal component analyses, we included common ancestral SNPs in our analyses to visualize the relative placement of the Neanderthal and Denisova among human populations. To assess the genetic similarities among the various hominin lineages, we performed genetic structure analyses to provide a comparison of genetic patterns found within contemporary human genomes that may have archaic or common ancestral roots. Our results indicate that 3.6% of the Neanderthal genome is shared with roughly 65.4% of the average European gene pool, which clinally diminishes with distance from Europe. Our results suggest that Neanderthal genetic associations with contemporary non-Sub-Saharan African populations, as well as the genetic affinities observed between Denisovans and Melanesians most likely result from the retention of ancient mutations in these populations. PMID:23872234

  2. Interleukin-10 Promoter Gene Polymorphisms and Susceptibility to Tuberculosis: A Meta-Analysis

    PubMed Central

    Gao, Xuan; Chen, Junjun; Tong, Zhongkai; Yang, Guangdie; Yao, Yinan; Xu, Fei; Zhou, Jianying

    2015-01-01

    Objective As an update to other recent meta-analyses, the purpose of this study was to explore whether interleukin-10 (IL-10) polymorphisms and their haplotypes contribute to tuberculosis (TB) susceptibility. Methods We searched for published case-control studies examining IL-10 polymorphisms and TB in PubMed, EMBASE, Cochrane Central Register of Controlled Trials (CENTRAL), Wanfang databases and the Chinese National Knowledge Infrastructure (CNKI). Odds ratios (ORs) with 95% confidence intervals (CIs) were used to calculate the strengths of the associations. Results A total of 28 studies comprising 8,242 TB patients and 9,666 controls were included in the present study. There were no significant associations between the -1082G/A, -819C/T, and -592A/C polymorphisms and TB in the pooled samples. Subgroup analyses revealed that the -819T allele was associated with an increased TB risk in Asians in all genetic models (T vs. C: OR=1.17, 95% CI=1.05-1.29, P=0.003; TT vs. CC: OR=1.37, 95% CI=1.09-1.72, P=0.006; CT+TT vs. CC: OR=1.33, 95% CI=1.09-1.63, P=0.006; TT vs. CT+CC: OR=1.17, 95% CI=1.02-1.35, P=0.03) and that the -592A/C polymorphism was significantly associated with TB in Europeans under two genetic models (A vs. C: OR=0.77, 95% CI=0.60-0.98, P=0.03; AA vs. CC: OR=0.53, 95% CI=0.30-0.95, P=0.03). Furthermore, the GCC IL-10 promoter haplotype was associated with an increased risk of TB (GCC vs. others: P=1.42, 95% CI=1.02-1.97, P=0.04). Subgroup analyses based on ethnicity revealed that the GCC haplotype was associated with a higher risk of TB in Europeans, whereas the ACC haplotype was associated with a lower TB risk in both Asians and Europeans. Conclusions This meta-analysis suggests that the IL-10-819T/C polymorphism is associated with the risk of TB in Asians and that the IL-10-592A/C polymorphism may be a risk factor for TB in Europeans. Furthermore, these data indicate that IL-10 promoter haplotypes play a vital role in the susceptibility to or protection

  3. UGT1A1 promoter polymorphisms and the development of hyperbilirubinemia and gallbladder disease in children with sickle cell anemia.

    PubMed

    Carpenter, Shannon L; Lieff, Susan; Howard, Thad A; Eggleston, Barry; Ware, Russell E

    2008-10-01

    Genetic modifiers contribute to phenotypic variability in patients with sickle cell anemia (SCA). The influence of the bilirubin UDP-glucuronosyltransferase (UGT) 1A1 (TA)(n)TAA promoter polymorphism on bilirubin levels and gallbladder disease in SCA was examined using prospectively collected data from the Cooperative Study of Sickle Cell Disease. A total of 324 children with HbSS (median age 6.9 years) had UGT1A1 genotyping; 243 (75%) had common (TA)(6) or (TA)(7) alleles, whereas 81 (25.0%) had variant (TA)(5) or (TA)(8) alleles. The UGT1A1 genotype significantly influenced average bilirubin levels for the common alleles: 6/6 genotype = 2.36 +/- 1.13 mg/dL, 6/7 genotype = 2.90 +/- 1.54 mg/dL, and 7/7 genotype = 4.24 +/- 2.11 mg/dL (P < 0.0001). Thirty-nine percent of children with the 7/7 genotype had documented gallbladder disease, compared with 18.2% with the 6/7 genotype and only 9.9% with the wildtype 6/6 UGT1A1 genotype (P = 0.001). To analyze the (TA)(5) and (TA)(8) variant alleles, three groups were generated, showing increasing bilirubin levels with increasing TA repeats and age. Group 3 (genotypes 6/8, 7/7, and 7/8) had a significantly greater rate of bilirubin change than Groups 1 (genotypes 5/6, 5/7, and 6/6) or 2 (genotype 6/7). These results validate previous smaller studies and confirm that the UGT1A1 promoter polymorphism exerts a powerful influence on bilirubin levels and the development of gallbladder disease in children with SCA. UGT1A1 genotyping should be considered as a screening tool for predicting children most likely to develop gallbladder disease at a young age. PMID:18756540

  4. Candidate genes and late-onset type 2 diabetes mellitus. Susceptibility genes or common polymorphisms?

    PubMed

    Hansen, Lars

    2003-11-01

    Several lines of evidence suggest that the aetio-pathogenesis of the common form of type 2 diabetes mellitus and its intrinsically related features of impaired insulin secretion and decreased insulin sensitivity (insulin resistance) includes a strong genetic component. At present, however, little is known about the nature of this genetic component although familial clustering of the disease has been described for decades. Major break-throughs in the genetic sciences of type 2 diabetes have been identifications of insulin receptor gene mutations in syndromes of severe insulin resistance and mutations in pancreatic beta-cell genes in the monogenic sub-group of type 2 diabetes: maturity-onset-diabetes-of-the-young, MODY. Pathophysiological models of insulin resistance in skeletal muscles and impaired glucose-induced insulin secretion in the beta-cells have formed a basis for selecting candidate genes with potential influence on the development of type 2 diabetes ("diabetogenes"). This process of selecting and analyzing genes for mutations that potentially associate with either type 2 diabetes mellitus, insulin resistance or impaired insulin secretion is often described as the "candidate gene approach". The studies reported in this thesis are excerpts from an extensive strategy of genetically dissecting (mutation analysis) in: 1) patients with the common form of late-onset type 2 diabetes mellitus the pathways that transduce the insulin signals from the plasma membrane to the activation of glycogen synthesis in skeletal muscle, and in 2) patients with either late-onset type diabetes or MODY the pathways involved in normal beta-cell development and beta-cell function (insulin secretion). Twelve of the genes that encode proteins in the insulin-signalling pathway from the insulin receptor through the phosphatidylinositide-regulated kinases down to the complex of phosphatases that regulate glycogen synthesis in skeletal muscle were analyzed. We could not confirm that a Val

  5. Common polymorphisms in nitric oxide synthase (NOS) genes influence quality of aging and longevity in humans.

    PubMed

    Montesanto, Alberto; Crocco, Paolina; Tallaro, Federica; Pisani, Francesca; Mazzei, Bruno; Mari, Vincenzo; Corsonello, Andrea; Lattanzio, Fabrizia; Passarino, Giuseppe; Rose, Giuseppina

    2013-04-01

    Nitric oxide (NO) triggers multiple signal transduction pathways and contributes to the control of numerous cellular functions. Previous studies have shown in model organisms that the alteration of NO production has important effects on aging and lifespan. We studied in a large sample (763 subjects, age range 19-107 years) the variability of the three human genes (NOS1, -2, -3) coding for the three isoforms of the NADPH-dependent enzymes named NO synthases (NOS) which are responsible of NO synthesis. We have then verified if the variability of these genes is associated with longevity, and with a number of geriatric parameters. We found that gene variation of NOS1 and NOS2 was associated with longevity. In addition NOS1 rs1879417 was also found to be associated with a lower cognitive performance, while NOS2 rs2297518 polymorphism showed to be associated with physical performance. Moreover, SNPs in the NOS1 and NOS3 genes were respectively associated with the presence of depression symptoms and disability, two of the main factors affecting quality of life in older individuals. On the whole, our study shows that genetic variability of NOS genes has an effect on common age related phenotypes and longevity in humans as well as previously reported for model organisms. PMID:23572278

  6. Identification of common, unique and polymorphic microsatellites among 73 cyanobacterial genomes.

    PubMed

    Kabra, Ritika; Kapil, Aditi; Attarwala, Kherunnisa; Rai, Piyush Kant; Shanker, Asheesh

    2016-04-01

    Microsatellites also known as Simple Sequence Repeats are short tandem repeats of 1-6 nucleotides. These repeats are found in coding as well as non-coding regions of both prokaryotic and eukaryotic genomes and play a significant role in the study of gene regulation, genetic mapping, DNA fingerprinting and evolutionary studies. The availability of 73 complete genome sequences of cyanobacteria enabled us to mine and statistically analyze microsatellites in these genomes. The cyanobacterial microsatellites identified through bioinformatics analysis were stored in a user-friendly database named CyanoSat, which is an efficient data representation and query system designed using ASP.net. The information in CyanoSat comprises of perfect, imperfect and compound microsatellites found in coding, non-coding and coding-non-coding regions. Moreover, it contains PCR primers with 200 nucleotides long flanking region. The mined cyanobacterial microsatellites can be freely accessed at www.compubio.in/CyanoSat/home.aspx. In addition to this 82 polymorphic, 13,866 unique and 2390 common microsatellites were also detected. These microsatellites will be useful in strain identification and genetic diversity studies of cyanobacteria. PMID:27030027

  7. The relationship between RAGE gene four common polymorphisms and breast cancer risk in northeastern Han Chinese.

    PubMed

    Pan, Hongming; He, Lan; Wang, Bin; Niu, Wenquan

    2014-01-01

    We aimed to evaluate the association of four common polymorphisms (rs1800625, rs1800624, rs2070600, and rs184003) in receptor for advanced glycation end products (RAGE) gene to evaluate their epistatic influence on breast cancer risk in northeastern Han Chinese. This is a hospital-based case-control study involving 509 histologically-proven breast cancer patients and 504 cancer-free controls. The genotype and allele distributions of rs184003 differed significantly between patients and controls, even after the Bonferroni correction. Individuals carrying the rs184003 T allele exhibited 1.62-fold increased risk of breast cancer (odds ratio (OR) = 1.62; 95% confidence interval (95% CI): 1.26-2.08; P < 0.001) after adjusting for confounders. The frequency of haplotype T-T-G-T (alleles in order of rs1800625, rs1800624, rs2070600, and rs184003) was remarkably higher in patients than in controls (Simulated P = 0.001), and this haplotype was significantly associated with a 1.43-fold (95% CI: 1.01-2.01; P = 0.041) increase in adjusted risk of breast cancer. Further analysis indicated that there was synergistic interaction between rs184003 and rs2070600, whereas their joint information gain value was relatively small (0.27%). Taken together, although there was no suggestive evidence for the presence of epistasis in RAGE gene, our findings clearly demonstrate that rs184003 might play a predominant role in the development of breast cancer. PMID:24619131

  8. A Common Phenotype Polymorphism in Mammalian Brains Defined by Concomitant Production of Prolactin and Growth Hormone

    PubMed Central

    Daude, Nathalie; Lee, Inyoul; Kim, Taek-Kyun; Janus, Christopher; Glaves, John Paul; Gapeshina, Hristina; Yang, Jing; Sykes, Brian D.; Carlson, George A.; Hood, Leroy E.; Westaway, David

    2016-01-01

    Pituitary Prolactin (PRL) and Growth Hormone (GH) are separately controlled and sub-serve different purposes. Surprisingly, we demonstrate that extra-pituitary expression in the adult mammalian central nervous system (CNS) is coordinated at mRNA and protein levels. However this was not a uniform effect within populations, such that wide inter-individual variation was superimposed on coordinate PRL/GH expression. Up to 44% of individuals in healthy cohorts of mice and rats showed protein levels above the norm and coordinated expression of PRL and GH transcripts above baseline occurred in the amygdala, frontal lobe and hippocampus of 10% of human subjects. High levels of PRL and GH present in post mortem tissue were often presaged by altered responses in fear conditioning and stress induced hyperthermia behavioral tests. Our data define a common phenotype polymorphism in healthy mammalian brains, and, given the pleiotropic effects known for circulating PRL and GH, further consequences of coordinated CNS over-expression may await discovery. PMID:26894278

  9. A Common Phenotype Polymorphism in Mammalian Brains Defined by Concomitant Production of Prolactin and Growth Hormone.

    PubMed

    Daude, Nathalie; Lee, Inyoul; Kim, Taek-Kyun; Janus, Christopher; Glaves, John Paul; Gapeshina, Hristina; Yang, Jing; Sykes, Brian D; Carlson, George A; Hood, Leroy E; Westaway, David

    2016-01-01

    Pituitary Prolactin (PRL) and Growth Hormone (GH) are separately controlled and sub-serve different purposes. Surprisingly, we demonstrate that extra-pituitary expression in the adult mammalian central nervous system (CNS) is coordinated at mRNA and protein levels. However this was not a uniform effect within populations, such that wide inter-individual variation was superimposed on coordinate PRL/GH expression. Up to 44% of individuals in healthy cohorts of mice and rats showed protein levels above the norm and coordinated expression of PRL and GH transcripts above baseline occurred in the amygdala, frontal lobe and hippocampus of 10% of human subjects. High levels of PRL and GH present in post mortem tissue were often presaged by altered responses in fear conditioning and stress induced hyperthermia behavioral tests. Our data define a common phenotype polymorphism in healthy mammalian brains, and, given the pleiotropic effects known for circulating PRL and GH, further consequences of coordinated CNS over-expression may await discovery. PMID:26894278

  10. Molecular analysis of common polymorphisms within the human Tyrosinase locus and genetic association with pigmentation traits

    PubMed Central

    Jagirdar, Kasturee; Smit, Darren J.; Ainger, Stephen A.; Lee, Katie J.; Brown, Darren L.; Chapman, Brett; Zhao, Zhen Zhen; Montgomery, Grant W.; Martin, Nicholas G.; Stow, Jennifer L.; Duffy, David L.; Sturm, Richard A.

    2014-01-01

    Summary We have compared the melanogenic activities of cultured melanocytes carrying two common TYR alleles as homozygous 192S-402R wildtype, heterozygous and homozygous variant. This includes assays of TYR protein, DOPAoxidase activity, glycosylation and temperature sensitivity of protein and DOPAoxidase levels. Homozygous wildtype strains on average had higher levels of TYR protein and enzyme activity than other genotypes. Homozygous 402Q/Q melanocytes produced significantly less TYR protein, displayed altered trafficking and glycosylation, with reduced DOPAoxidase. However, near wildtype TYR activity levels could be recovered at lower growth temperature. In a sample population from Southeast Queensland these two polymorphisms were present on four TYR haplotypes, designated as WT 192S-402R, 192Y-402R, 192S-402Q with a double variant 192Y-402Q of low frequency at 1.9%. Based on cell culture findings and haplotype associations, we have used an additive model to assess the penetrance of the ten possible TYR genotypes derived from the combination of these haplotypes. PMID:24739399

  11. Polymorphism within the distal RAD51 gene promoter is associated with colorectal cancer in a Polish population

    PubMed Central

    Mucha, Bartosz; Kabzinski, Jacek; Dziki, Adam; Przybylowska-Sygut, Karolina; Sygut, Andrzej; Majsterek, Ireneusz; Dziki, Lukasz

    2015-01-01

    Background: colorectal cancer (CRC) is one of the most common cancers in developed countries. Annually, over one million of new cases in the world are recorded. Majority of CRCs occur sporadically with dominant phenotype of chromosomal instability (CIN). Permanent exposure to DNA damaging agents such as ionizing radiation result in DNA double-stranded breaks, which create favorable conditions for chromosomal aberration to arise. Homologous recombination repair (HRR) is the leading process engaged in maintaining of the genome integrity. RAD51 protein was recognized as crucial in HRR. Single nucleotide polymorphisms are the primary source of genetic variation which presence in the RAD51 promoter region can affect on its expression and consequently modulate HR efficiency. Objectives: The aim of this study was to analyze the distribution of genotypes and allele frequencies of -4791A/T and -4601A/G RAD51 gene polymorphisms, followed by an assessment of their relationship with the risk of CRC. Material and methods: The study included 115 patients with confirmed CRC. Control group was consisted of 118 cancer-free individuals with a negative family history. The genotypes were identified by PCR-RFLP method. Conclusion: This study revealed statistically significant association between appearance of G/A genotype in position -4601 of RAD51 gene and CRC risk. PMID:26617897

  12. Role of a functional polymorphism in the F2R gene promoter in sarcoidosis

    PubMed Central

    Platé, Manuela; Lawson, Phillippa J.; Hill, Michael R.; Marshall, Richard P.; Booth, Helen L.; Kumari, Meena; Laurent, Geoffrey J.; Hurst, John R.

    2015-01-01

    Sarcoidosis is a multisystem granulomatous disease of unknown aetiology characterized by increased inflammation, and results from gene–environment interactions. Proteinase‐activated receptor‐1 mediates the interplay between coagulation and inflammation. The rs2227744G > A promoter single nucleotide polymorphism has been linked to inflammation, cardiovascular disease and chronic obstructive pulmonary disease exacerbations. Using a case‐control study (184 cases with sarcoidosis and 368 controls), we show that the rs2227744A allele significantly associates with protection from sarcoidosis (P = 0.003, OR = 0.68 (0.52–0.88)). PMID:26278396

  13. Development of polymorphic expressed sequence tag-single sequence repeat markers in the common Chinese cuttlefish, Sepiella maindroni.

    PubMed

    Li, R H; Lu, S K; Zhang, C L; Song, W W; Mu, C K; Wang, C L

    2014-01-01

    The common Chinese cuttlefish (Sepiella maindroni) is one of the popular edible cephalopod consumed across Asia. To facilitate the population genetic investigation of this species, we developed fourteen polymorphic microsatellite makers from expressed sequence tags of S. maindroni. The number of alleles at each locus ranged from 6 to 10 with an average of 7.9 alleles per locus. The ranges of observed and expected heterozygosity were from 0.615 to 0.962 and 0.685 to 0.888, respectively. Four loci were found deviated significantly from Hardy-Weinberg equilibrium. The polymorphism information content ranged from 0.638 to 0.833. These polymorphic microsatellite loci will be helpful for the population genetic, genetic linkage map, and other genetic studies of S. maindroni. PMID:25117305

  14. The effect of ponderal index at birth on the relationships between common LEP and LEPR polymorphisms and adiposity in adolescents.

    PubMed

    Labayen, Idoia; Ruiz, Jonatan R; Moreno, Luis A; Ortega, Francisco B; Beghin, Laurent; DeHenauw, Stefaan; Benito, Pedro J; Diaz, Ligia E; Ferrari, Marika; Moschonis, George; Kafatos, Anthony; Molnar, Dénes; Widhalm, Kurt; Dallongeville, Jean; Meirhaeghe, Aline; Gottrand, Frédéric

    2011-10-01

    This study examined the effect of ponderal index (PI) at birth on the relationships between eight common polymorphisms of the leptin (LEP) and leptin receptor (LEPR) genes and adiposity in adolescents. A total of 823 European adolescents (45.4% girls) aged 14.8 ± 1.4 years were genotyped for the LEP (rs2167270, rs12706832, rs10244329, rs2071045, and rs3828942) and LEPR (rs1137100, rs1137101, and rs8179183) polymorphisms. The PI was calculated from parental reports of birth weight and length. Fat mass index (FMI) was calculated. Analyses were adjusted for relevant confounders. An "adiposity-risk-allele score" based on genotypes at the three single-nucleotide polymorphisms (SNPs) associated with adolescents' FMI in adolescents within the lower tertile of PI was calculated. The LEP rs10244329 and rs3828942 polymorphisms were associated with higher FMI only in adolescents within the lower PI tertile (+0.55 kg/m(2) per minor T allele, P = 0.040, and +0.58 kg/m(2) per major G allele, P = 0.028, respectively). The LEPR rs8179183 polymorphism was significantly associated with higher FMI in adolescents within the lower PI tertile (+0.87 kg/m(2) per minor C allele, P = 0.006). After correction for multiple comparisons, only the association between the LEPR rs8179183 and FMI persisted. However, each additional risk allele conferred 0.53 kg/m(2) greater FMI in adolescents within the lower tertile of PI (P = 0.008). In conclusion, our results suggest that those adolescents born with lower PI could be more vulnerable to the influence of the LEP rs10244329 and rs3828942 polymorphisms and LEPR rs8179183 polymorphism on total adiposity content. Due to the relatively small sample size, these findings should be replicated in further larger population samples. PMID:21512510

  15. Polymorphisms within the promoter and the intron 2 of the serotonin transporter gene in a population of bulimic patients.

    PubMed

    Lauzurica, N; Hurtado, A; Escartí, A; Delgado, M; Barrios, V; Morandé, G; Soriano, J; Jáuregui, I; González-Valdemoro, M I; García-Camba, E; Fuentes, J A

    2003-12-11

    The serotonin transporter (5-HTT) gene is a firm candidate to explain eating disorders. In this association study, two different polymorphisms were analysed: a variable number of tandem repeat (VNTR) polymorphism in intron 2 and a deletion/insertion polymorphism (5-HTTLPR) in the promoter region. The hypothesis that these gene polymorphisms may be a susceptibility factor in bulimia nervosa (BN) was explored in a female population of 102 purgative bulimics. BN patients who have suffered preceding anorexia nervosa (AN) episodes formed the so-called previous AN bulimic patient group. In our sample of normal-eater controls and purging type bulimics, regardless of whether or not the BN patients had suffered prior AN episodes, no differences were found considering the frequencies of genotypes, alleles or haplotypes of both polymorphic regions of the 5-HTT gene. PMID:14625025

  16. Development and characterization of new single nucleotide polymorphism markers from expressed sequence tags in common carp (Cyprinus carpio).

    PubMed

    Zhu, Chuankun; Cheng, Lei; Tong, Jingou; Yu, Xiaomu

    2012-01-01

    The common carp (Cyprinus carpio) is an important aquaculture fish worldwide but only limited single nucleotide polymorphism (SNP) markers are characterized from expressed sequence tags (ESTs) in this species. In this study, 1487 putative SNPs were bioinformatically mined from 14,066 online ESTs mainly from the European common carp, with the occurrence rate of about one SNP every 173 bp. One hundred and twenty-one of these SNPs were selected for validation using PCR fragment sequencing, and 48 out of 81 primers could amplify the expected fragments in the Chinese common carp genome. Only 26 (21.5%) putative SNPs were validated, however, 508 new SNPs and 68 indels were identified. The ratios of transitions to transversions were 1.77 for exon SNPs and 1.05 for intron SNPs. All the 23 SNPs selected for population tests were polymorphic, with the observed heterozygosity (Ho) ranging from 0.053 to 0.526 (mean 0.262), polymorphism information content (PIC) from 0.095 to 0.357 (mean 0.246), and 21 SNPs were in Hardy-Weinberg equilibrium. These results suggest that different common carp populations with geographic isolation have significant genetic variation at the SNP level, and these new EST-SNP markers are readily available for genetics and breeding studies in common carp. PMID:22837697

  17. Polymorphisms in the Promoter Region of the Chinese Bovine PPARGC1A Gene

    PubMed Central

    Li, M. J.; Liu, M.; Liu, D.; Lan, X. Y.; Lei, C. Z.; Yang, D. Y.; Chen, H.

    2013-01-01

    The peroxisome proliferator-activated receptor gamma coactivator-1 alpha protein, encoded by the PPARGC1A gene, plays an important role in energy homeostasis. The genetic variations within the PPARGC1A gene promoter region were scanned in 808 Chinese native bovines belonging to three cattle breeds and yaks. A total of 6 SNPs and one 4 bp insertion variation in the promoter region of the bovine PPARGC1A gene were identified: SNP -259 T>A, -301_-298insCTTT, -915 A>G, -1175 T>G, -1590 C>T, -1665 C>T and -1690 G>A, which are in the binding sites of some important transcription factors: sex-determining region Y (SRY), myeloid-specific zinc finger-1 (MZF-1) and octamer factor 1(Oct-1). It is expected that these polymorphisms may regulate PPARGC1A gene transcription and might have consequences at a regulatory level. PMID:25049813

  18. Two promoter polymorphisms in TBX22 are associated with the risk of NSCLP in Indian women.

    PubMed

    Gurramkonda, Venkatesh B; Hussain, Syed A; Murthy, Jyotsna; Lakkakula, Bhaskar V K S

    2015-10-01

    The aetiology of nonsyndromic cleft lip with or without cleft palate (NSCLP) is complex and involves both genetic and environmental risk factors. Classical research has shown that growth and patterning of the developing palatal shelves depend on epithelial-mesenchymal interactions. Expression of several signalling molecules and transcription factors in the anterior palate during early palate development has been documented. TBX22 encodes a T-box containing transcription factor and mutations in this gene are responsible for X-linked cleft palate and ankyloglossia. In the present study, we analysed two TBX22 promoter rs7055763 and rs41307258 single-nucleotide polymorphisms (SNPs) in 173 patients with NSCLP and 176 normal controls of south Indian origin using Kbioscience KASPar chemistry, which is a competitive allele-specific PCR SNP genotyping system. As the SNPs are located on chromosome X, the association analysis was carried out separately in men and women. Significant associations of rs7055763 (P=0.034) and rs41307258 (P=0.022) with NSCLP were found only in women. Both polymorphisms increased the risk for NSCLP in the heterozygous and homozygous variant state, but this was not significant. Both SNPs were not associated with a risk for NSCLP in men. Pair-wise linkage disequilibrium between rs7055763 and rs41307258 was strong and significant (D'=0.97 and r2=0.77). Only three haplotypes were observed with an estimated frequency more than 5%. Haplotype AA, which carries both mutant alleles (rs7055763 A - rs41307258 A), was significantly associated with an increased risk of NSCLP in women, but not in men. Our study showed a significant role of TBX22 promoter polymorphisms (rs7055763 and rs41307258) in the pathogenesis of NSCLP and reinforces the previous findings of a strong link between X-linked genes and orofacial clefts. PMID:25918826

  19. Investigation of an interleukin-4 promoter polymorphism for associations with asthma and atopy.

    PubMed Central

    Walley, A J; Cookson, W O

    1996-01-01

    The cytokine cluster located on chromosome 5 has been shown by linkage studies to play a role in the genetic determination of circulating immunoglobulin E (IgE) levels in atopic subjects. In the study presented here, the reported chromosome 5 linkage has been investigated in two sets of subjects. The first consisted of a general population sample of 230 nuclear families (n = 1004) from Busselton, a small West Australian country town. The second group consisted of 124 unrelated atopic asthmatics and 59 unrelated non-atopic, non-asthmatic controls, all resident in the Oxfordshire Regional Health Authority area in the United Kingdom. A previously reported interleukin-4 (II-4) promoter polymorphism (-590 C-->T) was analysed in these populations by a newly designed method of specific PCR amplification and BsmFI restriction endonuclease digestion. In the Busselton population the polymorphism was shown to be weakly associated with specific IgE to house dust mite (Mann-Whitney-U test, p = 0.013) and to wheeze (MWU test, p = 0.029), but not with specific IgE to grass pollen, total serum IgE, bronchial hyperresponsiveness, eosinophil count, or asthma. In the Oxfordshire subjects there were no statistically significant associations with any measure of asthma or atopy. These data show that the -590 C-->T II-4 promoter polymorphism is only weakly associated with certain measures of asthma and atopy in some subjects. It was specifically not associated with serum IgE concentration or asthma in either of the two groups in this study. Images PMID:8863163

  20. VEGF gene promoter polymorphisms and risk of VTE in chemotherapy-treated cancer patients.

    PubMed

    Ferroni, Patrizia; Palmirotta, Raffaele; Riondino, Silvia; De Marchis, Maria Laura; Nardecchia, Antonella; Formica, Vincenzo; Guadagni, Fiorella; Roselli, Mario

    2016-01-01

    Among the possible genetic contributors to cancer-related venous thromboembolism (VTE), vascular endothelial growth factor (VEGFA) could play an important role, as an imbalance of the VEGFA system (either disease-related or drug-induced) may result in a disturbance of vascular homeostasis. Thus, this study was designed to investigate the predictive role of eight different VEGFA gene promoter single nucleotide polymorphisms (SNPs) for a first VTE episode in cancer out-patients undergoing chemotherapy. To this purpose, VEGFA gene promoter polymorphisms were analysed in 297 cancer patients using polymerase chain reaction amplification and direct DNA sequencing analysis. One hundred forty unrelated healthy subjects from the same geographical area were also analysed in order to evaluate and compare genotype/haplotype frequencies in our ethnicity. VTE occurred in 26 (9%) of cancer patients with a median time-to-event of 3.4 months. Association analyses showed that -1154G/A polymorphism was significantly associated with the risk of chemotherapy-triggered VTE, with the A allele exerting a protective role both in the overall population (hazard ratio [HR]: 0.21; 95% confidence interval [CI]: 0.07-0.58) or in bevacizumab-treated metastatic patients (HR: 0.09, 95%CI: 0.01-0.86) in whom VEGFA -1154AA genotype also conferred a reduced risk of early progression (HR: 0.58, 95%CI: 0.34-0.98). These results suggest that VEGFA may represent a candidate gene contributing to VTE development in chemotherapy treated cancer patients and that -1154G/A SNP might provide useful clinical information on the efficacy and toxicity of bevacizumab in metastatic patients. Validation studies are needed for translation into clinical practice. PMID:26336029

  1. Identification of a DMBT1 polymorphism associated with increased breast cancer risk and decreased promoter activity.

    PubMed

    Tchatchou, Sandrine; Riedel, Angela; Lyer, Stefan; Schmutzhard, Julia; Strobel-Freidekind, Olga; Gronert-Sum, Sabine; Mietag, Carola; D'Amato, Mauro; Schlehe, Bettina; Hemminki, Kari; Sutter, Christian; Ditsch, Nina; Blackburn, Anneke; Hill, Linda Zhai; Jerry, D Joseph; Bugert, Peter; Weber, Bernhard H F; Niederacher, Dieter; Arnold, Norbert; Varon-Mateeva, Raymonda; Wappenschmidt, Barbara; Schmutzler, Rita K; Engel, Christoph; Meindl, Alfons; Bartram, Claus R; Mollenhauer, Jan; Burwinkel, Barbara

    2010-01-01

    According to present estimations, the unfavorable combination of alleles with low penetrance but high prevalence in the population might account for the major part of hereditary breast cancer risk. Deleted in Malignant Brain Tumors 1 (DMBT1) has been proposed as a tumor suppressor for breast cancer and other cancer types. Genomewide mapping in mice further identified Dmbt1 as a potential modulator of breast cancer risk. Here, we report the association of two frequent and linked single-nucleotide polymorphisms (SNPs) with increased breast cancer risk in women above the age of 60 years: DMBT1 c.-93C>T, rs2981745, located in the DMBT1 promoter; and DMBT1 c.124A>C, p.Thr42Pro, rs11523871(odds ratio [OR]=1.66, 95% confidence interval [CI]=1.21-2.29, P=0.0017; and OR=1.66; 95% CI=1.21-2.28, P=0.0016, respectively), based on 1,195 BRCA1/2 mutation-negative German breast cancer families and 1,466 unrelated German controls. Promoter studies in breast cancer cells demonstrate that the risk-increasing DMBT1 -93T allele displays significantly decreased promoter activity compared to the DMBT1 -93C allele, resulting in a loss of promoter activity. The data suggest that DMBT1 polymorphisms in the 5'-region are associated with increased breast cancer risk. In accordance with previous results, these data link decreased DMBT1 levels to breast cancer risk. PMID:19830809

  2. Functional UQCRC1 polymorphisms affect promoter activity and body lipid accumulation.

    PubMed

    Kunej, Tanja; Wang, Zeping; Michal, Jennifer J; Daniels, Tyler F; Magnuson, Nancy S; Jiang, Zhihua

    2007-12-01

    Obesity and type 2 diabetes constitute leading public health problems worldwide. Studies have shown that insulin resistance affiliated with these conditions is associated with skeletal muscle lipid accumulation, while the latter is associated with mitochondrial dysfunctions. However, the initiation and regulation of mitochondrial biogenesis rely heavily on approximately 1000 nuclear-encoded mitochondrial regulatory proteins. In this study, we targeted the ubiquinol-cytochrome c reductase core protein I gene, a nuclear-encoded component of mitochondrial complex III, for its association with subcutaneous fat depth (SFD) and skeletal muscle lipid accumulation (SMLA) using cattle as a model. Four promoter polymorphisms were identified and genotyped on approximately 250 Wagyu x Limousin F2 progeny. Statistical analysis revealed that two completely linked polymorphic sites, g.13487C>T and g.13709G>C (r2 = 1), were significantly associated with both SFD (p < 0.01) and SMLA (p < 0.0001). The difference between TTCC and CCGG haplotypes was 0.178 cm for SFD and 0.624 scores for SMLA. Interestingly, the former haplotype produced higher promoter activities than the latter by 43% to 49% in three cell lines (p < 0.05). In addition to Rett syndrome and breast/ovarian cancer observed in other studies, we report evidence for the first time, to our knowledge, that overexpression of ubiquinol-cytochrome c reductase core protein I might affect mitochondrial morphology and/or physiology and lead to development of obesity and related conditions. PMID:18198295

  3. Novel polymorphisms of the APOA2 gene and its promoter region affect body traits in cattle.

    PubMed

    Zhou, Yang; Li, Caixia; Cai, Hanfang; Xu, Yao; Lan, Xianyong; Lei, Chuzhao; Chen, Hong

    2013-12-01

    Apolipoprotein A-II (APOA2) is one of the major constituents of high-density lipoprotein and plays a critical role in lipid metabolism and obesity. However, similar research for the bovine APOA2 gene is lacking. In this study, polymorphisms of the bovine APOA2 gene and its promoter region were detected in 1021 cows from four breeds by sequencing and PCR-RFLP methods. Totally, we detected six novel mutations which included one mutation in the promoter region, two mutations in the exons and three mutations in the introns. There were four polymorphisms within APOA2 gene were analyzed. The allele A, T, T and G frequencies of the four loci were predominant in the four breeds when in separate or combinations analysis which suggested cows with those alleles to be more adapted to the steppe environment. The association analysis indicated three SVs in Nangyang cows, two SVs in Qinchun cows and the 9 haplotypes in Nangyang cows were significantly associated with body traits (P<0.05 or P<0.01). The results of this study suggested the bovine APOA2 gene may be a strong candidate gene for body traits in the cattle breeding program. PMID:24004543

  4. Sex, drugs, and rock 'n' roll: hypothesizing common mesolimbic activation as a function of reward gene polymorphisms.

    PubMed

    Blum, Kenneth; Werner, Tonia; Carnes, Stefanie; Carnes, Patrick; Bowirrat, Abdalla; Giordano, John; Oscar-Berman, Marlene; Gold, Mark

    2012-01-01

    The nucleus accumbens, a site within the ventral striatum, plays a prominent role in mediating the reinforcing effects of drugs of abuse, food, sex, and other addictions. Indeed, it is generally believed that this structure mandates motivated behaviors such as eating, drinking, and sexual activity, which are elicited by natural rewards and other strong incentive stimuli. This article focuses on sex addiction, but we hypothesize that there is a common underlying mechanism of action for the powerful effects that all addictions have on human motivation. That is, biological drives may have common molecular genetic antecedents, which if impaired, lead to aberrant behaviors. Based on abundant scientific support, we further hypothesize that dopaminergic genes, and possibly other candidate neurotransmitter-related gene polymorphisms, affect both hedonic and anhedonic behavioral outcomes. Genotyping studies already have linked gene polymorphic associations with alcohol and drug addictions and obesity, and we anticipate that future genotyping studies of sex addicts will provide evidence for polymorphic associations with specific clustering of sexual typologies based on clinical instrument assessments. We recommend that scientists and clinicians embark on research coupling the use of neuroimaging tools with dopaminergic agonistic agents to target specific gene polymorphisms systematically for normalizing hyper- or hypo-sexual behaviors. PMID:22641964

  5. Sex, Drugs, and Rock ‘N’ Roll: Hypothesizing Common Mesolimbic Activation as a Function of Reward Gene Polymorphisms

    PubMed Central

    Blum, Kenneth; Werner, Tonia; Carnes, Stefanie; Carnes, Patrick; Bowirrat, Abdalla; Giordano, John; Marlene-Oscar-Berman; Gold, Mark

    2014-01-01

    The nucleus accumbens, a site within the ventral striatum, plays a prominent role in mediating the reinforcing effects of drugs of abuse, food, sex, and other addictions. Indeed, it is generally believed that this structure mandates motivated behaviors such as eating, drinking, and sexual activity, which are elicited by natural rewards and other strong incentive stimuli. This article focuses on sex addiction, but we hypothesize that there is a common underlying mechanism of action for the powerful effects that all addictions have on human motivation. That is, biological drives may have common molecular genetic antecedents, which if impaired, lead to aberrant behaviors. Based on abundant scientific support, we further hypothesize that dopaminergic genes, and possibly other candidate neurotransmitter-related gene polymorphisms, affect both hedonic and anhedonic behavioral outcomes. Genotyping studies already have linked gene polymorphic associations with alcohol and drug addictions and obesity, and we anticipate that future genotyping studies of sex addicts will provide evidence for polymorphic associations with specific clustering of sexual typologies based on clinical instrument assessments. We recommend that scientists and clinicians embark on research coupling the use of neuroimaging tools with dopaminergic agonistic agents to target specific gene polymorphisms systematically for normalizing hyper- or hypo-sexual behaviors. PMID:22641964

  6. Foxp3 promoter polymorphism (rs3761548) in breast cancer progression: a study from India.

    PubMed

    Jahan, Parveen; Ramachander, V R Vinish; Maruthi, G; Nalini, S; Latha, K Prasanna; Murthy, T S R

    2014-04-01

    Breast cancer is the most common female neoplasm that drives the transformation of normal mammary epithelial cells into highly malignant derivatives. Forkhead Box Protein3 (Foxp3), a tumor suppressor/immunomodulatory gene, which controls the function of Treg cells and oncogenes is down regulated in breast cancer. The main aim of the present study is to evaluate the potential influence of Foxp3-3279 C>A polymorphism (rs3761548) and -2383 C>T polymorphism (rs3761549) in 202 breast cancer patients and 130 normal healthy women of Indian origin. The genotypes were determined using ARMS-PCR for rs3761548 and PCR-RFLP method for rs3761549 using specific primers. The results revealed lack of association of these two polymorphisms with breast cancer susceptibility. However, with respect to AA genotype of rs3761548, we found highly significant association with the advanced stage (T3-4) of the tumor (OR = 3.90; 95% confidence interval (CI) = 1.56-9.70; p = 0.03). Stratified data also revealed an association of homozygous mutant genotype with advanced stage of tumor in premenopausal women (OR = 4.56; 95% CI = 1.07-19.38; p = 0.04) with disease duration of <6 months (OR =  .10; 95% CI = 1.80-20.50; p = 0.002) suggestive of modulating effect of rs3761548 in tumor progression. We conclude that Foxp3 rs37161548 has a potential to be a polymorphic marker for tumor progression in premenopausal breast cancer patients in Indian women. PMID:24338714

  7. Association of promoter polymorphisms of Fas -FasL genes with development of Chronic Myeloid Leukemia.

    PubMed

    Edathara, Prajitha Mohandas; Gorre, Manjula; Kagita, Sailaja; Vuree, Sugunakar; Cingeetham, Anuradha; Nanchari, Santhoshi Rani; Meka, Phanni Bhushann; Annamaneni, Sandhya; Digumarthi, Raghunadha Rao; Satti, Vishnupriya

    2016-04-01

    Chronic myeloid leukemia (CML) is a monoclonal myeloproliferative disorder of hematopoietic stem cells (HSCs), characterized by reciprocal translocation, leading to the formation of BCR-ABL oncogene with constitutive tyrosine kinase (TK) activity. This oncogene is known to deregulate different downstream pathways which ultimately lead to cell proliferation, defective DNA repair, and inhibition of apoptosis. Fas (Fas cell surface death receptor) is a member of tumor necrosis factor (TNF) superfamily which interacts with its ligand, FasL, to initiate apoptosis. Promoter polymorphisms in Fas-FasL genes are known to influence the apoptotic signaling. Hence, the present study has been aimed to find out the association of the promoter polymorphisms in Fas and FasL genes with the development and progression of CML. Blood samples from 772 subjects (386 controls and 386 cases) were collected and genotyped for Fas-FasL gene polymorphisms through PCR-RFLP method. The association between SNPs and clinical outcome was analyzed using statistical softwares like SPSS version 20, SNPSTATs, and Haploview 2.1. The study revealed a significant association of Fas -670 G>A and FasL -844 T>C polymorphisms with the development of CML while Fas -670 AG was associated with accelerated phase. Combined risk analysis by taking the risk genotypes in cases and controls revealed a significant increase in CML risk with increase in number of risk genotypes (one risk genotype-OR 1.99 (1.44-2.76), p < 0.0001; two risk genotypes-OR 3.33 (1.91-5.81), p < 0.0001). Kaplan-Meier survival analysis of Fas -670 A>G and FasL -844 T>C showed reduced event-free survival in patients carrying the variant genotypes, Fas -670 GG, 32.363 ± 6.33, and FasL -844 CC, 33.489 ± 5.83, respectively. Our findings revealed a significant association of Fas -670 GG, FasL -844 TC, and CC genotypes with increased risk of CML. PMID:26563376

  8. First functional polymorphism in CFTR promoter that results in decreased transcriptional activity and Sp1/USF binding

    SciTech Connect

    Taulan, M. Lopez, E.; Guittard, C.; Rene, C.; Baux, D.; Altieri, J.P.; DesGeorges, M.; Claustres, M.; Romey, M.C.

    2007-09-28

    Growing evidences show that functionally relevant polymorphisms in various promoters alter both transcriptional activity and affinities of existing protein-DNA interactions, and thus influence disease progression in humans. We previously reported the -94G>T CFTR promoter variant in a female CF patient in whom any known disease-causing mutation has been detected. To investigate whether the -94G>T could be a regulatory variant, we have proceeded to in silico analyses and functional studies including EMSA and reporter gene assays. Our data indicate that the promoter variant decreases basal CFTR transcriptional activity in different epithelial cells and alters binding affinities of both Sp1 and USF nuclear proteins to the CFTR promoter. The present report provides evidence for the first functional polymorphism that negatively affects the CFTR transcriptional activity and demonstrates a cooperative role of Sp1 and USF transcription factors in transactivation of the CFTR gene promoter.

  9. Promoter polymorphisms in the MATP (SLC45A2) gene are associated with normal human skin color variation.

    PubMed

    Graf, Justin; Voisey, Joanne; Hughes, Ian; van Daal, Angela

    2007-07-01

    Human pigmentation is a complex physical trait in which the membrane-associated transporter protein (MATP) plays an important role as it is involved in intracellular processing and trafficking of melanosomal proteins. Recently, pathogenic mutations in MATP have been shown to cause oculocutaneous albinism type 4, while other polymorphisms are known to have a role in normal pigmentation variation. We previously reported significant associations of two coding region polymorphisms with hair, skin, and eye color in Caucasians. Here we characterize the promoter region of MATP identifying two new transcription start sites and a novel duplication (c.-1176_-1174dupAAT). A total of 700 individuals from five different population groups (529 Caucasians, 38 Asians, 46 African Americans, 47 Australian Aborigines, and 40 Spanish Basques) were genotyped for known promoter polymorphisms c.-1721C>G (rs13289) and c.-1169G>A (rs6867641), as well as c.-1176_-1174dupAAT. Allele frequencies of all three polymorphisms were significantly different between population groups. In Caucasians, the -1721G, +dup, and -1169A alleles were significantly associated with olive skin color. The three promoter polymorphisms were found to be in linkage disequilibrium with each other but not with the two previously reported coding region polymorphisms. Functional analyses in a melanoma cell line showed that the promoter haplotype -1721G, +dup, -1169A significantly decreased MATP transcription. This report provides further evidence for the involvement of MATP in normal pigmentation variation by identifying associations between MATP alleles and skin color variation in Caucasians and demonstrating a functional significance of these polymorphisms. PMID:17358008

  10. Association of copy number polymorphisms at the promoter and translated region of COMT with Japanese patients with schizophrenia.

    PubMed

    Higashiyama, Ryoko; Ohnuma, Tohru; Takebayashi, Yuto; Hanzawa, Ryo; Shibata, Nobuto; Yamamori, Hidenaga; Yasuda, Yuka; Kushima, Itaru; Aleksic, Branko; Kondo, Kenji; Ikeda, Masashi; Hashimoto, Ryota; Iwata, Nakao; Ozaki, Norio; Arai, Heii

    2016-04-01

    Chromosome 22q11.2 deletion syndrome and genetic variations including single-nucleotide polymorphism (SNP) and copy number variation (CNV) in catechol-O-methyltransferase (COMT) situated at 22q11.2 remains controversial. Here, the genetic relationship between COMT and Japanese patients with schizophrenia was investigated by examining whether the SNPs correlated with schizophrenia based on a common disease-common variant hypothesis. Additionally, 22q11.2DS were screened based on a common disease-rare variant hypothesis; low-frequency CNVs situated at two COMT promoters and exons were investigated based on the low-frequency variants with an intermediate effect; and positive findings from the first stage were reconfirmed using a second-stage replication study including a larger sample size. Eight SNPs and 10 CNVs were investigated using Taqman SNP and CNV quantitative real-time polymerase chain reaction method. For the first-stage analysis, 513 unrelated Japanese patients with schizophrenia and 705 healthy controls were examined. For the second-stage replication study, positive findings from the first stage were further investigated using a larger sample size, namely 1,854 patients with schizophrenia and 2,137 controls. The first-stage analysis showed significant associations among schizophrenia, intronic SNP rs165774, CNV6 situated at promoter 1, CNV8 at exon 6, and CNV9 at exon 7. The second-stage study showed that intronic SNP rs165774 (χ(2)  = 8.327, P = 0.0039), CNV6 (χ(2)  = 19.66, P = 0.00005), and CNV8 (χ(2)  = 16.57, P = 0.00025) were significantly associated with schizophrenia. Large and rare CNVs as well as low-frequency CNVs and relatively small CNVs, namely <30 kb in COMT, may be genetic risk factors for schizophrenia. © 2016 Wiley Periodicals, Inc. PMID:26852906

  11. 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

  12. Association of the tumor necrosis factor -308 A/G promoter polymorphism with Tourette syndrome.

    PubMed

    Keszler, G; Kruk, E; Kenezloi, E; Tarnok, Z; Sasvari-Szekely, M; Nemoda, Z

    2014-12-01

    Several lines of evidence suggest that certain subtypes of obsessive-compulsive and tic disorders might be paediatric manifestations of post-streptococcal autoimmunity caused by cross-reactive autoantibodies. As tumor necrosis factor (TNF) is known to play a seminal role in coordinating the humoral immune response, TNF gene polymorphisms have been proposed as genetic risk factors both in obsessive-compulsive disorder (OCD) and Tourette syndrome (TS). The aim of this study was to investigate two TNF promoter polymorphisms (-238 A/G: rs361525 and -308 A/G: rs1800629) on the genetic susceptibility to OCD and TS in a child psychiatric sample (102 patients with OCD and 117 patients with TS). In the case-control set-up, the genotype and allele frequencies were compared to a control group from the general population (n = 405). As a control child psychiatric sample, 194 children with attention-deficit hyperactivity disorder were also genotyped. Our results revealed that the TNF -308 G-allele was more frequent in children with TS compared to controls (90.2% vs 84.8%, P = 0.037). For confirmation of this genetic association, a family-based analysis, the transmission disequilibrium test was used, which showed preferential transmission of the G-allele to patients with TS (nominal P-value 0.011). Moreover, this allele was also transmitted more frequently to children with tic symptoms (nominal P-value 0.039). No association was found between OCD or obsessive-compulsive symptoms and the studied TNF polymorphisms. Based on these findings, the TNF -308 G-allele can be associated with Tourette syndrome, highlighting the potential pathophysiological role of TNF dysregulation. PMID:25256363

  13. DNA polymorphisms and mutations of the tumor necrosis factor-alpha (TNF-alpha) promoter in Langerhans cell histiocytosis (LCH).

    PubMed

    Wu, W S; McClain, K L

    1997-10-01

    Langerhans cell histiocytosis (LCH) is a clonal proliferation of dendritic histiocytes expressing elevated levels of tumor necrosis factor-alpha (TNF-alpha), interferon-gamma (IFN-gamma) granulocyte-macrophage colony-stimulating factor (GM-CSF), interleukin-1 (IL-1), and leukemia inhibitory factor (LIF). The cause of the increased cytokine levels is unknown, but DNA sequence changes in promoters could alter expression. The TNF-alpha and IFN-gamma promoter DNA sequences of 12 LCH patients were studied and compared with normal individuals by dideoxy fingerprinting and DNA sequencing. Functional consequences of polymorphic or mutated sequences were assessed by cloning altered and control promoter sequences into a luciferase reporter gene vector. Electrophoretic mobility shifts (EMSA) after binding of nuclear extracts from a macrophage cell line (U-937) by mutated promoters were compared with controls. Five of 12 LCH patients had alterations in the TNF-alpha promoter DNA sequence. None were found in the IFN-gamma gene promoter. Of the 5 with TNF-alpha DNA alterations, 2 were at position -308, which has been described as a G-A polymorphism associated with upregulation of TNF-alpha in some patients with infections or immune-mediated diseases. The polymorphism at -308 but not the other TNF-alpha promoter mutations caused a 3-fold to 7-fold increased production of the luciferase reporter gene. EMSA showed that the -308 mutant promoters bound fewer nuclear proteins than normals. Polymorphisms of the TNF-alpha promoter in LCH patients could increase the production of that cytokine. PMID:9355965

  14. Common VDR polymorphisms and idiopathic short stature in children from northern Greece

    PubMed Central

    Emmanouilidou, E; Galli-Tsinopoulou, A; Kyrgios, I; Gbandi, E; Goulas, A

    2015-01-01

    Background: A Vitamin D Receptor gene (VDR) polymorphism, rs10735810 (Fok1), has been associated in the past with idiopathic short stature (ISS) in a linkage study. We have investigated the association of the same, as well as a different polymorphism in the same gene [rs731236 (Taq1)] with ISS, in an independent study in Greek children. Methods: The VDR rs10735810 (Fok1) and rs731236 (Taq1) polymorphisms were genotyped in a group of ISS children (n= 47) and an age and sex-matched group of normal height children (n= 60) from northern Greece. Genotyping was accomplished through established PCR-RFLP methods. Results: An association trend of rs10735810 with ISS was observed, with the TT (ff) genotype being apparently underrepresented among ISS children compared to controls (p= 0.076; OR= 0.165, 95% CI= 0.025-1.094). Conclusions: The above results, together with recent evidence related to the functionality of the rs10735810 polymorphism, cannot exclude an involvement of VDR in the pathogenesis of ISS. Hippokratia 2015, 19 (1): 25-29. PMID:26435642

  15. Prevalence of common vitamin D receptor gene polymorphisms in HIV-infected and uninfected South Africans

    PubMed Central

    McNamara, Lynne; Takuva, Simbarashe; Chirwa, Tobias; MacPhail, Patrick

    2016-01-01

    Background: Host genetic factors may a play role in susceptibility to infection. Vitamin-D is an immunomodulator that may play a role in HIV infection. Vitamin-D action is mediated by the vitamin-D receptor. We establish prevalence of ApaI, BsmI, FokI and TaqI polymorphisms (VDRPs) amongst a black southern African HIV+ve population and investigate polymorphic differences between HIV+ve and -ve people. Methods: Seventy-nine sex and age-group matched HIV+ve patients of African origin initiating antiretroviral therapy (ART) and 79 HIV-ve participants, also of African origin, were recruited from a public sector HIV testing and treatment clinic and investigated for the 4 polymorphisms. The genotype frequencies were compared, odds ratios and 95% confidence intervals of the association of HIV status and each genotype were calculated. Both dominant, co-dominant, recessive and allele models were tested. Results: We found no evidence of difference in distribution and association between HIV infection and the genotypes of the BsmI, FokI and TaqI VDR polymorphisms. The genotype distributions were consistent with Hardy-Weinberg equilibrium for these genotypes. The ApaI genotype showed differences in distribution by HIV status in the dominant and co-dominant models. However this finding is cautiously stated as the ApaI genotype violated the Hardy-Weinberg equilibrium and frequency of the minor variant was unexpectedly low in this population. Conclusion: We do not show convincing differences in distribution of the VDR genotypes among HIV+ve and HIV-ve black southern African persons. Future studies need to be replicated in larger study populations as understanding polymorphic differences and similarities may offer insights into the different susceptibility and progression of HIV in southern African populations. PMID:27186331

  16. No Evidence of Association between Common Autoimmunity STAT4 and IL23R Risk Polymorphisms and Non-Anterior Uveitis

    PubMed Central

    Cordero-Coma, Miguel; Gorroño-Echebarría, Marina Begoña; Fonollosa, Alejandro; Adán, Alfredo; Martínez-Berriotxoa, Agustín; Díaz Valle, David; Pato, Esperanza; Blanco, Ricardo; Cañal, Joaquín; Díaz-Llopis, Manuel; García Serrano, José Luis; de Ramón, Enrique; del Rio, María José; Martín-Villa, José Manuel; Molins, Blanca; Ortego-Centeno, Norberto; Martín, Javier

    2013-01-01

    Objective STAT4 and IL23R loci represent common susceptibility genetic factors in autoimmunity. We decided to investigate for the first time the possible role of different STAT4/IL23R autoimmune disease-associated polymorphisms on the susceptibility to develop non-anterior uveitis and its main clinical phenotypes. Methods Four functional polymorphisms (rs3821236, rs7574865, rs7574070, and rs897200) located within STAT4 gene as well as three independent polymorphisms (rs7517847, rs11209026, and rs1495965) located within IL23R were genotyped using TaqMan® allelic discrimination in a total of 206 patients with non-anterior uveitis and 1553 healthy controls from Spain. Results No statistically significant differences were found when allele and genotype distributions were compared between non-anterior uveitis patients and controls for any STAT4 (rs3821236: P=0.39, OR=1.12, CI 95%=0.87-1.43; rs7574865: P=0.59 OR=1.07, CI 95%=0.84-1.37; rs7574070: P=0.26, OR=0.89, CI 95%=0.72-1.10; rs897200: P=0.22, OR=0.88, CI 95%=0.71-1.08;) or IL23R polymorphisms (rs7517847: P=0.49, OR=1.08, CI 95%=0.87-1.33; rs11209026: P=0.26, OR=0.78, CI 95%=0.51-1.21; rs1495965: P=0.51, OR=0.93, CI 95%=0.76-1.15). Conclusion Our results do not support a relevant role, similar to that described for other autoimmune diseases, of IL23R and STAT4 polymorphisms in the non-anterior uveitis genetic predisposition. Further studies are needed to discard a possible weak effect of the studied variant. PMID:24312163

  17. Common chimpanzees have greater diversity than humans at two of the three highly polymorphic MHC class I genes.

    PubMed

    Adams, E J; Cooper, S; Thomson, G; Parham, P

    2000-05-01

    MHC class I polymorphism improves the defense of vertebrate species against viruses and other intracellular pathogens. To see how polymorphism at the same class I genes can evolve in different species we compared the MHC-A, MHC-B, and MHC-C loci of common chimpanzees and humans. Diversity in 23 Patr-A, 32 Patr-B, and 18 Patr-C alleles obtained from study of 48 chimpanzees was compared to diversity in 66 HLA-A, 149 HLA-B, and 41 HLA-C alleles obtained from a study of over 1 million humans. At each locus, alleles group hierarchically into families and then lineages. No alleles or families are shared by the two species, commonality being seen only at the lineage level. The overall nucleotide sequence diversity of MHC class I is estimated to be greater for modern chimpanzees than humans. Considering the numbers of lineages, families, and alleles, Patr-B and Patr-C have greater diversity than the HLA-B and HLA-C, respectively. In contrast, Patr-A has less polymorphism than HLA-A, due to the absence of A2 lineage alleles. The results are consistent with ancestral humans having passed through a narrower population bottleneck than chimpanzees, and with pathogen-mediated selection having favored either preservation of A2 lineage alleles on the human line and/or their extinction on the chimpanzee line. PMID:10866107

  18. [POLYMORPHISM OF ALFA-AMYLASE AND CONJUGATION IN COMMON WHEAT ENZYME TYPES WITH QUANTITATIVE TRAITS OF PLANTS].

    PubMed

    Netsvetaev, V P; Bondarenko, L S; Motorina, I P

    2015-01-01

    Using polymorphism of alpha-amylase in the winter common wheat studied inheritance isoenzymes and its conjugation enzyme types with germinating grain on the "vine", grain productivity, plant height and time of ear formation. It is shown that the polymorphism isoenzyme of alpha-amylase wheat is limited by the presence of different loci whose products are similar in electrophoretic parameters. In this regard, one component of the enzyme can be controlling at one or two or three genes. Identification of a locus controlling alpha-amylase isoenzyme in the fast moving part of the electrophoretogram, designated as α-Amy-B7. Determine the distance of the locus to factor α-Amy-B6. PMID:26841490

  19. Association of a Monoamine Oxidase-A Gene Promoter Polymorphism with ADHD and Anxiety in Boys with Autism Spectrum Disorder

    ERIC Educational Resources Information Center

    Roohi, Jasmin; DeVincent, Carla J.; Hatchwell, Eli; Gadow, Kenneth D.

    2009-01-01

    The aim of the present study was to examine the association between a variable number tandem repeat (VNTR) functional polymorphism in the promoter region of the MAO-A gene and severity of ADHD and anxiety in boys with ASD. Parents and teachers completed a DSM-IV-referenced rating scale for 5- to 14-year-old boys with ASD (n = 43). Planned…

  20. Regulatory polymorphisms modulate the expression of HLA class II molecules and promote autoimmunity.

    PubMed

    Raj, Prithvi; Rai, Ekta; Song, Ran; Khan, Shaheen; Wakeland, Benjamin E; Viswanathan, Kasthuribai; Arana, Carlos; Liang, Chaoying; Zhang, Bo; Dozmorov, Igor; Carr-Johnson, Ferdicia; Mitrovic, Mitja; Wiley, Graham B; Kelly, Jennifer A; Lauwerys, Bernard R; Olsen, Nancy J; Cotsapas, Chris; Garcia, Christine K; Wise, Carol A; Harley, John B; Nath, Swapan K; James, Judith A; Jacob, Chaim O; Tsao, Betty P; Pasare, Chandrashekhar; Karp, David R; Li, Quan Zhen; Gaffney, Patrick M; Wakeland, Edward K

    2016-01-01

    Targeted sequencing of sixteen SLE risk loci among 1349 Caucasian cases and controls produced a comprehensive dataset of the variations causing susceptibility to systemic lupus erythematosus (SLE). Two independent disease association signals in the HLA-D region identified two regulatory regions containing 3562 polymorphisms that modified thirty-seven transcription factor binding sites. These extensive functional variations are a new and potent facet of HLA polymorphism. Variations modifying the consensus binding motifs of IRF4 and CTCF in the XL9 regulatory complex modified the transcription of HLA-DRB1, HLA-DQA1 and HLA-DQB1 in a chromosome-specific manner, resulting in a 2.5-fold increase in the surface expression of HLA-DR and DQ molecules on dendritic cells with SLE risk genotypes, which increases to over 4-fold after stimulation. Similar analyses of fifteen other SLE risk loci identified 1206 functional variants tightly linked with disease-associated SNPs and demonstrated that common disease alleles contain multiple causal variants modulating multiple immune system genes. PMID:26880555

  1. Regulatory polymorphisms modulate the expression of HLA class II molecules and promote autoimmunity

    PubMed Central

    Raj, Prithvi; Rai, Ekta; Song, Ran; Khan, Shaheen; Wakeland, Benjamin E; Viswanathan, Kasthuribai; Arana, Carlos; Liang, Chaoying; Zhang, Bo; Dozmorov, Igor; Carr-Johnson, Ferdicia; Mitrovic, Mitja; Wiley, Graham B; Kelly, Jennifer A; Lauwerys, Bernard R; Olsen, Nancy J; Cotsapas, Chris; Garcia, Christine K; Wise, Carol A; Harley, John B; Nath, Swapan K; James, Judith A; Jacob, Chaim O; Tsao, Betty P; Pasare, Chandrashekhar; Karp, David R; Li, Quan Zhen; Gaffney, Patrick M; Wakeland, Edward K

    2016-01-01

    Targeted sequencing of sixteen SLE risk loci among 1349 Caucasian cases and controls produced a comprehensive dataset of the variations causing susceptibility to systemic lupus erythematosus (SLE). Two independent disease association signals in the HLA-D region identified two regulatory regions containing 3562 polymorphisms that modified thirty-seven transcription factor binding sites. These extensive functional variations are a new and potent facet of HLA polymorphism. Variations modifying the consensus binding motifs of IRF4 and CTCF in the XL9 regulatory complex modified the transcription of HLA-DRB1, HLA-DQA1 and HLA-DQB1 in a chromosome-specific manner, resulting in a 2.5-fold increase in the surface expression of HLA-DR and DQ molecules on dendritic cells with SLE risk genotypes, which increases to over 4-fold after stimulation. Similar analyses of fifteen other SLE risk loci identified 1206 functional variants tightly linked with disease-associated SNPs and demonstrated that common disease alleles contain multiple causal variants modulating multiple immune system genes. DOI: http://dx.doi.org/10.7554/eLife.12089.001 PMID:26880555

  2. Association of a Human FABP1 Gene Promoter Region Polymorphism with Altered Serum Triglyceride Levels

    PubMed Central

    Zhu, Yi-bing; Huang, Rong-dong; Lu, Qing-Qing; Lin, Xu

    2015-01-01

    Liver fatty acid-binding protein (L-FABP), also known as fatty acid-binding protein 1 (FABP1), is a key regulator of hepatic lipid metabolism. Elevated FABP1 levels are associated with an increased risk of cardiovascular disease (CVD) and metabolic syndromes. In this study, we examine the association of FABP1 gene promoter variants with serum FABP1 and lipid levels in a Chinese population. Four promoter single-nucleotide polymorphisms (SNPs) of FABP1 gene were genotyped in a cross-sectional survey of healthy volunteers (n = 1,182) from Fuzhou city of China. Results showed that only the rs2919872 G>A variant was significantly associated with serum TG concentration(P = 0.032).Compared with the rs2919872 G allele, rs2919872 A allele contributed significantly to reduced serum TG concentration, and this allele dramatically decreased the FABP1 promoter activity(P < 0.05). The rs2919872 A allele carriers had considerably lower serum FABP1 levels than G allele carriers (P < 0.01). In the multivariable linear regression analysis, the rs2919872 A allele was negatively associated with serum FABP1 levels (β = —0.320, P = 0.003), while serum TG levels were positively associated with serum FABP1 levels (β = 0.487, P = 0.014). Our data suggest that compared with the rs2919872 G allele, the rs2919872 A allele reduces the transcriptional activity of FABP1 promoter, and thereby may link FABP1 gene variation to TG level in humans. PMID:26439934

  3. Association of a Human FABP1 Gene Promoter Region Polymorphism with Altered Serum Triglyceride Levels.

    PubMed

    Peng, Xian-E; Wu, Yun-Li; Zhu, Yi-Bing; Huang, Rong-Dong; Lu, Qing-Qing; Lin, Xu

    2015-01-01

    Liver fatty acid-binding protein (L-FABP), also known as fatty acid-binding protein 1 (FABP1), is a key regulator of hepatic lipid metabolism. Elevated FABP1 levels are associated with an increased risk of cardiovascular disease (CVD) and metabolic syndromes. In this study, we examine the association of FABP1 gene promoter variants with serum FABP1 and lipid levels in a Chinese population. Four promoter single-nucleotide polymorphisms (SNPs) of FABP1 gene were genotyped in a cross-sectional survey of healthy volunteers (n = 1,182) from Fuzhou city of China. Results showed that only the rs2919872 G>A variant was significantly associated with serum TG concentration(P = 0.032).Compared with the rs2919872 G allele, rs2919872 A allele contributed significantly to reduced serum TG concentration, and this allele dramatically decreased the FABP1 promoter activity(P < 0.05). The rs2919872 A allele carriers had considerably lower serum FABP1 levels than G allele carriers (P < 0.01). In the multivariable linear regression analysis, the rs2919872 A allele was negatively associated with serum FABP1 levels (β = -0.320, P = 0.003), while serum TG levels were positively associated with serum FABP1 levels (β = 0.487, P = 0.014). Our data suggest that compared with the rs2919872 G allele, the rs2919872 A allele reduces the transcriptional activity of FABP1 promoter, and thereby may link FABP1 gene variation to TG level in humans. PMID:26439934

  4. HIV-1 Promoter Single Nucleotide Polymorphisms Are Associated with Clinical Disease Severity.

    PubMed

    Nonnemacher, Michael R; Pirrone, Vanessa; Feng, Rui; Moldover, Brian; Passic, Shendra; Aiamkitsumrit, Benjamas; Dampier, Will; Wojno, Adam; Kilareski, Evelyn; Blakey, Brandon; Ku, Tse-Sheun Jade; Shah, Sonia; Sullivan, Neil T; Jacobson, Jeffrey M; Wigdahl, Brian

    2016-01-01

    The large majority of human immunodeficiency virus type 1 (HIV-1) markers of disease progression/severity previously identified have been associated with alterations in host genetic and immune responses, with few studies focused on viral genetic markers correlate with changes in disease severity. This study presents a cross-sectional/longitudinal study of HIV-1 single nucleotide polymorphisms (SNPs) contained within the viral promoter or long terminal repeat (LTR) in patients within the Drexel Medicine CNS AIDS Research and Eradication Study (CARES) Cohort. HIV-1 LTR SNPs were found to associate with the classical clinical disease parameters CD4+ T-cell count and log viral load. They were found in both defined and undefined transcription factor binding sites of the LTR. A novel SNP identified at position 108 in a known COUP (chicken ovalbumin upstream promoter)/AP1 transcription factor binding site was significantly correlated with binding phenotypes that are potentially the underlying cause of the associated clinical outcome (increase in viral load and decrease in CD4+ T-cell count). PMID:27100290

  5. HIV-1 Promoter Single Nucleotide Polymorphisms Are Associated with Clinical Disease Severity

    PubMed Central

    Feng, Rui; Moldover, Brian; Passic, Shendra; Aiamkitsumrit, Benjamas; Dampier, Will; Wojno, Adam; Kilareski, Evelyn; Blakey, Brandon; Ku, Tse-Sheun Jade; Shah, Sonia; Sullivan, Neil T.; Jacobson, Jeffrey M.; Wigdahl, Brian

    2016-01-01

    The large majority of human immunodeficiency virus type 1 (HIV-1) markers of disease progression/severity previously identified have been associated with alterations in host genetic and immune responses, with few studies focused on viral genetic markers correlate with changes in disease severity. This study presents a cross-sectional/longitudinal study of HIV-1 single nucleotide polymorphisms (SNPs) contained within the viral promoter or long terminal repeat (LTR) in patients within the Drexel Medicine CNS AIDS Research and Eradication Study (CARES) Cohort. HIV-1 LTR SNPs were found to associate with the classical clinical disease parameters CD4+ T-cell count and log viral load. They were found in both defined and undefined transcription factor binding sites of the LTR. A novel SNP identified at position 108 in a known COUP (chicken ovalbumin upstream promoter)/AP1 transcription factor binding site was significantly correlated with binding phenotypes that are potentially the underlying cause of the associated clinical outcome (increase in viral load and decrease in CD4+ T-cell count). PMID:27100290

  6. Comparison of ADH3 promoter with commonly used promoters for recombinant protein production in Pichia pastoris.

    PubMed

    Karaoglan, Mert; Karaoglan, Fidan Erden; Inan, Mehmet

    2016-05-01

    Recombinant protein production under the control of the PADH3 was compared with Pichia pastoris PAOX1 and PGAP. The single-copy-clones expressing Aspergillus niger xylanase (XylB) gene with the three different promoters were tested in shake flask and 5 L fed-batch fermentation processes. Recombinant protein production with PADH3, PAOX1 and PGAP were initiated by addition of ethanol, methanol and glucose, respectively in the culture medium. The fermentation process was carried out for 72 h at 30 °C, pH 5 and 30% dissolved oxygen. Extracellular protein production yield for PADH3 (3725 U/mL) was higher than for PAOX1 (2095 U/mL) and PGAP (580 U/mL) at fermentor scale under the conditions tested. These results show that the PADH3 promoter is a promising tool for large scale production of recombinant proteins and can be an alternative to the PAOX1 and PGAP. PMID:26835836

  7. Study of regulatory promoter polymorphism (-248 G>A) of Bax gene in patients with gastric cancer in the northern provinces of Iran

    PubMed Central

    Mirmajidi, Seyedeh Habibeh; Najafi, Mojtaba; Mirmajidi, Seyedeh Tahereh; Nasri Nasrabadi, Nafiseh

    2016-01-01

    Aim: The aim of this study is to evaluate the polymorphism in Bax gene and its association with some clinical pathology traits in gastric cancer. Background: Gastric cancer is considered as the fourth most common cancer in the north and northwest of Iran. Bcl2 family has a key role in regulation of apoptosis, and any changes in the expression of Bcl2 lead to cancer. Patients and methods: Blood samples were collected from 100 cases and 89 controls in the northern provinces of Iran to evaluate promoter polymorphism (-248Gpolymorphism in the above-mentioned region of Bax gene. Sixty-nine patients (%69) with genotype GG and 31 patients (%31) with genotype AG were observed in the case group. No mutant genotype was found among cases. Sixty-seven individuals (%75/28) with genotype GG, 21 individuals (%23/59) with genotype AG and only one mutant genotype (AA) were demonstrated in the control group. The bioinformatics analysis showed that this polymorphism removed the probable Sp1 motifs, which may affect its expression in the cells. Conclusion: Allele G was the most frequent between both patient and control samples. Polymorphism may be effective on Bax expression, but it requires further investigation. Our results showed significant effects between genotypes and features of gender and age, whereas no significant relation were observed between the genotypes and grade, stage as well as smoking traits. PMID:26744613

  8. Genetic polymorphisms of MMP1, MMP3 and MMP7 gene promoter and risk of colorectal adenoma

    PubMed Central

    Lièvre, Astrid; Milet, Jacqueline; Carayol, Jérôme; Le Corre, Delphine; Milan, Chantal; Pariente, Alexandre; Nalet, Bernard; Lafon, Jacques; Faivre, Jean; Bonithon-Kopp, Claire; Olschwang, Sylviane; Bonaiti-Pellié, Catherine; Laurent-Puig, Pierre

    2006-01-01

    Background Matrix metalloproteinases (MMP) have been shown to play a role in colorectal cancer (CRC). More recently, MMP1, MMP3 and MMP7 functional gene promoter polymorphisms have been found to be associated with CRC occurrence and prognosis. To document the role of MMP polymorphisms in the early step of colorectal carcinogenesis, we investigated their association with colorectal adenoma risk in a case-control study comprising 295 patients with large adenomas (LA), 302 patients with small adenomas (SA) and 568 polyp-free (PF) controls. Methods Patients were genotyped using automated fragment analysis for MMP1 -1607 ins/del G and MMP3 -1612 ins/delA (MMP3.1) polymorphisms and allelic discrimination assay for MMP3 -709 A/G (MMP3.2) and MMP7 -181 A/G polymorphisms. Association between MMP genotypes and colorectal adenomas was first tested for each polymorphism separately and then for combined genotypes using the combination test. Adjustment on relevant variables and estimation of odds ratios were performed using unconditional logistic regression. Results No association was observed between the polymorphisms and LA when compared to PF or SA. When comparing SA to PF controls, analysis revealed a significant association between MMP3 -1612 ins/delA polymorphism and SA with an increased risk associated with the 6A/6A genotype (OR = 1.67, 95%CI: 1.20–2.34). Using the combination test, the best association was found for MMP3.1-MMP1 (p = 0.001) with an OR of 1.88 (95%CI: 1.08–3.28) for the combined genotype 2G/2G-6A/6A estimated by logistic regression. Conclusion These data show a relation between MMP1 -1607 ins/del G and MMP3 -1612 ins/delA combined polymorphisms and risk of SA, suggesting their potential role in the early steps of colorectal carcinogenesis. PMID:17125518

  9. Tumor Necrosis Factor Alpha Promoter Polymorphism and Severity of Acute Kidney Injury

    PubMed Central

    Susantitaphong, Paweena; Perianayagam, Mary C.; Tighiouart, Hocine; Liangos, Orfeas; Bonventre, Joseph V.; Jaber, Bertrand L.

    2016-01-01

    Background Tumor necrosis factor-alpha is a proinflammatory cytokine that has been implicated in the pathobiology of acute kidney injury (AKI). Methods We explored the association of a functional polymorphism in the promoter region (rs1800629) of the TNFA gene with severity of AKI, as defined by level of glomerular filtration (serum cystatin C and creatinine) and tubular injury (urinary NAG, KIM-1, α-GST, and π-GST) markers, in 262 hospitalized adults. Results In unadjusted analyses, compared with the GG genotype, the TNFA GA and AA genotype groups tended to have higher enrollment (p = 0.08), peak (p = 0.004), and discharge (p = 0.004) serum creatinine levels, and the AA genotype tended to have a higher enrollment serum cystatin C level (p = 0.04). Compared with the GG genotype, the TNFA GA and AA genotype groups tended to have a higher urinary KIM-1 level (p = 0.03), and the AA genotype group tended to have a higher urinary π-GST level (p = 0.03). After adjustment for sex, race, age, baseline estimated glomerular filtration rate, sepsis, and dialysis requirement, compared with the GG genotype, the TNFA minor A-allele group had a higher peak serum creatinine of 1.03 mg/dl (0.43, 1.63; p = 0.001) and a higher urinary KIM-1 (relative ratio: 1.73; 95% CI: 1.16, 2.59; p = 0.008). The TNFA minor A-allele group also had a higher Multiple Organ Failure score of 0.26 (95% CI: 0.03, 0.49; p = 0.024) after adjustment for sex, race, age, and sepsis. Conclusions The TNFA rs1800629 gene polymorphism is associated with markers of kidney disease severity and distant organ dysfunction among patients with AKI. Larger studies are needed to confirm these relationships. PMID:23796916

  10. Could single-nucleotide polymorphisms (SNPs) affecting the tumour necrosis factor promoter be considered as part of rheumatoid arthritis evolution?

    PubMed

    Aguillón, Juan C; Cruzat, Andrea; Aravena, Octavio; Salazar, Lorena; Llanos, Carolina; Cuchacovich, Miguel

    2006-01-01

    Tumour necrosis factor (TNF), a cytokine mainly produced by macrophages, is associated with a broad spectrum of biological effects, mainly associated with the host defense against microbes. The TNF gene is located on chromosome six within the major histocompatibility complex (MHC). Rheumatoid arthritis (RA) is a systemic autoimmune disease where TNF plays a central role in its etiology and pathogenesis. Written medical evidence of RA can be traced at least as far back as the 17th century, while human paleopathological studies appear to show the presence of RA prior to this period. The fact that RA has experienced an increment both in severity and mortality could be explained by many causes, particularly the crucial role of the immune system. Single-nucleotide polymorphisms (SNPs) are the most common genetic variations and occur at a frequency of approximately 1 in 1000 bp throughout the genome. The -308 TNF SNP is a mutation that affects the promoter region of the TNF gene. It defines the TNF1 and TNF2 alleles, determining low and high levels of TNF expression, respectively. The presence of the TNF2 allele has also been linked to increased susceptibility to and severity in a variety of autoimmune and inflammatory disorders, including RA, systemic lupus erythematosus, and ankylosing spondylitis. Studies on the functional significance of -308 SNP have detected higher levels of TNF production by cells from TNF2-carrying individuals than cells from TNF1 individuals. This difference does not appear to be due to other genes lying within the MHC region. Since the presence of the TNF2 allele may increase the host's resistance to local infection, by increasing local production of TNF at the infection site, we may suggest that such a mutation has emerged as a selective advantage to carriers of the TNF2 allele. This hypothesis may prove itself by observing the high incidence of tuberculosis and other infectious processes in those patients treated with anti-TNF therapy. Since

  11. Molecular-level origins of biomass recalcitrance: decrystallization free energies for four common cellulose polymorphs.

    PubMed

    Beckham, Gregg T; Matthews, James F; Peters, Baron; Bomble, Yannick J; Himmel, Michael E; Crowley, Michael F

    2011-04-14

    Cellulose is a crystalline polymer of β1,4-D-glucose that is difficult to deconstruct to sugars by enzymes. The recalcitrance of cellulose microfibrils is a function of both the shape of cellulose microfibrils and the intrinsic work required to decrystallize individual chains, the latter of which is calculated here from the surfaces of four crystalline cellulose polymorphs: cellulose Iβ, cellulose Iα, cellulose II, and cellulose III(I). For edge chains, the order of decrystallization work is as follows (from highest to lowest): Iβ, Iα, ΙΙΙ(Ι), and II. For cellulose Iβ, we compare chains from three different locations on the surface and find that an increasing number of intralayer hydrogen bonds (from 0 to 2) increases the intrinsic decrystallization work. From these results, we propose a microkinetic model for the deconstruction of cellulose (and chitin) by processive enzymes, which when taken with a previous study [Horn et al. Proc. Natl. Acad. Sci. U.S.A. 2006, 103, 18089] identifies the thermodynamic and kinetic attributes of enzyme and substrate engineering for enhanced cellulose (or chitin) conversion. Overall, this study provides new insights into the molecular interactions that form the structural basis of cellulose, which is the primary building block of plant cell walls, and highlights the need for experimentally determining microfibril shape at the nanometer length scale when comparing conversion rates of cellulose polymorphs by enzymes. PMID:21425804

  12. Association between a polymorphic poly-T repeat sequence in the promoter of the somatostatin gene and hypertension.

    PubMed

    Tremblay, Monique; Brisson, Diane; Gaudet, Daniel

    2016-06-01

    Despite the numerous common pathways connecting blood pressure regulation to somatostatin (SST) metabolism, the SST gene has never been seen as a significant blood pressure modulator. The aim of this study was to evaluate the association between a poly-T repeat sequence (rs34872250) in the promoter of the SST gene and blood pressure, according to the obesity status. We genotyped 1918 French-Canadian subjects from a founder population. Analyses were performed according to the length of the poly-T repeat sequence on both alleles and divided into two groups, the 13/13-13/14 group and the 13/15-13/16 group. The effect of age, gender, body mass index, antihypertensive drugs and diabetic status were considered. Systolic, diastolic and mean blood pressures are significantly higher among the 13/15-13/16 group in the whole sample (P<0.05). Whereas the differences remain significant in women, they turn to be non-significant when men are considered alone. The risk of hypertension is increased in the 13/15-13/16 group, particularly among overweight/obese subjects. Systolic blood pressure is significantly higher among overweight/obese carriers of the 13/15-13/16 alleles in the whole sample (P<0.001), in men (P=0.006) and in women (P=0.002), even after correction for age and antihypertensive drugs. These results suggest that the poly-T repeat sequence polymorphism in the promoter of the SST gene is associated with significant variations of blood pressure and could modulate the risk of hypertension, particularly among women. PMID:26818653

  13. Neonatal Fc receptor promoter gene polymorphism does not predict pharmacokinetics of IVIg or the clinical course of GBS.

    PubMed

    Fokkink, Willem-Jan R; Haarman, Annechien E G; Tio-Gillen, Anne P; van Rijs, Wouter; Huizinga, Ruth; van Doorn, Pieter A; Jacobs, Bart C

    2016-07-01

    Treatment of Guillain-Barré syndrome with a standard course of high-dose intravenous immunoglobulin (IVIg) results in a variable clinical recovery which is associated with changes in serum IgG levels after treatment. The neonatal Fc-receptor protects IgG from degradation, and a genetic polymorphism in its promoter region that influences the expression of Fc-receptor, may in part explain the variation in IgG levels and outcome. This polymorphism was determined by polymerase chain reaction in a cohort of 257 patients with Guillain-Barré syndrome treated with IVIg. We could not demonstrate a relation between this polymorphism, the pharmacokinetics of IVIg, or the clinical course and outcome. PMID:27386503

  14. Common polymorphism in a highly variable region upstream of the human lactase gene affects DNA-protein interactions.

    PubMed

    Hollox, E J; Poulter, M; Wang, Y; Krause, A; Swallow, D M

    1999-01-01

    In most mammals lactase activity declines after weaning when lactose is no longer part of the diet, but in many humans lactase activity persists into adult life. The difference responsible for this phenotypic polymorphism has been shown to be cis-acting to the lactase gene. The causal sequence difference has not been found so far, but a number of polymorphic sites have been found within and near to the lactase gene. We have shown previously that in Europeans there are two polymorphic sites in a small region between 974 bp and 852 bp upstream from the start of transcription, which are detectable by denaturing gradient gel electrophoresis (DGGE). In this study, analysis of individuals from five other population groups by the same DGGE method reveals four new alleles resulting from three additional nucleotide changes within this very small region. Analysis of sequence in four primate species and comparison with the published pig sequence shows that the overall sequence of this highly variable human region is conserved in pigs as well as primates, and that it lies within a 1kb region which has been shown to control lactase downregulation in pigs. Electrophoretic mobility shift assay (EMSA) studies were carried out to determine whether common variation affected protein-DNA binding and several binding activities were found using this technique. A novel two base-pair deletion that is common in most populations tested, but is not present in Europeans, caused no change in binding activity. However, a previously published C to T transition at -958bp dramatically reduced binding activity, although the functional significance of this is not clear. PMID:10573012

  15. A Meta-Analysis of the Effects of the 5-Hydroxytryptamine Transporter Gene-Linked Promoter Region Polymorphism on Susceptibility to Lifelong Premature Ejaculation

    PubMed Central

    Wu, Sheng; Shao, Hongbao; Dai, Feng; Peng, Tao; Qin, Feng; Feng, Ninghan

    2013-01-01

    Objective Premature ejaculation (PE) has been reported as the most common male sexual dysfunction with global prevalence rates estimated at approximately 30%. The neurobiogenesis of ejaculation is very complex and involves the serotoninergic (5-hydroxytryptamine, 5-HT) system. Recently, genetic polymorphisms located on SLC6A4 gene codifying for 5-HT transporter (5-HTT), the major regulator of serotonic neurotransmission, have been linked with the pathogenesis and risk of PE. Apparently studies of this type of polymorphism in PE have show conflicting results. Methods A meta-analysis was performed that are available in relation with 5-HTT gene-linked promoter region (5-HTTLPR) polymorphism and the risk of lifelong PE (LPE) in men to clarify this relationship. We searched Pubmed and Embase (last search updated on Aug 2012) using ‘premature ejaculation’, ‘polymorphism or variant’, ‘genotype’, ‘ejaculatory function’, and ‘rapid ejaculation’ as keywords and reference lists of studies corresponded to the inclusion criteria for meta-analysis. These studies involved the total number of 481 LPE men and 466 health control men subjects. Odds ratio (OR) and 95% confidence intervals (CIs) were used to evaluate this relationship. Results In the overall analysis, significant associations between LPE risk and 5-HTTLPR polymorphism were found (L-allele vs. S-allele OR = 0.86, 95% CI = 0.79–0.95, P = 0.002; LL vs. SS: OR = 0.80, 95% CI = 0.68–0.95, P = 0.009; LS vs. SS: OR = 0.85, 95% CI = 0.76–0.97, P = 0.012 and LL+LS vs. SS: OR = 0.88, 95% CI = 0.81–0.95, P = 0.002). Moreover, in subgroup analysis based on ethnicity, similar significant associations were detected. The Egger’s test did not reveal presence of a publication bias. Conclusions Our investigations demonstrate that 5-HTTLPR (L>S) polymorphism might protect men against LPE risk. Further studies based on larger sample size and gene

  16. Promoter Polymorphism (rs12770170, -184C/T) of Microseminoprotein, Beta as a Risk Factor for Benign Prostatic Hyperplasia in Korean Population

    PubMed Central

    Ban, Ju Yeon

    2014-01-01

    Purpose Benign prostatic hyperplasia (BPH) is the most common prostate disease in aging men. Microseminoprotein-beta (MSMB) is abundant in semen. In this study, we investigated association between single nucleotide polymorphisms (SNPs) at the promoter of the MSMB gene and the risk for developing BPH in a Korean population. Methods We genotyped two promoter polymorphisms (rs12770171, -184C/T and rs10993994, -2C/T) of the MSMB gene by direct sequencing. Ninety-five BPH patients and 78 control subjects were recruited for this study. SNPStats and Haploview version 4.2 were used for genetic analyses. Multiple logistic regression models (codominant, dominant, recessive, and log-additive models) were applied to determine the odds ratio (OR), 95% confidence interval (CI), and P-value. Results Genotype frequency of the rs12770171 SNP showed significant difference between BPH patients and controls (OR, 2.14; 95% CI, 1.07-4.27; P=0.032 in the codominant 1 model; OR, 2.31; 95% CI, 1.19-4.47; P=0.011 in the dominant model; and OR, 2.05; 95% CI, 1.17-3.61; P=0.009 in the log-additive model). Moreover, the SNP also showed association between the two groups (OR, 2.05; 95% CI, 1.19-3.52; P=0.009). The rs10993994 SNP was not associated with BPH. In haplotype analysis, CC and TT haplotypes were associated with BPH (P<0.05). Conclusions This result indicates that a promoter polymorphism (rs12770170, -184C/T) in the MSMB gene may be associated with BPH development in a Korean population. PMID:24987558

  17. Genetic polymorphisms of tumour necrosis factor alpha (TNF-α) promoter gene and response to TNF-α inhibitors in Spanish patients with inflammatory bowel disease.

    PubMed

    López-Hernández, R; Valdés, M; Campillo, J A; Martínez-Garcia, P; Salama, H; Salgado, G; Boix, F; Moya-Quiles, M R; Minguela, A; Sánchez-Torres, A; Miras, M; Garcia, A; Carballo, F; Álvarez-López, M R; Muro, M

    2014-02-01

    Tumour necrosis factor alpha (TNF-α) has an important role in inflammatory response. Alterations in the regulation of TNF-α have been implicated in a variety of inflammatory disorders, including Inflammatory bowel disease (IBD). Indeed, a common treatment for IBD is the use of TNF-α inhibitors. Polymorphisms in the TNF-α promoter region are known to affect the level of gene expression. Our aim was to investigate the influence of these single nucleotide polymorphisms (SNPs) in TNF-α promoter gene play in the risk of IBD in a Spanish population and their individual response to anti-TNF-α treatment. DNA samples from patients with IBD and controls were screened for TNF-α -238G/A (rs361525) and -308G/A (rs1800629) SNPs by PCR-SSOP using a microbeads luminex assay and compared with response to TNF-α inhibitors. There were not statistical differences in -238G/A and -308G/A allele and genotype frequencies between patients. However, we found an increased frequency of -308A allele and -308GA genotype in these nonresponders patients to TNF-α inhibitors with respect to responders patients (Pc < 0.05). This -308GA genotype has been classified as high producer of this cytokine. This fact could actually be interesting to explain the different response of patients with IBD with respect to TNF-α inhibitors. TNF-α promoter gene polymorphism does not seem to play a role in IBD susceptibility, but particular TNF-α genotypes may be involved in the different responses to TNF-α inhibitor treatment in Spanish patients with IBD. PMID:23590430

  18. Matrix metalloproteinase (MMP) -2, -7 and -9 promoter polymorphisms in colorectal cancer in ethnic Kashmiri population - A case-control study and a mini review.

    PubMed

    Banday, Mujeeb Zafar; Sameer, Aga Syed; Mir, Ashaq Hussain; Mokhdomi, Taseem A; Chowdri, Nissar A; Haq, Ehtishamul

    2016-09-01

    Matrix metalloproteinases (MMPs) are proteolytic enzymes that play a pivotal role in the transformation and progression of tumors at all stages, especially during the invasion and metastasis. The aim of this study was to determine the genetic association of MMP2, MMP7 and MMP9 promoter polymorphisms with colorectal cancer (CRC) susceptibility and development risk in ethnic Kashmiri population. The genotype frequencies of MMP2-1306C/T, MMP7-181A/G and MMP9-1562C/T SNPs were compared between 142 CRC patients and 184 healthy controls by using PCR-RFLP method. The association between all the three MMP promoter polymorphisms and the modulation of risk of CRC was found to be significant (p≤0.05). The heterozygous genotype (CT) of MMP2-1306C/T SNP and variant genotype (GG) of MMP7-181A/G SNP showed a significant association with decreased risk for the development of CRC [OR, 0.61 (95%CI, 0.37-1.01); p=0.05 and OR, 0.43 (95%CI, 0.20-0.90); p=0.02, respectively] whereas the heterozygous genotype (CT) of MMP9-1562C/T SNP showed a significant association with increased risk for the development of colorectal cancer [OR, 1.88 (95%CI, 1.11-3.18); p=0.02]. Further, the less common MMP9-1562T allele was found to be significantly associated with an increased risk of colorectal cancer [OR, 1.74 (95%CI, 1.15-2.62); p=0.007]. Our results suggest that these MMP2, MMP7 and MMP9 promoter polymorphisms play a role as one of the key modulators of the risk of developing colorectal cancer in Kashmiri population. PMID:27222481

  19. The Catalase –262C/T Promoter Polymorphism and Diabetic Complications in Caucasians with Type 2 Diabetes

    PubMed Central

    dos Santos, Kátia Gonçalves; Canani, Luís Henrique; Gross, Jorge Luiz; Tschiedel, Balduíno; Souto, Kátia Elisabete Pires; Roisenberg, Israel

    2006-01-01

    Catalase is a central antioxidant enzyme constituting the primary defense against oxidative stress. In this study, we investigated whether the functional –262C/T polymorphism in the promoter of catalase gene is associated with the presence of diabetic retinopathy (DR), diabetic nephropathy (DN) and ischemic heart disease (IHD) in 520 Caucasian-Brazilians with type 2 diabetes. The –262C/T polymorphism was also examined in 100 Caucasian blood donors. Patients underwent a clinical and laboratory evaluation consisting of a questionnaire, physical examination, assessment of diabetic complications and laboratory tests. Genotype analysis was performed using the polymerase chain reaction followed by digestion with restriction enzyme. The genotype and allele frequencies of the –262C/T polymorphism in patients with type 2 diabetes were very similar to those of blood donors (T allele frequency = 0.20 and 0.18, respectively). Likewise, there were no differences in either genotype or allele frequencies between type 2 diabetic patients with or without DR, DN or IHD. Thus, our results do not support the hypothesis that the –262C/T polymorphism is related to the development of DR, DN or IHD in patients with type 2 diabetes. Further studies are necessary to elucidate the role of catalase gene polymorphisms in the pathogenesis of diabetic complications. PMID:17264407

  20. Intravarietal polymorphisms reveal possible common ancestor of native Schinus terebinthifolius Raddi populations in Brazil.

    PubMed

    Pinto, J V C; Crispim, B A; Vasconcelos, A A; Geelen, D; Grisolia, A B; Vieira, M C

    2016-01-01

    Schinus terebinthifolius Raddi is a perennial native from Atlantic forest. It is of high ecological plasticity and is used in traditional medicine. Based on promising reports concerning its bioactivity, it was included as a species of great interest for distribution through the National Health System. A number of agronomic studies to guide its crop production are therefore underway. This study examined diversity and phylogenetic relationships among native S. terebinthifolius populations from different Brazilian ecosystems: Cerrado; sandbanks; dense rainforest; and deciduous forest. The intergenic regions rpl20-5'rps12, trnH-psbA, and trnS-trnG were sequenced from cpDNA and aligned using BLASTn. There were few fragments for comparison in GenBank and so only region trnS-trnG was informative. There were variations among and within populations with intravarietal polymorphisms and three distinct haplotypes (HpSM, HpDDO, HpNE), once populations from NE (sandbanks and rainforest) clustered together. Sequences from HpSM, HpNE, and HpDDO returned greater similarity to haplotypes A (AY928398.1), B (AY928399.1), and C (AY928400.1), respectively. A network, built by median-joining among native haplotypes and 10 available on GenBank, revealed HpSM as the origin of all other haplogroups. HpDDO showed the most mutations and was closely related to haplogroups from Argentina. While this could indicate hybridization, we believe that the polymorphisms resulted from adaptation to events such as deforestation, fire, rising temperature, and seasonal drought during the transition from Atlantic forest to Cerrado. While more detailed phylogeographical studies are needed, these results indicate eligible groups for distinct climates as an important step for pre-breeding programs before field propagation. PMID:26909905

  1. Evaluation of cytokine genetic polymorphisms in adult patients with common variable immunodeficiency: A single-center study.

    PubMed

    Perovic, Dijana; Perovic, Vladimir; Pravica, Vera; Bonaci-Nikolic, Branka; Mijanovic, Radovan; Bunjevacki, Vera

    2016-08-01

    Common variable immunodeficiency (CVID) is a heterogeneous disease characterized by impaired B-cell differentiation and maturation accompanied with the defective antibody production. Several investigators addressed the possibility that disturbed cytokine production of TNF, IL-6, IFN-γ and IL-10, among a variety of others, may be implicated in CVID. The aim of this study was to test the hypothesis that genetic polymorphisms involving TNF (-308G/A), IFNG (+874 T/A), IL10 (-1082G/A, -819T/C and -592A/C), and IL6 (-174G/C) cytokine genes might contribute to susceptibility to CVID. Thirty five patients with CVID and 250 healthy controls were genotyped for indicated single nucleotide polymorphisms (SNP) in TNF, IL6, IFNG and IL10 using Taqman-based assays. CVID patients had significantly higher frequency of TNF A allele and AA genotype than in healthy subjects (p=0.006; OR=2.27; 95%CI=1.24-4.17 and p=0.038, OR=15.64; 95%CI=1.38-177.20, respectively). In addition, the frequency of GG genotype was significantly higher in healthy controls than in patient group (p=0.019, OR=0.43, 95%CI=0.21-0.89). Genetic analysis of IL6 SNP showed that allele G confers increased risk for CVID (p=0.037, OR=1.78, 95% CI=1.03-3.08) while IFNG allele T was associated with splenomegaly in CVID (p=0.032; OR=2.86; 95% CI=1.08-7.56). We observed no association between genotypes, alleles and haplotypes of IL-10 gene and CVID or its clinical complications. In conclusion, our results indicated association between CVID and cytokine gene polymorphisms -308G/A TNF and -174G/C IL6. In addition, we demonstrated that splenomegaly, one of the most common complications in this disease, is associated with +874T/A IFNG polymorphism. These findings add further support to the notion that cytokines may play significant role in pathogenesis of this primary antibody deficiency. However, further investigation that would involve a larger study group of CVID patients is warranted to confirm our findings. PMID:27288995

  2. Single-nucleotide polymorphisms and activity analysis of the promoter and enhancer of the pig lactase gene.

    PubMed

    Du, Hai-Ting; Zhu, Hong-Yan; Wang, Jia-Mei; Zhao, Wei; Tao, Xiao-Li; Ba, Cai-Feng; Tian, Yu-Min; Su, Yu-Hong

    2014-07-15

    Lactose intolerance in northern Europeans is strongly associated with a single-nucleotide polymorphism (SNP) located 14 kb upstream of the human lactase gene: -13,910 C/T. We examined whether SNPs in the 5' flanking region of the pig lactase gene are similar to those in the human gene and whether these polymorphisms play a functional role in regulating pig lactase gene expression. The 5' flanking region of the lactase gene from several different breeds of pigs was cloned and analyzed for gene regulatory activity of a luciferase reporter gene. One SNP was found in the enhancer region (-797 G/A) and two were found in the promoter region (-308G/C and -301 A/G). The promoter C-308,G-301(Pro-CG) strongly promotes the expression of the lactase gene, but the promoter G-308,A-301(Pro-GA) does not. The enhancer A-797(Enh-A) genotype for Pro-GA can significantly enhance promoter activity, but has an inhibitory effect on Pro-CG. The Enhancer G-797(Enh-G) has a significant inhibitory effect on both promoters. In conclusion, the order of effectiveness on the pig lactase gene is Enh-A+Pro-GA>Enh-A/G+Pro-CG>Enh-G+Pro-GA. PMID:24809963

  3. A common IL-13 Arg130Gln single nucleotide polymorphism among Chinese atopy patients with allergic rhinitis.

    PubMed

    Wang, Min; Xing, Zhi-Min; Lu, Chao; Ma, You-Xiang; Yu, De-Lin; Yan, Zheng; Wang, Shen-Wu; Yu, Li-Sheng

    2003-10-01

    Allergic rhinitis is a major public health problem and has seen its prevalence increase during the past few decades. Interleukin 13 (IL-13) has been implicated in the pathogenesis and in the regulation of immunoglobulin E (IgE) production. Single nucleotide polymorphisms (SNPs) have been found in both the coding sequence and the promoter region of IL-13, and such SNPs have been associated with allergic asthma. We have investigated whether IL-13 SNPs are associated with allergic rhinitis. Among 188 Chinese adult patients with allergic rhinitis and 87 normal controls, no significant difference was found in either allele or haplotype frequency of the SNPs between the two groups. Within patients, there was a significant association of the IL-13 Arg130Gln SNP, but not of the IL-13 promoter -1112(C/T) SNP, with serum total IgE levels. Patients with a Gln/Gln genotype showed much higher serum total IgE than those with an Arg/Arg genotype. When tested for serum-specific IgE, patients allergic to Derp 1, but not those allergic to Artemisia pollen, showed a significant association with the IL-13 promoter SNP. Thus, our results suggest a possible involvement of IL-13 SNPs in the regulation of IgE production in response to allergens in this Chinese population. PMID:12928861

  4. Unfulfilled Promises: How Inventories, Instruments and Institutions Subvert Discourses of Diversity and Promote Commonality

    ERIC Educational Resources Information Center

    Ritter, Leonora

    2007-01-01

    This paper looks at the paradox of how recognition of diversity through research into individual differences, in such areas as learning style, cognitive style and personality, has had the reductionist effect of promoting commonality. This has been the outcome of the competition between inventories; the reduction of diversity to characteristics…

  5. FSHB promoter polymorphism within evolutionary conserved element is associated with serum FSH level in men

    PubMed Central

    Grigorova, Marina; Punab, Margus; Ausmees, Kristo; Laan, Maris

    2008-01-01

    BACKGROUND No polymorphisms affecting serum FSH levels have been described in the human FSHB gene. We have identified a potential regulatory single nucleotide polymorphism (SNP, rs10835638; G/T) 211 bp upstream from the FSHB mRNA transcription start-site, located within a highly conserved region among placental mammals. We aimed to determine the correlation of carrier status of rs10835638 alternative alleles with serum FSH level in men, and testicular and hormonal parameters. METHODS A quantitative genetic association study using a cohort of healthy men (n = 554; age 19.2 ± 1.7 years) visiting the Centre of Andrology, Tartu University Hospital, Estonia. RESULTS Rs10835638 (allele frequencies: G 87.6%, T 12.4%) was significantly associated with serum FSH level (analysis of variance: F = 13.0, P = 0.0016, df = 1; regression testing for a linear trend: P = 0.0003). Subjects with the GG genotype exhibited higher FSH levels (3.37 ± 1.79 IU/l, n = 423) compared with heterozygotes (2.84 ± 1.54 IU/l, n = 125) (P = 0.0005), the group of T-allele carriers (GT+TT, 2.78 ± 1.51 IU/l, n = 131) (P = 0.0005) and TT-homozygotes (2.02 ± 0.81 IU/L, n = 6) (P = 0.031). Rs10835638 was also associated with significant (P < 0.05) reduction in free testosterone index and testes volume, but increased semen volume, sex hormone-binding globulin, serum testosterone and estradiol. LH and inhibin-B levels did not differ significantly between groups. CONCLUSIONS The identification of a regulatory SNP in FSHB promoter paves the way to study the effect of constitutively low FSH on male health and fertility. As FSH contributes to follicular development and sex steroid production in women, the role of this FSHB variant in female reproductive success is still to be addressed. PMID:18567894

  6. Association analysis of polymorphism in thyroglobulin gene promoter with milk production traits in riverine buffalo (Bubalus bubalis)

    PubMed Central

    Dubey, P.K.; Goyal, S.; Mishra, S.K.; Yadav, A.K.; Kathiravan, P.; Arora, R.; Malik, R.; Kataria, R.S.

    2015-01-01

    Polymorphism within the promoter region of bovine thyroglobulin has been reported to be associated with milk and meat quality. In this study, we investigated the genetic variation within thyroglobulin promoter region of swamp and riverine buffaloes using PCR–SSCP technique and sequencing, and also analyzing association of polymorphism with the milk production traits. The study revealed four conformational patterns, A, B, C, and D among 323 buffaloes of two riverine breeds and different swamp populations. The frequency of SSCP variant ‘A’ was found to be invariably high among all buffalo populations. Variant ‘C’ was found to be absent in pure swamp population and present with higher frequency among riverine dairy breeds Mehsana and Nili Ravi. Frequency of D variant was observed to be highest in buffalo population, representing riverine and hybrid types. Sequencing of three representative PCR products of each of the SSCP variants, revealed three polymorphic sites responsible, 33C > T, 176G > T and 221C > T, in the buffalo TG promoter region. Further, association studies of SSCP variants with various milk production and milk quality traits indicated significant effect on fat percentage in buffaloes belonging to Mehsana and Nili Ravi dairy breeds. The preliminary results also showed the substantial variations in the distribution of SSCP variants' frequencies across swamp and riverine buffaloes, two distinct populations being reared for meat and milk production, respectively. PMID:26273563

  7. A Common Polymorphism in EC-SOD Affects Cardiopulmonary Disease Risk by Altering Protein Distribution

    PubMed Central

    Hartney, John M.; Stidham, Timothy; Goldstrohm, David A.; Oberley-Deegan, Rebecca E.; Weaver, Michael R.; Valnickova-Hansen, Zuzana; Scavenius, Carsten; Benninger, Richard K.P.; Leahy, Katelyn F.; Johnson, Richard; Gally, Fabienne; Kosmider, Beata; Zimmermann, Angela K.; Enghild, Jan J.; Nozik-Grayck, Eva; Bowler, Russell P.

    2014-01-01

    Background The enzyme extracellular superoxide dismutase (EC-SOD; SOD3) is a major antioxidant defense in lung and vasculature. A nonsynonomous single nucleotide polymorphism (SNP) in EC-SOD (rs1799895) leads to an arginine to glycine (Arg->Gly) amino acid substitution at position 213 (R213G) in the heparin-binding domain (HBD). In recent human genetic association studies, this SNP attenuates the risk of lung disease, yet paradoxically increases the risk of cardiovascular disease. Methods and Results Capitalizing on the complete sequence homology between human and mouse in the HBD, we created an analogous R213G SNP knockin mouse. The R213G SNP did not change enzyme activity, but shifted the distribution of EC-SOD from lung and vascular tissue to extracellular fluid (e.g. bronchoalveolar lavage fluid (BALF) and plasma). This shift reduces susceptibility to lung disease (lipopolysaccharide-induced lung injury) and increases susceptibility to cardiopulmonary disease (chronic hypoxic pulmonary hypertension). Conclusions We conclude that EC-SOD provides optimal protection when localized to the compartment subjected to extracellular oxidative stress: thus, the redistribution of EC-SOD from the lung and pulmonary circulation to the extracellular fluids is beneficial in alveolar lung disease but detrimental in pulmonary vascular disease. These findings account for the discrepant risk associated with R213G in humans with lung diseases compared with cardiovascular diseases. PMID:25085920

  8. Efficiency of immunoglobulin G replacement therapy in common variable immunodeficiency: correlations with clinical phenotype and polymorphism of the neonatal Fc receptor.

    PubMed

    Gouilleux-Gruart, V; Chapel, H; Chevret, S; Lucas, M; Malphettes, M; Fieschi, C; Patel, S; Boutboul, D; Marson, M-N; Gérard, L; Lee, M; Watier, H; Oksenhendler, E

    2013-02-01

    Treatment of common variable immunodeficiency disorders (CVID) is based on replacement therapy using intravenous (i.v.) or subcutaneous (s.c.) immunoglobulin (Ig)G. Interindividual variation of IgG dose is common. A total of 380 CVID patients on stable IgG replacement from two prospective cohorts were analysed. An 'efficiency' index was defined as the ratio of serum IgG trough level minus IgG residual to the average weekly dose of IgG infusion. A reduced efficiency of IgG was associated independently with the i.v. route (P < 0·001) and with the presence of at least one CVID disease-related phenotype (lymphoproliferation, autoimmune cytopenia or enteropathy) (P < 0·001). High IgG efficiency was noted in patients homozygotes for the variable number tandem repeat (VNTR) 3/3 polymorphism of the neonatal Fc receptor gene [IgG Fc fragment receptor transporter alpha chain (FCGRT)] promoter, and this was particularly significant in patients treated with IVIG (P < 0.01). In a multivariate analysis, FCGRT VNTR 3/3 genotype (P = 0·008) and high serum albumin (P < 0·001) were associated independently with increased efficiency of i.v. Ig. PMID:23286945

  9. Efficiency of immunoglobulin G replacement therapy in common variable immunodeficiency: correlations with clinical phenotype and polymorphism of the neonatal Fc receptor

    PubMed Central

    Gouilleux-Gruart, V; Chapel, H; Chevret, S; Lucas, M; Malphettes, M; Fieschi, C; Patel, S; Boutboul, D; Marson, M-N; Gérard, L; Lee, M; Watier, H; Oksenhendler, E

    2013-01-01

    Treatment of common variable immunodeficiency disorders (CVID) is based on replacement therapy using intravenous (i.v.) or subcutaneous (s.c.) immunoglobulin (Ig)G. Interindividual variation of IgG dose is common. A total of 380 CVID patients on stable IgG replacement from two prospective cohorts were analysed. An ‘efficiency’ index was defined as the ratio of serum IgG trough level minus IgG residual to the average weekly dose of IgG infusion. A reduced efficiency of IgG was associated independently with the i.v. route (P < 0·001) and with the presence of at least one CVID disease-related phenotype (lymphoproliferation, autoimmune cytopenia or enteropathy) (P < 0·001). High IgG efficiency was noted in patients homozygotes for the variable number tandem repeat (VNTR) 3/3 polymorphism of the neonatal Fc receptor gene [IgG Fc fragment receptor transporter alpha chain (FCGRT)] promoter, and this was particularly significant in patients treated with IVIG (P < 0.01). In a multivariate analysis, FCGRT VNTR 3/3 genotype (P = 0·008) and high serum albumin (P < 0·001) were associated independently with increased efficiency of i.v. Ig. PMID:23286945

  10. Promoter Polymorphisms in the Nitric Oxide Synthase 3 Gene Are Associated With Ischemic Stroke Susceptibility in Young Black Women

    PubMed Central

    Howard, Timothy D.; Giles, Wayne H.; Xu, Jianfeng; Wozniak, Marcella A.; Malarcher, Ann M.; Lange, Leslie A.; Macko, Richard F.; Basehore, Monica J.; Meyers, Deborah A.; Cole, John W.; Kittner, Steven J.

    2006-01-01

    Background and Purpose Endothelial nitric oxide exerts a variety of protective effects on endothelial cells and blood vessels, and therefore the nitric oxide synthase 3 gene (NOS3) is a logical candidate gene for stroke susceptibility. Methods We used the population-based Stroke Prevention in Young Women case-control study to assess the association of five NOS3 polymorphisms in 110 cases (46% black) with ischemic stroke and 206 controls (38% black), 15 to 44 years of age. Polymorphisms included 3 single nucleotide polymorphisms (SNPs) in the promoter region (−1468 T>A, −922 G>A, −786 T>C), 1 SNP in exon 7 (G894T), and 1 insertion/deletion polymorphism within intron 4. Results Significant associations with both the −922 G>A and −786 T>C SNPs with ischemic stroke were observed in the black, but not the white, population. This association was attributable to an increased prevalence of the −922 A allele (OR=3.0, 95% CI=1.3 to 6.8; P=0.005) and the −786 T allele (OR=2.9, 95% CI=1.3 to 6.4; P=0.005) in cases versus controls. These 2 SNPs were in strong linkage disequilibrium (D′=1.0), making it impossible to determine, within the confines of this genetic study, whether 1 or both of these polymorphisms are functionally related to NOS3 expression. Two sets of haplotypes were also identified, 1 of which may confer an increased susceptibility to stroke in blacks, whereas the other appears to be protective. Conclusion Promoter variants in NOS3 may be associated with ischemic stroke susceptibility among young black women. PMID:16100023

  11. Association between TNF promoter -308 G>A and LTA 252 A>G polymorphisms and systemic lupus erythematosus.

    PubMed

    Ahmed, Hanan Hosni; Taha, Fatma Mohamed; Darweesh, Hanan El-Sayed; Morsi, Heba Mohamed Abdelhafiz

    2014-01-01

    Tumor necrosis factor (TNF) and lymphotoxin alpha (LTA) are pivotal cytokines in the pathogenesis of systemic lupus erythematosus (SLE). To investigate the possible association of the polymorphism of the TNF promoter gene -308 and that of the LTA gene 252 with susceptibility to SLE and with phenotypic disease features in Egyptian patients. A case control study involving 100 SLE patients and 100 unrelated healthy controls. Polymerase chain reaction and restriction fragment length polymorphism methods were applied to detect genetic polymorphism. We found that TNF-308 genotype AA was significantly increase by 26 % in SLE patients compared to 10 % in the control group (p = 0.003; OR 3.16; CI 1.43-6.98) and the frequency of the A allele of the TNF promoter -308 was significantly higher in the SLE patients (42 %) than in the control subjects (24 %) (p < 0.001; OR 2.29; 95 % CI 1.49-3.52). Genotype LTA 252 GG showed a significant increase by 22 % in SLE patients compared to 6 % in the control group (p = 0.001; OR 4.42; 95 % CI 1.71-11.44), and the frequency of the G allele of the LTA was significantly higher in the SLE patients (38 %) than in the control subjects (21 %) (p < 0.001; OR 2.31; 95 % CI 1.48-3.6). Genotype (AA+GA) of TNF was significantly associated with clinical manifestations as malar rash, arthritis, oral ulcers, serositis and systemic lupus erythematosus disease activity index. Genotype (GG+GA) of LTA was significantly associated with arthritis. These results suggest that TNF and LTA genetic polymorphisms contribute to SLE susceptibility in the Egyptian population and are associated with disease characteristics. TNF-308 and LTA+252 polymorphic markers may be used for early diagnosis of SLE and early prediction of clinical manifestations, like arthritis. PMID:24420856

  12. Common Polymorphisms at the CYP17A1 Locus Associate With Steroid Phenotype: Support for Blood Pressure Genome-Wide Association Study Signals at This Locus.

    PubMed

    Diver, Louise A; MacKenzie, Scott M; Fraser, Robert; McManus, Frances; Freel, E Marie; Alvarez-Madrazo, Samantha; McClure, John D; Friel, Elaine C; Hanley, Neil A; Dominiczak, Anna F; Caulfield, Mark J; Munroe, Patricia B; Connell, John M; Davies, Eleanor

    2016-04-01

    Genome-wide association studies implicate the CYP17A1 gene in human blood pressure regulation although the causative polymorphisms are as yet unknown. We sought to identify common polymorphisms likely to explain this association. We sequenced the CYP17A1 locus in 60 normotensive individuals and observed 24 previously identified single-nucleotide polymorphisms with minor allele frequency >0.05. From these, we selected, for further studies, 7 polymorphisms located ≤ 2 kb upstream of the CYP17A1 transcription start site. In vitro reporter gene assays identified 3 of these (rs138009835, rs2150927, and rs2486758) as having significant functional effects. We then analyzed the association between the 7 polymorphisms and the urinary steroid metabolites in a hypertensive cohort (n=232). Significant associations included that of rs138009835 with aldosterone metabolite excretion; rs2150927 associated with the ratio of tetrahydrodeoxycorticosterone to tetrahydrodeoxycortisol, which we used as an index of 17α-hydroxylation. Linkage analysis showed rs138009835 to be the only 1 of the 7 polymorphisms in strong linkage disequilibrium with the blood pressure-associated polymorphisms identified in the previous studies. In conclusion, we have identified, characterized, and investigated common polymorphisms at the CYP17A1 locus that have functional effects on gene transcription in vitro and associate with corticosteroid phenotype in vivo. Of these, rs138009835--which we associate with changes in aldosterone level--is in strong linkage disequilibrium with polymorphisms linked by genome-wide association studies to blood pressure regulation. This finding clearly has implications for the development of high blood pressure in a large proportion of the population and justifies further investigation of rs138009835 and its effects. PMID:26902494

  13. Common Genetic Polymorphisms within NFκB-Related Genes and the Risk of Developing Invasive Aspergillosis

    PubMed Central

    Lupiañez, Carmen B.; Villaescusa, María T.; Carvalho, Agostinho; Springer, Jan; Lackner, Michaela; Sánchez-Maldonado, José M.; Canet, Luz M.; Cunha, Cristina; Segura-Catena, Juana; Alcazar-Fuoli, Laura; Solano, Carlos; Fianchi, Luana; Pagano, Livio; Potenza, Leonardo; Aguado, José M.; Luppi, Mario; Cuenca-Estrella, Manuel; Lass-Flörl, Cornelia; Einsele, Hermann; Vázquez, Lourdes; Ríos-Tamayo, Rafael; Loeffler, Jurgen; Jurado, Manuel; Sainz, Juan

    2016-01-01

    Invasive Aspergillosis (IA) is an opportunistic infection caused by Aspergillus, a ubiquitously present airborne pathogenic mold. A growing number of studies suggest a major host genetic component in disease susceptibility. Here, we evaluated whether 14 single-nucleotide polymorphisms within NFκB1, NFκB2, RelA, RelB, Rel, and IRF4 genes influence the risk of IA in a population of 834 high-risk patients (157 IA and 677 non-IA) recruited through a collaborative effort involving the aspBIOmics consortium and four European clinical institutions. No significant overall associations between selected SNPs and the risk of IA were found in this large cohort. Although a hematopoietic stem cell transplantation (HSCT)-stratified analysis revealed that carriers of the IRF4rs12203592T/T genotype had a six-fold increased risk of developing the infection when compared with those carrying the C allele (ORREC = 6.24, 95%CI 1.25–31.2, P = 0.026), the association of this variant with IA risk did not reach significance at experiment-wide significant threshold. In addition, we found an association of the IRF4AATC and IRF4GGTC haplotypes (not including the IRF4rs12203592T risk allele) with a decreased risk of IA but the magnitude of the association was similar to the one observed in the single-SNP analysis, which indicated that the haplotypic effect on IA risk was likely due to the IRF4rs12203592 SNP. Finally, no evidence of significant interactions among the genetic markers tested and the risk of IA was found. These results suggest that the SNPs on the studied genes do not have a clinically relevant impact on the risk of developing IA. PMID:27570521

  14. Effects of EZH2 promoter polymorphisms and methylation status on oral squamous cell carcinoma susceptibility and pathology

    PubMed Central

    Su, Kuo-Jung; Lin, Chiao-Wen; Chen, Mu-Kuan; Yang, Shun-Fa; Yu, Yung-Luen

    2015-01-01

    Oral squamous cell carcinoma (OSCC), which is malignant tumors in oral cavity, is the fourth most common male cancer in Taiwan. EZH2 plays a key role in transcriptional repression through chromatin remodeling and in cancer development. Although the EZH2 expression in OSCC is highly correlated with tumorigenesis, it has not been determined if specific EZH2 genetic variants are associated with OSCC risk. The aim of this study was to investigate the relationship between genetic polymorphisms of EZH2 and susceptibility to OSCC in Taiwan. Here, four SNPs of EZH2 (rs6950683, rs2302427, rs3757441, and rs41277434) were analyzed by a real-time PCR genotyping in 576 patients with oral cancer and 552 cancer-free controls. After adjusting for other co-variants, we found that carrying CC genotype at EZH2 rs6950683 and rs3757441 had a lower risk of developing OSCC than did wild-type carriers. The CCCA or CCTA haplotype among the four EZH2 sites was also associated with a reduced risk of OSCC. Furthermore, OSCC patients who carried CC genotype at EZH2 rs6950683 had a higher methylation than TC genotype. Our results suggest that the two SNPs of EZH2 (rs6950683 and rs3757441) might contribute to the prediction of OSCC susceptibility. Moreover, rs6950683 CC genotype exhibits hypermethylation in EZH2 promoter. This is the first study to provide insight into risk factors associated with EZH2 variants and epigenetic changes in carcinogenesis of OSCC in Taiwan. PMID:26807327

  15. CHARACTERIZATION OF SEVEN POLYMORPHIC MICROSATELLITE LOCI IN THE COMMON LOON (GAVIA IMMER)

    EPA Science Inventory

    We describe polymerase chain reaction (PCR) primers and conditions to amplify seven microsatellite DNA loci isolated from the Common Loon (Gavia immer). The PCR primers were tested on 83 individuals from ten locations in North America, including breeding, migration stopover, and...

  16. Genotyping the GGGCGG Tandem Repeat Promoter Polymorphism in the 5-Lipoxygenase Enzyme Gene (ALOX5) by Pyrosequencing Assay

    PubMed Central

    Schentrup, Anzeela M.; Allayee, Hooman; Lima, John J.; Johnson, Julie A.

    2009-01-01

    Aims: Efficient genotyping methods for many biologically significant repeat genetic polymorphisms, particularly in GC-rich regions of the genome, are limited. In particular, a short tandem repeat polymorphism [GGCGGG] in the promoter region of ALOX5 has been implicated as an important marker for inflammatory diseases. We developed a pyrosequencing assay to genotype the ALOX5 short tandem repeat polymorphism using pyrosequencing technology that will make assessing this important genetic marker in large, diverse populations more accessible than using current methods. Materials and Methods: We used a nested polymerase chain reaction approach to amplify DNA for pyrosequencing. Population allele frequencies were assessed in two cohorts of previously collected human DNA samples with 188 and 1032 samples, respectively. Sixteen genetic samples with known genotypes were used to confirm the accuracy of the method. Results and Discussion: Genotypes were 100% concordant with samples of known genotype. Genotype frequencies in European American, Hispanic, and African American agreed with previously published results (wild-type homozygotes 66%, 64%, and 19%, respectively). The method presented here will facilitate both genetic association and pharmacogenomic research on this polymorphism in large samples that are ethnically and/or racially admixed. PMID:19473080

  17. The functional significance of common polymorphisms in zinc finger transcription factors.

    PubMed

    Lockwood, Sarah H; Guan, Anna; Yu, Abigail S; Zhang, Chi; Zykovich, Artem; Korf, Ian; Rannala, Bruce; Segal, David J

    2014-09-01

    Variants that alter the DNA-binding specificity of transcription factors could affect the specificity for and expression of potentially many target genes, as has been observed in several tumor-derived mutations. Here we examined if such trans expression quantitative trait loci (trans-eQTLs) could similarly result from common genetic variants. We chose to focus on the Cys2-His2 class of zinc finger transcription factors because they are the most abundant superfamily of transcription factors in human and have well-characterized DNA binding interactions. We identified 430 SNPs that cause missense substitutions in the DNA-contacting residues. Fewer common missense SNPs were found at DNA-contacting residues compared with non-DNA-contacting residues (P = 0.00006), consistent with possible functional selection against SNPs at DNA-contacting positions. Functional predictions based on zinc finger transcription factor (ZNF) DNA binding preferences also suggested that many common substitutions could potentially alter binding specificity. However, Hardy-Weinberg Equilibrium analysis and examination of seven orthologs within the primate lineage failed to find evidence of trans-eQTLs associated with the DNA-contacting positions or evidence of a different selection pressure on a contemporary and evolutionary timescales. The overall conclusion was that common SNPs that alter the DNA-contacting residues of these factors are unlikely to produce strong trans-eQTLs, consistent with the observations by others that trans-eQTLs in humans tend to be few and weak. Some rare SNPs might alter specificity and remained rare due to purifying selection. The study also underscores the need for large-scale eQTLs mapping efforts that might provide experimental evidence for SNPs that alter the choice of transcription factor binding sites. PMID:24970883

  18. The Functional Significance of Common Polymorphisms in Zinc Finger Transcription Factors

    PubMed Central

    Lockwood, Sarah H.; Guan, Anna; Yu, Abigail S.; Zhang, Chi; Zykovich, Artem; Korf, Ian; Rannala, Bruce; Segal, David J.

    2014-01-01

    Variants that alter the DNA-binding specificity of transcription factors could affect the specificity for and expression of potentially many target genes, as has been observed in several tumor-derived mutations. Here we examined if such trans expression quantitative trait loci (trans-eQTLs) could similarly result from common genetic variants. We chose to focus on the Cys2-His2 class of zinc finger transcription factors because they are the most abundant superfamily of transcription factors in human and have well-characterized DNA binding interactions. We identified 430 SNPs that cause missense substitutions in the DNA-contacting residues. Fewer common missense SNPs were found at DNA-contacting residues compared with non-DNA-contacting residues (P = 0.00006), consistent with possible functional selection against SNPs at DNA-contacting positions. Functional predictions based on zinc finger transcription factor (ZNF) DNA binding preferences also suggested that many common substitutions could potentially alter binding specificity. However, Hardy-Weinberg Equilibrium analysis and examination of seven orthologs within the primate lineage failed to find evidence of trans-eQTLs associated with the DNA-contacting positions or evidence of a different selection pressure on a contemporary and evolutionary timescales. The overall conclusion was that common SNPs that alter the DNA-contacting residues of these factors are unlikely to produce strong trans-eQTLs, consistent with the observations by others that trans-eQTLs in humans tend to be few and weak. Some rare SNPs might alter specificity and remained rare due to purifying selection. The study also underscores the need for large-scale eQTLs mapping efforts that might provide experimental evidence for SNPs that alter the choice of transcription factor binding sites. PMID:24970883

  19. Systematic Functional Study of Cytochrome P450 2D6 Promoter Polymorphisms in the Chinese Han Population

    PubMed Central

    Gong, Xueli; Liu, Yichen; Zhang, Xiaoqing; Wei, Zhiyun; Huo, Ran; Shen, Lu; He, Lin; Qin, Shengying

    2013-01-01

    The promoter polymorphisms of drug-metabolizing genes can lead to interindividual differences in gene expression, which may result in adverse drug effects and therapeutic failure. Based on the database of CYP2D6 gene polymorphisms in the Chinese Han population established by our group, we functionally characterized the single nucleotide polymorphisms (SNPs) of the promoter region and corresponding haplotypes in this population. Using site-directed mutagenesis, all the five SNPs identified and ten haplotypes with a frequency equal to or greater than 0.01 in the population were constructed on a luciferase reporter system. Dual luciferase reporter systems were used to analyze regulatory activity. The activity produced by Haplo3(−2183G>A, −1775A>G, −1589G>C, −1431C>T, −1000G>A, −678A>G), Haplo8(−2065G>A, −2058T>G, −1775A>G, −1589G>C, −1235G>A, −678A>G) and MU3(−498C>A) was 0.7−, 0.7−, 1.2− times respectively compared with the wild type in human hepatoma cell lines(p<0.05). These findings might be useful for optimizing pharmacotherapy and the design of personalized medicine. PMID:23469064

  20. Stabilization of population fluctuations due to cannibalism promotes resource polymorphism in fish.

    PubMed

    Andersson, Jens; Bystrom, Par; Claessen, David; Persson, Lennart; De Roos, Andre M

    2007-06-01

    Resource polymorphism is a well-known phenomenon in many taxa, assumed to be a consequence of strong competition for resources and to be facilitated by stable environments and the presence of several profitable resources on which to specialize. In fish, resource polymorphism, in the form of planktivore-benthivore pairs, is found in a number of species. We gathered literature data on life-history characteristics and population dynamics for 15 fish species and investigated factors related to the presence of such resource polymorphism. This investigation indicated that early cannibalism and low overall population variability are typically associated with the presence of resource polymorphism. These findings match previously reported patterns of population dynamics for size-structured fish populations, whereby early cannibalism has been shown to decrease temporal variation in population dynamics and to equalize the profitability of the zooplankton and macroinvertebrate resources. Our study suggests that competition alone is not a sufficient condition for the development of resource polymorphism because overly strong competition is typically associated with increased temporal variation (environmental instability). We conclude that although resource competition is an important factor regulating the development of resource polymorphism, cannibalism may also play a fundamental role by dampening population oscillations and possibly by equalizing the profitability of different resources. PMID:17479467

  1. Association of Functional Kallikrein-1 Promoter Polymorphisms and Acute Kidney Injury: A Case-Control and Longitudinal Cohort Study

    PubMed Central

    Susantitaphong, Paweena; Perianayagam, Mary C.; Kang, Sun Woo; Zhang, Wenyi; Rao, Fangwen; O’Connor, Daniel T.; Jaber, Bertrand L.

    2013-01-01

    Background Kallikrein-1 (KLK1) is a highly conserved serine protease that is expressed in the kidney and involved in blood pressure regulation. The activity of this enzyme is diminished in acute kidney injury (AKI). Methods We first evaluated the potential role of functional multiallelic KLK1 promoter gene polymorphisms in a case-control study of 481 subjects (214 hospitalized patients with AKI of mixed causes and 267 healthy subjects). The complex, multiallelic G/C-rich repeat region of the proximal KLK1 promoter was determined by direct Sanger/capillary resequencing. Results 16 alleles were identified in a complex, polymorphic G/C-rich region of the KLK1 proximal promoter; 5 of these alleles (F, G, H, I, and K) were associated with development of AKI. Alleles I and G were classified as risk-alleles (unadjusted OR 1.86; 95% CI 1.23, 2.81; p = 0.003), whereas alleles F, H, and K were classified as protective-alleles (unadjusted OR 0.32; 95% CI 0.22, 0.46; p < 0.001) according to their directional association with development of AKI. After adjustment for sex, race, preexisting chronic kidney disease and APACHE II score, the KLK1 risk-allele (I or G) carrier state was associated with the composite of ≥ 2-fold increase in serum creatinine, oliguria, or dialysis requirement (adjusted OR 2.71; 95% CI 1.14, 6.44; p = 0.02). The KLK1 risk-allele carrier state was also marginally associated with the composite of ≥2-fold increase in serum creatinine, oliguria, dialysis requirement, or in-hospital death (adjusted OR 2.33; 95% CI 0.98, 5.52; p = 0.06). Conclusions KLK1 promoter polymorphisms are associated with development of AKI and adverse outcomes. Further studies are needed to validate these findings. PMID:23635481

  2. Promoter polymorphism of the erythropoietin gene in severe diabetic eye and kidney complications

    PubMed Central

    Tong, Zongzhong; Yang, Zhenglin; Patel, Shrena; Chen, Haoyu; Gibbs, Daniel; Yang, Xian; Hau, Vincent S.; Kaminoh, Yuuki; Harmon, Jennifer; Pearson, Erik; Buehler, Jeanette; Chen, Yuhong; Yu, Baifeng; Tinkham, Nicholas H.; Zabriskie, Norman A.; Zeng, Jiexi; Luo, Ling; Sun, Jennifer K.; Prakash, Manvi; Hamam, Rola N.; Tonna, Stephen; Constantine, Ryan; Ronquillo, Cecinio C.; Sadda, SriniVas; Avery, Robert L.; Brand, John M.; London, Nyall; Anduze, Alfred L.; King, George L.; Bernstein, Paul S.; Watkins, Scott; Jorde, Lynn B.; Li, Dean Y.; Aiello, Lloyd Paul; Pollak, Martin R.; Zhang, Kang

    2008-01-01

    Significant morbidity and mortality among patients with diabetes mellitus result largely from a greatly increased incidence of microvascular complications. Proliferative diabetic retinopathy (PDR) and end stage renal disease (ESRD) are two of the most common and severe microvascular complications of diabetes. A high concordance exists in the development of PDR and ESRD in diabetic patients, as well as strong familial aggregation of these complications, suggesting a common underlying genetic mechanism. However, the precise gene(s) and genetic variant(s) involved remain largely unknown. Erythropoietin (EPO) is a potent angiogenic factor observed in the diabetic human and mouse eye. By a combination of case–control association and functional studies, we demonstrate that the T allele of SNP rs1617640 in the promoter of the EPO gene is significantly associated with PDR and ESRD in three European-American cohorts [Utah: P = 1.91 × 10−3; Genetics of Kidneys in Diabetes (GoKinD) Study: P = 2.66 × 10−8; and Boston: P = 2.1 × 10−2]. The EPO concentration in human vitreous body was 7.5-fold higher in normal subjects with the TT risk genotype than in those with the GG genotype. Computational analysis suggests that the risk allele (T) of rs1617640 creates a matrix match with the EVI1/MEL1 or AP1 binding site, accounting for an observed 25-fold enhancement of luciferase reporter expression as compared with the G allele. These results suggest that rs1617640 in the EPO promoter is significantly associated with PDR and ESRD. This study identifies a disease risk-associated gene and potential pathway mediating severe diabetic microvascular complications. PMID:18458324

  3. Detailed analysis of association between common single nucleotide polymorphisms and subclinical atherosclerosis: The Multi-ethnic Study of Atherosclerosis

    PubMed Central

    Vargas, Jose D.; Manichaikul, Ani; Wang, Xin-Qun; Rich, Stephen S.; Rotter, Jerome I.; Post, Wendy S.; Polak, Joseph F.; Budoff, Matthew J.; Bluemke, David A.

    2016-01-01

    Previously identified single nucleotide polymorphisms (SNPs) in genome wide association studies (GWAS) of cardiovascular disease (CVD) in participants of mostly European descent were tested for association with subclinical cardiovascular disease (sCVD), coronary artery calcium score (CAC) and carotid intima media thickness (CIMT) in the Multi-Ethnic Study of Atherosclerosis (MESA). The data in this data in brief article correspond to the article Common Genetic Variants and Subclinical Atherosclerosis: The Multi-Ethnic Study of Atherosclerosis [1]. This article includes the demographic information of the participants analyzed in the article as well as graphical displays and data tables of the association of the selected SNPs with CAC and of the meta-analysis across ethnicities of the association of CIMT-c (common carotid), CIMT-I (internal carotid), CAC-d (CAC as dichotomous variable with CAC>0) and CAC-c (CAC as continuous variable, the log of the raw CAC score plus one) and CVD. The data tables corresponding to the 9p21 fine mapping experiment as well as the power calculations referenced in the article are also included. PMID:26958643

  4. Detailed analysis of association between common single nucleotide polymorphisms and subclinical atherosclerosis: The Multi-ethnic Study of Atherosclerosis.

    PubMed

    Vargas, Jose D; Manichaikul, Ani; Wang, Xin-Qun; Rich, Stephen S; Rotter, Jerome I; Post, Wendy S; Polak, Joseph F; Budoff, Matthew J; Bluemke, David A

    2016-06-01

    Previously identified single nucleotide polymorphisms (SNPs) in genome wide association studies (GWAS) of cardiovascular disease (CVD) in participants of mostly European descent were tested for association with subclinical cardiovascular disease (sCVD), coronary artery calcium score (CAC) and carotid intima media thickness (CIMT) in the Multi-Ethnic Study of Atherosclerosis (MESA). The data in this data in brief article correspond to the article Common Genetic Variants and Subclinical Atherosclerosis: The Multi-Ethnic Study of Atherosclerosis [1]. This article includes the demographic information of the participants analyzed in the article as well as graphical displays and data tables of the association of the selected SNPs with CAC and of the meta-analysis across ethnicities of the association of CIMT-c (common carotid), CIMT-I (internal carotid), CAC-d (CAC as dichotomous variable with CAC>0) and CAC-c (CAC as continuous variable, the log of the raw CAC score plus one) and CVD. The data tables corresponding to the 9p21 fine mapping experiment as well as the power calculations referenced in the article are also included. PMID:26958643

  5. Mannose-Binding Lectin Promoter Polymorphisms and Gene Variants in Pulmonary Tuberculosis Patients from Cantabria (Northern Spain)

    PubMed Central

    Lavín-Alconero, Lucía; Sánchez-Velasco, Pablo; Guerrero-Alonso, M.-Ángeles; Ausín, Fernando; Fariñas, M.-Carmen; Leyva-Cobián, Francisco

    2012-01-01

    Mannose-binding lectin is a central molecule of the innate immune system. Mannose-binding lectin 2 promoter polymorphisms and structural variants have been associated with susceptibility to tuberculosis. However, contradictory results among different populations have been reported, resulting in no convincing evidence of association between mannose-binding lectin 2 and susceptibility to tuberculosis. For this reason, we conducted a study in a well genetically conserved Spanish population in order to shed light on this controversial association. We analysed the six promoter and structural mannose-binding lectin 2 gene variants in 107 patients with pulmonary tuberculosis and 441 healthy controls. Only D variant and HYPD haplotype were significantly more frequents in controls which would indicate that this allele could confer protection against pulmonary tuberculosis, but this difference disappeared after statistical correction. Neither the rest of alleles nor the haplotypes were significantly associated with the disease. These results would indicate that mannose-binding lectin promoter polymorphisms and gene variants would not be associated with an increased risk to pulmonary tuberculosis. Despite the slight trend of the D allele and HYPD haplotype in conferring protection against pulmonary tuberculosis, susceptibility to this disease would probably be due to other genetic factors, at least in our population. PMID:23304495

  6. Mannose-binding lectin promoter polymorphisms and gene variants in pulmonary tuberculosis patients from cantabria (northern Spain).

    PubMed

    Ocejo-Vinyals, J-Gonzalo; Lavín-Alconero, Lucía; Sánchez-Velasco, Pablo; Guerrero-Alonso, M-Ángeles; Ausín, Fernando; Fariñas, M-Carmen; Leyva-Cobián, Francisco

    2012-01-01

    Mannose-binding lectin is a central molecule of the innate immune system. Mannose-binding lectin 2 promoter polymorphisms and structural variants have been associated with susceptibility to tuberculosis. However, contradictory results among different populations have been reported, resulting in no convincing evidence of association between mannose-binding lectin 2 and susceptibility to tuberculosis. For this reason, we conducted a study in a well genetically conserved Spanish population in order to shed light on this controversial association. We analysed the six promoter and structural mannose-binding lectin 2 gene variants in 107 patients with pulmonary tuberculosis and 441 healthy controls. Only D variant and HYPD haplotype were significantly more frequents in controls which would indicate that this allele could confer protection against pulmonary tuberculosis, but this difference disappeared after statistical correction. Neither the rest of alleles nor the haplotypes were significantly associated with the disease. These results would indicate that mannose-binding lectin promoter polymorphisms and gene variants would not be associated with an increased risk to pulmonary tuberculosis. Despite the slight trend of the D allele and HYPD haplotype in conferring protection against pulmonary tuberculosis, susceptibility to this disease would probably be due to other genetic factors, at least in our population. PMID:23304495

  7. Analysis of the effects of depression associated polymorphisms on the activity of the BICC1 promoter in amygdala neurones.

    PubMed

    Davidson, S; Shanley, L; Cowie, P; Lear, M; McGuffin, P; Quinn, J P; Barrett, P; MacKenzie, A

    2016-08-01

    The Bicaudal C Homolog 1 (BICC1) gene, which encodes an RNA binding protein, has been identified by genome wide association studies (GWAS) as a candidate gene associated with major depressive disorder (MDD). We explored the hypothesis that MDD associated single-nucleotide polymorphisms (SNPs) affected the ability of cis-regulatory elements within intron 3 of the BICC1 gene to modulate the activity of the BICC1 promoter region. We initially established that the BICC1 promoter drove BICC1 mRNA expression in amygdala, hippocampus and hypothalamus. Intriguingly, we provide evidence that MDD associated polymorphisms alter the ability of the BICC1 promoter to respond to PKA signalling within amygdala neurones. Considering the known role of amygdala PKA pathways in fear learning and mood these observations suggest a possible mechanism through which allelic changes in the regulation of the BICC1 gene in amygdala neurones may contribute to mood disorders. Our findings also suggest a novel direction for the identification of novel drug targets and the design of future personalised therapeutics.The Pharmacogenomics Journal advance online publication, 6 October 2015; doi:10.1038/tpj.2015.62. PMID:26440730

  8. Analysis of the effects of depression associated polymorphisms on the activity of the BICC1 promoter in amygdala neurones

    PubMed Central

    Davidson, S; Shanley, L; Cowie, P; Lear, M; McGuffin, P; Quinn, J P; Barrett, P; MacKenzie, A

    2016-01-01

    The Bicaudal C Homolog 1 (BICC1) gene, which encodes an RNA binding protein, has been identified by genome wide association studies (GWAS) as a candidate gene associated with major depressive disorder (MDD). We explored the hypothesis that MDD associated single-nucleotide polymorphisms (SNPs) affected the ability of cis-regulatory elements within intron 3 of the BICC1 gene to modulate the activity of the BICC1 promoter region. We initially established that the BICC1 promoter drove BICC1 mRNA expression in amygdala, hippocampus and hypothalamus. Intriguingly, we provide evidence that MDD associated polymorphisms alter the ability of the BICC1 promoter to respond to PKA signalling within amygdala neurones. Considering the known role of amygdala PKA pathways in fear learning and mood these observations suggest a possible mechanism through which allelic changes in the regulation of the BICC1 gene in amygdala neurones may contribute to mood disorders. Our findings also suggest a novel direction for the identification of novel drug targets and the design of future personalised therapeutics. PMID:26440730

  9. Interethnic diversity of the CD209 (rs4804803) gene promoter polymorphism in African but not American sickle cell disease

    PubMed Central

    Noble, Jenelle A.; Duru, Kimberley C.; Guindo, Aldiouma; Yi, Li; Imumorin, Ikhide G.; Diallo, Dapa A.

    2015-01-01

    Elucidating the genomic diversity of CD209 gene promoter polymorphism could assist in clarifying disease pathophysiology as well as contribution to co-morbidities. CD209 gene promoter polymorphism has been shown to be associated with susceptibility to infection. We hypothesize that CD209 mutant variants occur at a higher frequency among Africans and in sickle cell disease. We analyzed the frequency of the CD209 gene (rs4804803) in healthy control and sickle cell disease (SCD) populations and determined association with disease. Genomic DNA was extracted from blood samples collected from 145 SCD and 231 control Africans (from Mali), 331 SCD and 379 control African Americans and 159 Caucasians. Comparative analysis among and between groups was carried out by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP). Per ethnic diversification, we found significant disparity in genotypic (23.4% versus 16.9% versus 3.2%) and allelic frequencies (48.7% versus 42.1% versus 19.8%) of the homozygote mutant variant of the CD209 (snp 309A/G) gene promoter between Africans, African Americans and Caucasians respectively. Comparative evaluation between disease and control groups reveal a significant difference in genotypic (10.4% versus 23.4%; p = 0.002) and allelic frequencies (39.7% versus 48.7%; p = 0.02) of the homozygote mutant variant in African SCD and healthy controls respectively, an observation that is completely absent among Americans. Comparing disease groups, we found no difference in the genotypic (p = 0.19) or allelic (p = 0.72) frequencies of CD209 homozygote mutant variant between Africans and Americans with sickle cell disease. The higher frequency of CD209 homozygote mutant variants in the African control group reveals a potential impairment of the capacity to mount an immune response to infectious diseases, and possibly delineate susceptibility to or severity of infectious co-morbidities within and between groups. PMID:25755928

  10. Heme oxygenase-1 gene promoter polymorphism is associated with reduced incidence of acute chest syndrome among children with sickle cell disease

    PubMed Central

    Bean, Christopher J.; Boulet, Sheree L.; Ellingsen, Dorothy; Pyle, Meredith E.; Barron-Casella, Emily A.; Casella, James F.; Payne, Amanda B.; Driggers, Jennifer; Trau, Heidi A.; Yang, Genyan; Jones, Kimberly; Ofori-Acquah, Solomon F.; Hooper, W. Craig

    2012-01-01

    Sickle cell disease is a common hemolytic disorder with a broad range of complications, including vaso-occlusive episodes, acute chest syndrome (ACS), pain, and stroke. Heme oxygenase-1 (gene HMOX1; protein HO-1) is the inducible, rate-limiting enzyme in the catabolism of heme and might attenuate the severity of outcomes from vaso-occlusive and hemolytic crises. A (GT)n dinucleotide repeat located in the promoter region of the HMOX1 gene is highly polymorphic, with long repeat lengths linked to decreased activity and inducibility. We examined this polymorphism to test the hypothesis that short alleles are associated with a decreased risk of adverse outcomes (hospitalization for pain or ACS) among a cohort of 942 children with sickle cell disease. Allele lengths varied from 13 to 45 repeats and showed a trimodal distribution. Compared with children with longer allele lengths, children with 2 shorter alleles (4%; ≤ 25 repeats) had lower rates of hospitalization for ACS (incidence rate ratio 0.28, 95% confidence interval, 0.10-0.81), after adjusting for sex, age, asthma, percentage of fetal hemoglobin, and α-globin gene deletion. No relationship was identified between allele lengths and pain rate. We provide evidence that genetic variation in HMOX1 is associated with decreased rates of hospitalization for ACS, but not pain. This study is registered at www.clinicaltrials.gov as #NCT00072761. PMID:22966170

  11. Evaluating the association of interleukin-10 gene promoter -592 A/C polymorphism with lupus nephritis susceptibility

    PubMed Central

    Abdallah, Emad; Waked, Emam; Abdelwahab, Mahmoud A.

    2015-01-01

    Background Interleukin-10 (IL-10) is an important immunoregulatory cytokine. There are few studies evaluating the association between IL-10 and lupus nephritis (LN). The aim of this study was to evaluate the association of IL-10 gene promoter -592 A/C with LN susceptibility. Methods The study was conducted on 84 patients with systemic lupus erythematosus (SLE). Patients were divided into LN group (Group I, 48 patients) and non-LN group (Group II, 36 patients). The -592 A/C polymorphisms in IL-10 promoter gene were determined by polymerase chain reaction and restriction fragment length polymorphism in both groups. IL-10 was determined by enzyme-linked immunosorbent assay. Frequencies of the genotypes were compared between LN and non-LN patients and among LN patients with different pathologic classes. Results There was a significant increase in serum level of IL-10 (P = 0.001) in Group I compared with Group II and significant positive correlation between serum IL-10 and SLE disease activity index (r = 0.466, P = 0.001) in Group I. There were no significant differences in the distribution of the IL-10 gene promoter -592 A/C genotypes or the allele frequencies between Groups I and II. There was no significant difference between AC/CC and AA genotypes with SLE disease activity index, proteinuria, hematuria, anti-double-stranded DNA, and IL-10 in Group I. There was no significant difference in the distribution of AC and CC genotypes among different pathologic LN classes. Conclusion IL-10 suggested to play a role in pathogenesis and development of LN. However, the promoter -592 A/C of IL-10 gene suggested to be not associated with serum IL-10 levels or LN susceptibility. In addition, it appears that promoter -592 A/C of IL-10 gene not associated with LN activity or the pathologic classes of LN. PMID:27069855

  12. Genetic Polymorphism in the Promoter Region of Serotonin Transporter: Implications for Ethanol Abuse in Children and Adolescents

    PubMed Central

    de Oliveira, Carlos Eduardo Coral; Oda, Julie Massayo Maeda; Ariza, Carolina Batista; Guembarovski, Roberta Losi; Hirata, Bruna Karina Banin; de Almeida, Felipe Campos; André, Nayara Delgado; Fungaro, Maria Helena Pelegrinelli; Watanabe, Maria Angelica Ehara

    2016-01-01

    Objectives: To provide a review of published literature regarding genetic polymorphism of serotonin transporter gene, named as 5-HTTLPR, and its potential role as a susceptibility marker for ethanol abuse in childhood and adolescence. Methods: A literature review of several databases was conducted with the following keywords: 5-HTTLPR, children or adolescents or teenagers, susceptibility, alcohol or ethanol, abuse or misuse. Results: Alcohol interacts with serotonergic synaptic transmission in several ways, and the reduced availability of serotonin transporters might foster brain dysfunction, driving to alcohol abuse. The initial use of ethanol in children and adolescents is determined primarily by environmental influences, whereas the establishment of drinking patterns is strongly controlled by genetic factors. Functional polymorphic variants in the promoter region of the 5-HTTLPR gene have age-dependent effects in alcohol abuse. This polymorphism, mapped to the 5′ region of the SLC6A4, is a variable number of tandem repeats (VNTR) and involves a direct repeat of 20–23 base pairs GC-rich sequences, comprising a short (S) allele, consisting of 14 repeats, and a long (L) allele, with 16 repeats. Additional variants have been described, although their influences on childhood and adolescence ethanol use are not clear. Conclusion: The influence of the 5-HTTLPR allelic variants in children and adolescent misuse of alcohol might be considered for clinical management, preventing long-term behavior problem. Identifying genetic markers associated to the potential alcohol misuse or abuse could be useful in guiding management and formulating effective coping strategies. PMID:27047556

  13. Two bi-allelic single nucleotide polymorphisms within the promoter region of the horse tumour necrosis factor alpha gene.

    PubMed

    Matiasovic, J; Lukeszová, L; Horín, P

    2002-08-01

    Primers based on GenBank sequences within the 5' untranslated region (UTR) of the human and horse tumour necrosis factor alpha (TNF-alpha) genes were designed and used to amplify a 522-bp product. Sequencing of five clones derived from five independent PCRs obtained from three different animals of three different breeds (Old Kladruber, Akhal-Teke and Shetland Pony) revealed a high level of sequence identity to the TNF-alpha promoter regions of other species. The existing GenBank horse sequences were confirmed and extended upstream by 230 nucleotides. Based on the sequence obtained, a new horse-specific forward primer was designed to amplify a 213-bp PCR product, which was screened for polymorphism using single-strand conformation polymorphism (SSCP). Three allelic variants of the horse TNF-alpha gene were identified and sequenced (GenBank accession numbers ADF 349558-60). Two single nucleotide polymorphisms explained the existence of the three SSCP alleles detected: C/T and T/C single base pair substitutions at positions 137 and 147, respectively. Differences in allelic frequencies between Old Kladruber and Akhal-Teke breeds were observed. PMID:12121271

  14. A COMMON POLYMORPHISM IN THE METHYLENETETRAHYDROFOLATE REDUCTASE (MTHFR) GENE IS ASSOCIATED WITH QUANTITATIVE ULTRASOUND IN THOSE WITH LOW PLASMA FOLATE

    Technology Transfer Automated Retrieval System (TEKTRAN)

    A study of a polymorphism in the MTHFR gene, plasma folate, and bone phenotypes in 1632 individuals revealed that the genotype effect on BMD and quantitative ultrasound was dependent on the level of folate. Our findings support the hypothesis that the association between an MTHFR polymorphism and bo...

  15. Neuromarkers of the common angiotensinogen polymorphism in healthy older adults: A comprehensive assessment of white matter integrity and cognition.

    PubMed

    Salminen, Lauren E; Schofield, Peter R; Pierce, Kerrie D; Zhao, Yi; Luo, Xi; Wang, Youdan; Laidlaw, David H; Cabeen, Ryan P; Conturo, Thomas E; Tate, David F; Akbudak, Erbil; Lane, Elizabeth M; Heaps, Jodi M; Bolzenius, Jacob D; Baker, Laurie M; Cagle, Lee M; Paul, Robert H

    2016-01-01

    The common angiotensinogen (AGT) M268T polymorphism (rs699; historically referred to as M235T) has been identified as a significant risk factor for cerebrovascular pathologies, yet it is unclear if healthy older adults carrying the threonine amino acid variant have a greater risk for white matter damage in specific fiber tracts. Further, the impact of the threonine variant on cognitive function remains unknown. The present study utilized multiple indices of diffusion tensor imaging (DTI) and neuropsychological assessment to examine the integrity of specific white matter tracts and cognition between individuals with homozygous genotypes of M268T (MetMet n=27, ThrThr n=27). Differences in subcortical hyperintensity (SH) volume were also examined between groups. Results indicated that the threonine variant was associated with significantly reduced integrity in the superior longitudinal fasciculus (SLF) and the cingulate gyrus segment of the cingulum bundle (cingulum CG) compared to those with the methionine variant, and poorer cognitive performance on tests of attention/processing speed and language. Despite these associations, integrity of these tracts did not significantly mediate relationships between cognition and genetic status, and SH did not differ significantly between groups. Collectively our results suggest that the threonine variant of M268T is a significant risk factor for abnormalities in specific white matter tracts and cognitive domains in healthy older adults, independent of SH burden. PMID:26318936

  16. Association Between Promoter Polymorphisms of the GRP78 Gene and Risk of Type 2 Diabetes in a Chinese Han Population

    PubMed Central

    Liu, Shengyuan; Li, Tao; Xiong, Xingdong; Yao, Songpo; Chen, Zhongwei; Wang, Changyi

    2013-01-01

    There are large amounts of unfolding or misfolding protein accumulation in the endoplasmic reticulum in patients with type 2 diabetes (T2D), which in turn induces the expression of the glucose-regulated protein 78 (GRP78) that plays a key role in influencing insulin secretion and maintaining glucose homeostasis in pancreatic beta cells. The aim in the study is to analyze the potential association between single-nucleotide polymorphisms (SNPs) of GRP78 and the risk of T2D. To assess the association between GRP78 polymorphisms and T2D, a case–control study was conducted among 1058 consecutive unrelated subjects. Of the 1058 subjects, 523 of them were diagnosed with T2D and 535 of them were healthy controls. Four SNPs with R2>0.8 and the minor allele frequency>0.05 (rs391957, rs17840761, rs17840762, and rs11355458) in the GRP78 gene promoter were analyzed. Overall, no associations of GRP78 polymorphisms with T2D were observed in genotypic analyses. In addition, haplotypes combining those SNPs in the promoter in high linkage disequilibrium were also not associated with a T2D risk. However, the levels of fasting plasma glucose and HbA1c in patients with the −415AA/−180GG genotype were significantly lower than those of the patients with −415GG/−180deldel and −415AG/−180Gdel genotypes, and the level of fasting insulin in patients with the −415AA/−180GG genotype was significantly lower than that of the patients with −415GG/−180deldel. The study does not support a role for promoter polymorphisms of GRP78 in T2D in a Chinese Han population, but it does provide a clue for association between low levels of fasting plasma glucose, HbA1c and fasting insulin, and the −415AA/−180GG model. PMID:23402331

  17. The functional serotonin 1a receptor promoter polymorphism, rs6295, is associated with psychiatric illness and differences in transcription

    PubMed Central

    Donaldson, Z R; le Francois, B; Santos, T L; Almli, L M; Boldrini, M; Champagne, F A; Arango, V; Mann, J J; Stockmeier, C A; Galfalvy, H; Albert, P R; Ressler, K J; Hen, R

    2016-01-01

    The G/C single-nucleotide polymorphism in the serotonin 1a receptor promoter, rs6295, has previously been linked with depression, suicide and antidepressant responsiveness. In vitro studies suggest that rs6295 may have functional effects on the expression of the serotonin 1a receptor gene (HTR1A) through altered binding of a number of transcription factors. To further explore the relationship between rs6295, mental illness and gene expression, we performed dual epidemiological and biological studies. First, we genotyped a cohort of 1412 individuals, randomly split into discovery and replication cohorts, to examine the relationship between rs6295 and five psychiatric outcomes: history of psychiatric hospitalization, history of suicide attempts, history of substance or alcohol abuse, current posttraumatic stress disorder (PTSD), current depression. We found that the rs6295G allele is associated with increased risk for substance abuse, psychiatric hospitalization and suicide attempts. Overall, exposure to either childhood or non-childhood trauma resulted in increased risk for all psychiatric outcomes, but we did not observe a significant interaction between rs6295 and trauma in modulating psychiatric outcomes. In conjunction, we also investigated the potential impact of rs6295 on HTR1A expression in postmortem human brain tissue using relative allelic expression assays. We found more mRNA produced from the C versus the G-allele of rs6295 in the prefrontal cortex (PFC), but not in the midbrain of nonpsychiatric control subjects. Further, in the fetal cortex, rs6295C allele exhibited increased relative expression as early as gestational week 18 in humans. Finally, we found that the C:G allelic expression ratio was significantly neutralized in the PFC of subjects with major depressive disorder (MDD) who committed suicide as compared with controls, indicating that normal patterns of transcription may be disrupted in MDD/suicide. These data provide a putative biological

  18. The functional serotonin 1a receptor promoter polymorphism, rs6295, is associated with psychiatric illness and differences in transcription.

    PubMed

    Donaldson, Z R; le Francois, B; Santos, T L; Almli, L M; Boldrini, M; Champagne, F A; Arango, V; Mann, J J; Stockmeier, C A; Galfalvy, H; Albert, P R; Ressler, K J; Hen, R

    2016-01-01

    The G/C single-nucleotide polymorphism in the serotonin 1a receptor promoter, rs6295, has previously been linked with depression, suicide and antidepressant responsiveness. In vitro studies suggest that rs6295 may have functional effects on the expression of the serotonin 1a receptor gene (HTR1A) through altered binding of a number of transcription factors. To further explore the relationship between rs6295, mental illness and gene expression, we performed dual epidemiological and biological studies. First, we genotyped a cohort of 1412 individuals, randomly split into discovery and replication cohorts, to examine the relationship between rs6295 and five psychiatric outcomes: history of psychiatric hospitalization, history of suicide attempts, history of substance or alcohol abuse, current posttraumatic stress disorder (PTSD), current depression. We found that the rs6295G allele is associated with increased risk for substance abuse, psychiatric hospitalization and suicide attempts. Overall, exposure to either childhood or non-childhood trauma resulted in increased risk for all psychiatric outcomes, but we did not observe a significant interaction between rs6295 and trauma in modulating psychiatric outcomes. In conjunction, we also investigated the potential impact of rs6295 on HTR1A expression in postmortem human brain tissue using relative allelic expression assays. We found more mRNA produced from the C versus the G-allele of rs6295 in the prefrontal cortex (PFC), but not in the midbrain of nonpsychiatric control subjects. Further, in the fetal cortex, rs6295C allele exhibited increased relative expression as early as gestational week 18 in humans. Finally, we found that the C:G allelic expression ratio was significantly neutralized in the PFC of subjects with major depressive disorder (MDD) who committed suicide as compared with controls, indicating that normal patterns of transcription may be disrupted in MDD/suicide. These data provide a putative biological

  19. A promoter polymorphism of MSTN g.-371T>A and its associations with carcass traits in Korean cattle.

    PubMed

    Han, Sang-Hyun; Cho, In-Cheol; Ko, Moon-Suck; Kim, Eun-Young; Park, Se-Pill; Lee, Sung-Soo; Oh, Hong-Shik

    2012-04-01

    A promoter polymorphism of bovine Myostatin (MSTN) gene g.-371T>A was screened in Holstein and two Korean indigenous cattle breeds, Hanwoo and Jeju Black cattle (JBC). The MSTN g.-371T>A polymorphism was found in all three cattle breeds tested. An allele MSTN g.-371A was the most frequent in the JBC breed among breeds tested. The association of MSTN genotypes for carcass traits was also tested in the Hanwoo population. Significant differences were found between the genotypes and level of meat quality grade index which converted the marbling score levels (P < 0.05), reflecting the metabolic role of MSTN for inhibition of preadipocyte differentiation in intramuscular fat deposition. In addition, significant differences were found for fat color index of backfat according to MSTN genotypes (P < 0.05), suggesting that MSTN may play a role in deposition of white-yellow adipocytes in backfat. However, there was no detection of significant association of genotypes with the live weight, carcass weight, backfat thickness, eye muscle area, marbling score, or meat color index (P > 0.05). Despite the lack of statistical association, wild type g.-371T/-showed association patterns similar to those of A/A homozygotes, such as heavier weights, thinner backfat, larger eye muscle area, and lower marbling score. The results of the present study suggest that MSTN promoter polymorphism g.-371T>A may affect carcass traits, which could be a useful molecular marker for planning improvements in the economic traits of Korean cattle breeds. PMID:21743995

  20. Polymorphic tandem repeats within gene promoters act as modifiers of gene expression and DNA methylation in humans

    PubMed Central

    Quilez, Javier; Guilmatre, Audrey; Garg, Paras; Highnam, Gareth; Gymrek, Melissa; Erlich, Yaniv; Joshi, Ricky S.; Mittelman, David; Sharp, Andrew J.

    2016-01-01

    Despite representing an important source of genetic variation, tandem repeats (TRs) remain poorly studied due to technical difficulties. We hypothesized that TRs can operate as expression (eQTLs) and methylation (mQTLs) quantitative trait loci. To test this we analyzed the effect of variation at 4849 promoter-associated TRs, genotyped in 120 individuals, on neighboring gene expression and DNA methylation. Polymorphic promoter TRs were associated with increased variance in local gene expression and DNA methylation, suggesting functional consequences related to TR variation. We identified >100 TRs associated with expression/methylation levels of adjacent genes. These potential eQTL/mQTL TRs were enriched for overlaps with transcription factor binding and DNaseI hypersensitivity sites, providing a rationale for their effects. Moreover, we showed that most TR variants are poorly tagged by nearby single nucleotide polymorphisms (SNPs) markers, indicating that many functional TR variants are not effectively assayed by SNP-based approaches. Our study assigns biological significance to TR variations in the human genome, and suggests that a significant fraction of TR variations exert functional effects via alterations of local gene expression or epigenetics. We conclude that targeted studies that focus on genotyping TR variants are required to fully ascertain functional variation in the genome. PMID:27060133

  1. TNF-α Promoter Polymorphisms Predict the Response to Etanercept More Powerfully than that to Infliximab/Adalimumab in Spondyloarthritis.

    PubMed

    Liu, Jing; Dong, Zheng; Zhu, Qi; He, Dongyi; Ma, Yanyun; Du, Aiping; He, Fan; Zhao, Dongbao; Xu, Xia; Zhang, Hui; Jin, Li; Wang, Jiucun

    2016-01-01

    While previous studies have researched in association analyses between TNFα promoter polymorphisms and responses to TNF blockers in spondyloarthritis patients, their results were conflicting. Therefore, we aimed to determine whether TNFα promoter polymorphisms could predict response to TNF blockers and find the source of heterogeneity. Data were extracted and analyzed from published articles and combined with our unpublished data. We found that the greatest potential sources of heterogeneity in the results were gender ratio, disease type, continents, and TNF blockers. Then Stratification analysis showed that the TNFα -308 G allele and the -238 G allele predicted a good response to TNF blockers (OR = 2.64 [1.48-4.73]; 2.52 [1.46-4.37]). However, G alleles of TNFα -308 and -238 could predict the response to etanercept (OR = 4.02 [2.24-7.23]; 5.17 [2.29-11.67]) much more powerfully than the response to infiliximab/adalimumab (OR = 1.68 [1.02-2.78]; 1.28 [0.57-2.86]). TNFα -857 could not predict the response in either subgroup. Cumulative meta-analysis performed in ankylosing spondylitis patients presented the odds ratio decreased with stricter response criteria. In conclusion, TNFα -308 A/G and -238 A/G are more powerful to predict the response to Etanercept and it is dependent on the criteria of response. PMID:27578555

  2. Polymorphic tandem repeats within gene promoters act as modifiers of gene expression and DNA methylation in humans.

    PubMed

    Quilez, Javier; Guilmatre, Audrey; Garg, Paras; Highnam, Gareth; Gymrek, Melissa; Erlich, Yaniv; Joshi, Ricky S; Mittelman, David; Sharp, Andrew J

    2016-05-01

    Despite representing an important source of genetic variation, tandem repeats (TRs) remain poorly studied due to technical difficulties. We hypothesized that TRs can operate as expression (eQTLs) and methylation (mQTLs) quantitative trait loci. To test this we analyzed the effect of variation at 4849 promoter-associated TRs, genotyped in 120 individuals, on neighboring gene expression and DNA methylation. Polymorphic promoter TRs were associated with increased variance in local gene expression and DNA methylation, suggesting functional consequences related to TR variation. We identified >100 TRs associated with expression/methylation levels of adjacent genes. These potential eQTL/mQTL TRs were enriched for overlaps with transcription factor binding and DNaseI hypersensitivity sites, providing a rationale for their effects. Moreover, we showed that most TR variants are poorly tagged by nearby single nucleotide polymorphisms (SNPs) markers, indicating that many functional TR variants are not effectively assayed by SNP-based approaches. Our study assigns biological significance to TR variations in the human genome, and suggests that a significant fraction of TR variations exert functional effects via alterations of local gene expression or epigenetics. We conclude that targeted studies that focus on genotyping TR variants are required to fully ascertain functional variation in the genome. PMID:27060133

  3. Association of the BRCA1 promoter polymorphism rs11655505 with the risk of familial breast and/or ovarian cancer.

    PubMed

    Bielinska, Beata; Gaj, Pawel; Kluska, Anna; Nowakowska, Dorota; Balabas, Aneta; Dabrowska, Michalina; Niwinska, Anna; Gruchota, Jakub; Zub, Renata; Skasko, Elzbieta; Steffen, Jan; Ostrowski, Jerzy; Siedlecki, Janusz A

    2013-12-01

    Germline mutations in the BRCA1 tumor suppressor gene predispose affected individuals to breast cancer; however, incomplete cancer penetrance and the presence of phenocopies in BRCA1 families also indicate genetic and environmental modifiers of breast cancer risk. In this study, we have tested the single nucleotide polymorphism rs1655505 of the BRCA1 promoter, as candidate for the modifier of breast cancer risk. The polymorphic variants were genotyped in BRCA1-negative (729), familial breast and/or ovarian cancer cases (FBOC), including cases with a reported maternal history (154), nonfamilal (sporadic) cases (600), hereditary breast/ovarian cases with BRCA1 mutations (190) and population controls (1,590) from Central Poland. An association with the risk of FBOC was observed for the minor (T) allele and (TT) genotype (T: p = 0.006, OR = 1.40, 95% CI = 1.10-1.79; TT: p = 0.001, OR = 2.23, 95% CI = 1.37-3.62) in female cases with a reported maternal history, specifically in women with the onset of disease after 50 years of age (T: p = 0.004, OR = 1.77, 95% CI = 1.20-2.62; TT: p = 0.001, OR = 3.7, 95% CI = 1.62-8.46). The presented evidence suggests a need to conduct larger studies on the association between genetic variations at the BRCA1 promoter and the breast cancer risk, according to maternal/paternal lineage. PMID:23657760

  4. Early modification of sickle cell disease clinical course by UDP-glucuronosyltransferase 1A1 gene promoter polymorphism.

    PubMed

    Martins, Rute; Morais, Anabela; Dias, Alexandra; Soares, Isabel; Rolão, Cristiana; Ducla-Soares, J L; Braga, Lígia; Seixas, Teresa; Nunes, Baltazar; Olim, Gabriel; Romão, Luísa; Lavinha, João; Faustino, Paula

    2008-01-01

    Elevated erythrocyte destruction in sickle cell disease (SCD) results in chronic hyperbilirubinaemia and, in a subset of patients, cholelithiasis occurs. We investigated whether the (TA)n promoter polymorphism in the UDP-glucuronosyltransferase 1A1 gene (UGT1A1) may modify bilirubin metabolism, influencing bilirubinaemia, predisposition to cholelithiasis and subsequent cholecystectomy, in a group of 153 young SCD patients (mean age 12.0 +/- 9.0 years) predominantly of Bantu beta S haplotype. The concomitant effect of alpha thalassaemia was also analysed. Among the several UGT1A1 genotypes found, the most frequent were the (TA)6/(TA)6 (n = 37), (TA)6/(TA)7 (n = 60) and (TA)7/(TA)7 (n = 29). These groups of patients did not significantly differ in age, gender ratio and haemoglobin, foetal haemoglobin and reticulocyte levels. On the other hand, total bilirubin levels were significantly different between groups, with an increased (TA) repeat number being associated with higher bilirubinaemia. Furthermore, both cholelithiasis and cholecystectomy were more frequent in groups with higher (TA) repeat number, although the former association was not statistically significant. None of the mentioned parameters is statistically different within UGT1A1 groups with the presence of alpha thalassaemia. Thus, the UGT1A1 promoter polymorphism may represent an important nonglobin genetic modifier of Bantu SCD patients' clinical manifestations, even at a young age. PMID:18392554

  5. Polymorphisms in the CCR5 promoter region influence disease progression in perinatally human immunodeficiency virus type 1-infected children.

    PubMed

    Ometto, L; Bertorelle, R; Mainardi, M; Zanchetta, M; Tognazzo, S; Rampon, O; Ruga, E; Chieco-Bianchi, L; De Rossi, A

    2001-03-01

    The effect of CC-chemokine receptor 5 (CCR5) promoter polymorphisms on the natural history of human immunodeficiency virus (HIV) disease was studied in 73 HIV-1-infected children. The CCR5(59338-59537) promoter haplotype, CCR5-59029A/G polymorphism, and CCR5Delta32 and CCR2-64I alterations were investigated. After exclusion of carriers of CCR5Delta32 or CCR2-64I, Kaplan-Meier analysis disclosed that children with the P1/P1(59353C,59356C,59402A) genotype progressed faster to disease than did children with other haplotypes (P=.016). When CCR2-64I carriers were included, this effect had borderline significance (P=.065) and was lost when CCR5Delta32 carriers were also considered (P=.387). The P1/P1 effect was strongest early after infection, when progression to disease was mainly associated with CCR5 coreceptor-using viruses. These results indicate that the P1/P1 genotype is predictive of rapid progression in HIV-1-infected children lacking CCR5Delta32 or CCR5-64I alleles. The observation of a linkage disequilibrium between P1 and 59029A might explain the previously reported association between 59029A homozygosity and rapid disease progression. PMID:11181160

  6. Interleukin-6 Gene Promoter Polymorphisms and Cardiovascular Risk Factors. A family study

    PubMed Central

    Guzmán-Guzmán, Iris Paola; Muñoz-Valle, José Francisco; Flores-Alfaro, Eugenia; Salgado-Goytia, Lorenzo; Salgado-Bernabé, Aralia Berenice; Parra-Rojas, Isela

    2010-01-01

    Interleukin-6 (IL-6) is a cytokine involved in inflammatory process, as well as in glucose and lipid metabolism. Several studies of the biological relevance of IL-6 gene polymorphisms have indicated a relationship with cardiovascular disease. The aim of this study was to assess whether the –174 G/C and –572 G/C of IL-6 gene polymorphisms are associated with cardiovascular risk factors in Mexican families. Ninety members of 30 Mexican families, in which an index case (proband) had obesity, were included in the study. We evaluated the body composition by bioelectrical impedance. Peripheral blood samples were collected to determine biochemical and hematological parameters. High sensitivity C- reactive protein levels were measurement for nephelometric analysis. Screening for both polymorphisms studied was performed by PCR-RFLP. In the parents, both polymorphisms were in Hardy-Weinberg's equilibrium. The genotypes –174 GC/CC were associated with T2D (OR = 1.23, IC95% 1.01–1.5) and highest levels of hsCRP (p = 0.02), whereas genotype –572 GG was associated with T2D (OR = 1.24, IC95% 1.04–1.47) with an inflammatory state determined by the increase in the leukocyte count (OR = 1.24, IC95% 1.02–1.51). The genotypes –174 GC/CC and –572 GG may confer susceptibility for the development of subclinical inflammation and type 2 diabetes in Mexican families. PMID:20164544

  7. Polymorphism rs7278468 is associated with Age-related cataract through decreasing transcriptional activity of the CRYAA promoter

    PubMed Central

    Ma, Xiaoyin; Jiao, Xiaodong; Ma, Zhiwei; Hejtmancik, J. Fielding

    2016-01-01

    CRYAA plays critical functional roles in lens transparency and opacity, and polymorphisms near CRYAA have been associated with age-related cataract (ARC). This study examines polymorphisms in the CRYAA promoter region for association with ARC and elucidates the mechanisms of this association. Three SNPs nominally associated with ARC were identified in the promoter region of CRYAA: rs3761382 (P = 0.06, OR (Odds ratio) = 1.5), rs13053109 (P = 0.04, OR = 1.6), rs7278468 (P = 0.007, OR = 0.6). The C-G-T haplotype increased the risk for ARC overall (P = 0.005, OR = 1.8), and both alleles and haplotypes show a stronger association with cortical cataract (rs3761382, P = 0.002, OR = 2.1; rs13053109, P = 0.002, OR = 2.1; rs7278468, P = 0.0007, OR = 0.5; C-G-T haplotype, P = 0.0003, OR = 2.2). The C-G-T risk haplotype decreased transcriptional activity through rs7278468, which lies in a consensus binding site for the transcription repressor KLF10. KLF10 binding inhibited CRYAA transcription, and both binding and inhibition were greater with the T rs7278468 allele. Knockdown of KLF10 in HLE cells partially rescued the transcriptional activity of CRYAA with rs7278468 T allele, but did not affect activity with the G allele. Thus, our data suggest that the T allele of rs7278468 in the CRYAA promoter is associated with ARC through increasing binding of KLF-10 and thus decreasing CRYAA transcription. PMID:26984531

  8. A single-nucleotide polymorphism in the human p27kip1 gene (-838C>A) affects basal promoter activity and the risk of myocardial infarction

    PubMed Central

    González, Pelayo; Díez-Juan, Antonio; Coto, Eliecer; Álvarez, Victoria; Reguero, Julian R; Batalla, Alberto; Andrés, Vicente

    2004-01-01

    Background Excessive proliferation of vascular smooth muscle cells and leukocytes within the artery wall is a major event in the development of atherosclerosis. The growth suppressor p27kip1 associates with several cyclin-dependent kinase/cyclin complexes, thereby abrogating their capacity to induce progression through the cell cycle. Recent studies have implicated p27kip1 in the control of neointimal hyperplasia. For instance, p27kip1 ablation in apolipoprotein-E-null mice enhanced arterial cell proliferation and accelerated atherogenesis induced by dietary cholesterol. Therefore, p27kip1 is a candidate gene to modify the risk of developing atherosclerosis and associated ischaemic events (i.e., myocardial infarction and stroke). Results In this study we found three common single-nucleotide polymorphisms in the human p27kip1 gene (+326T>G [V109G], -79C>T, and -838C>A). The frequency of -838A carriers was significantly increased in myocardial infarction patients compared to healthy controls (odds ratio [OR] = 1.73, 95% confidence interval [95%CI] = 1.12–2.70). In addition, luciferase reporter constructs driven by the human p27kip1 gene promoter containing A at position -838 had decreased basal transcriptional activity when transiently transfected in Jurkat cells, compared with constructs bearing C in -838 (P = 0.04). Conclusions These data suggest that -838A is associated with reduced p27kip1 promoter activity and increased risk of myocardial infarction. PMID:15061869

  9. Common Variants on Cytotoxic T Lymphocyte Antigen-4 Polymorphisms Contributes to Type 1 Diabetes Susceptibility: Evidence Based on 58 Studies

    PubMed Central

    Ma, Junhua; Sun, Fei; Zhao, Zefei; Gu, Mingjun

    2014-01-01

    In the past decade, a number of case–control studies have been carried out to investigate the relationship between the CTLA4 gene polymorphisms and type 1 diabetes (T1D). However, these studies have yielded contradictory results. To investigate this inconsistency, we performed a meta-analysis of all available studies dealing with the relationship between the CTLA4 polymorphism and T1D. In total, 58 association studies on two CTLA4 polymorphisms (G49A and C60T) and risk of T1D, including a total of 30,723 T1D cases and 45,254 controls were included. In a combined analysis, the summary per-allele odds ratio (OR) for T1D of the G49A and C60T polymorphism was 1.42 [95% confidence interval (CI): 1.31–1.53, P<10−5] and 1.23 (95% CI: 1.18–1.29, P<10−5), respectively. Significant results were also observed using dominant or recessive genetic model. In the subgroup analysis by ethnicity and sample size, significantly increased risks were also found for these polymorphisms. This meta-analysis demonstrated that the G49A and C60T polymorphism of CTLA4 is a risk factor associated with increased T1D susceptibility, but these associations vary in different ethnic populations. PMID:24465825

  10. The promoter polymorphism of the interleukin-6 gene regulates interleukin-6 production in neonates but not in adults.

    PubMed

    Kilpinen, S; Hulkkonen, J; Wang, X Y; Hurme, M

    2001-03-01

    In the promoter region of the IL-6 gene there is a single base exchange (G --> C) polymorphism at position -174. Recent findings suggest that this polymorphism may affect the transcription rate of the IL-6 gene and IL-6 plasma levels. To analyse its biological significance, we examined IL-6 plasma levels in cord blood and IL-6 production by neonatal cells after LPS-stimulation in relation to the presence of the IL-6G and IL-6C alleles. We hypothesized that since healthy neonates lack a previous exposure to exogenous antigens, their cytokine production could be genetically regulated. We also assumed that the normal labour-related stress could provide a physiological stimulus for IL-6 production. Cord blood was collected from 50 healthy, full-term neonates after normal vaginal delivery (VD) and from 42 healthy, full-term neonates after elective caesarean section (ECS). Adult samples were obtained from 450 healthy adult controls. The -174 polymorphism was analysed using PCR. IL-6 plasma levels and in vitro IL-6 production were measured using an ELISA method. Generally, IL-6 plasma levels in neonates were significantly higher than those in adults (neonates born by VD versus adults p < 0.001 and neonates born by ECS versus adults p < 0.001); the median value for neonates born by VD was 11.4 pg/ml (4.5-45.9), for neonates born by ECS 2.9 pg/ml (1.9-6.4) and for adults, 1.2 pg/ml (0.7-2.0). Surprisingly, cord blood IL-6 levels after VD differed significantly from those after ECS (p < 0.001). An analysis was carried out to ascertain if there was a genetic association between different IL-6 genotypes and IL-6 plasma levels in neonates. In the group of VD neonates with the CC genotype, non-carriers of the G allele, secreted significantly more IL-6 than carriers of the G allele (p < 0.03); 21.4 pg/ml (9.5-81.3) and 9.6 pg/ml (3.5-36.2) respectively. In line with this, ECS newborns with the CC genotype had higher IL-6 plasma levels than carriers of the G allele (p < 0

  11. A Potential Polymorphism in the Promoter of Let-7 is Associated With an Increased Risk of Intracranial Aneurysm

    PubMed Central

    Sima, Xiutian; Sun, Hong; Zhou, Peizhi; You, Chao

    2015-01-01

    Abstract Let-7 family plays a key role in the progression of atherosclerosis and intracranial aneurysm (IA). We hypothesized that rs10877887 and rs13293512 polymorphisms in the promoters of let-7 family may be associated with the susceptibility of IA. We genotyped the 2 single nucleotide polymorphisms (SNPs) in 305 patients with IA and 401 healthy controls. The rs10877887 was analyzed using a polymerase chain reaction-restriction fragment length polymorphism assay, and the rs13293512 was analyzed using a TaqMan SNP genotyping method. The relative expression of let-7 family was measured in plasma of cases and controls using real-time PCR. We found that the rs13293512CT genotype was associated with a significantly increased risk of developing IA in a heterozygote comparison (adjusted OR = 1.43, 95% CI, 1.00–2.05, P = 0.048) and dominant comparison (adjusted OR = 1.44, 95% CI, 1.02–2.03, P = 0.04). Combined analysis showed that the rs10877887TT and rs13293512CC/CT genotypes had a significantly increased risk of IA (OR = 1.67, 95% CI, 1.04–2.68, P = 0.03). Moreover, the levels of let-7a, let-7d, and let-7f were downregulated in IA patients, and patients with the rs13293512CC/CT genotypes had a lower level of let-7a than those with rs13293512TT genotype (P = 0.03). These findings indicate that the rs13293512CC/CT is a risk factor for the development of IA, possibly because of the genotypes resulting in a lower level of let-7a. PMID:26705209

  12. CYP2C9 Promoter Variable Number Tandem Repeat Polymorphism Regulates mRNA Expression in Human Livers

    PubMed Central

    Sun, Xiaochun; Gong, Yan; Gawronski, Brian E.; Langaee, Taimour Y.; Shahin, Mohamed Hossam A.; Khalifa, Sherief I.; Johnson, Julie A.

    2012-01-01

    CYP2C9 is involved in metabolism of nearly 25% of clinically used drugs. Coding region polymorphisms CYP2C9*2 and *3 contribute to interperson variability in drug dosage and clinical outcomes, whereas the role of a regulatory polymorphism remains uncertain. Measuring allelic RNA expression in 87 human liver samples, combined with genotyping, sequencing, and reporter gene assays, we identified a promoter variable number tandem repeat polymorphism (pVNTR) that fully accounted for allelic CYP2C9 mRNA expression differences. Present in three different variant forms [short (pVNTR-S), medium (pVNTR-M), and long (pVNTR-L)], only the pVNTR-S allele reduced the CYP2C9 mRNA level compared with the pVNTR-M (reference) allele. pVNTR-S is in linkage disequilibrium with *3, with linkage disequilibrium r2 of 0.53 to 0.75 in different populations. In patients who were taking a maintenance dose of warfarin, the mean warfarin dose was associated with the copies of pVNTR-S (p = 0.0001). However, in multivariate regression models that included the CYP2C9*3, pVNTR-S was no longer a significant predictor of the warfarin dose (p = 0.60). These results indicate that although pVNTR-S reduced CYP2C9 mRNA expression, the in vivo effects of pVNTR-S on warfarin metabolism cannot be separated from the effects of *3. Therefore, it is not necessary to consider pVNTR-S as an additional biomarker for warfarin dosing. Larger clinical studies are needed to define whether the pVNTR-S has a minimal effect in vivo, or whether the effect attributed to *3 is really a combination of effects on expression by the pVNTR-S along with effects on catalytic activity from the nonsynonymous *3 variant. PMID:22289258

  13. Common Polymorphisms in the Solute Carrier SLC30A10 are Associated With Blood Manganese and Neurological Function

    PubMed Central

    Kippler, Maria; Alhamdow, Ayman; Rahman, Syed Moshfiqur; Smith, Donald R.; Vahter, Marie; Lucchini, Roberto G.; Broberg, Karin

    2016-01-01

    Manganese (Mn) is an essential nutrient in humans, but excessive exposure to Mn may cause neurotoxicity. Despite homeostatic regulation, Mn concentrations in blood vary considerably among individuals. We evaluated if common single-nucleotide polymorphisms (SNPs) in SLC30A10, which likely encodes an Mn transporter, influence blood Mn concentrations and neurological function. We measured blood Mn concentrations by ICP-MS or atomic absorption spectroscopy and genotyped 2 SLC30A10 non-coding SNPs (rs2275707 and rs12064812) by TaqMan PCR in cohorts from Bangladesh (N = 406), the Argentinean Andes (N = 198), and Italy (N = 238). We also measured SLC30A10 expression in whole blood by TaqMan PCR in a sub-group (N = 101) from the Andean cohort, and neurological parameters (sway velocity and finger-tapping speed) in the Italian cohort. The rs2275707 variant allele was associated with increased Mn concentrations in the Andes (8%, P = .027) and Italy (10.6%, P = .012), but not as clear in Bangladesh (3.4%, P = .21; linear regression analysis adjusted for age, gender, and plasma ferritin). This allele was also associated with increased sway velocity (15%, P = .033; adjusted for age and sex) and reduced SLC30A10 expression (−24.6%, P = .029). In contrast, the rs12064812 variant homozygous genotype was associated with reduced Mn concentrations, particularly in the Italian cohort (−18.4%, P = .04), and increased finger-tapping speed (8.7%, P = .025). We show that common SNPs in SLC30A10 are associated with blood Mn concentrations in 3 unrelated cohorts and that their influence may be mediated by altered SLC30A10 expression. Moreover, the SNPs appeared to influence neurological functions independent of blood Mn concentrations, suggesting that SLC30A10 could regulate brain Mn levels. PMID:26628504

  14. Association between two common polymorphisms (single nucleotide polymorphism -250G/A and -514C/T) of the hepatic lipase gene and coronary artery disease in type 2 diabetic patients

    PubMed Central

    Mohammadzadeh, Ghorban; Ghaffari, Mohammad-Ali; Bazyar, Mohammad; Kheirollah, Alireza

    2016-01-01

    Background: Variations in the hepatic lipase (HL) gene are the potential candidate for coronary artery disease (CAD) especially in type 2 diabetes mellitus (T2DM) in diverse populations. We assessed the association of -514C/T and -250G/A polymorphisms in HL (LIPC) gene with CAD risk in Iranian population with type 2 diabetes. Materials and Methods: We evaluated 322 type 2 diabetic patients, 166 patients with normal angiograms as controls and 156 patients those identified with CAD undergoing their first coronary angiography as CAD cases. Genotyping of -514C/T and -250G/A polymorphisms in the promoter of the LIPC gene were studied by polymerase chain reaction (PCR)-restriction fragment length polymorphism technique. Results: Genotype distributions in CAD cases (73.7%, 20.5%, and 5.8% for −250G/A) and (62.2%, 32.7%, and 5.1% for -514C/T) were significantly different from those in controls (60.8%, 37.4%, and 1.8% for -250G/A) and (51.2%, 48.2%, and 0.6% for -514C/T). CAD cases had lower A-allele frequency than controls (0.131 vs. 0.196, P = 0.028). The odds ratio for the presence of -250 (GG + GA) genotype and A allele in CAD cases were 2.206 (95% confidence interval [CI] =1.33–3.65, P = 0.002) and 1.609 (95% CI = 1.051 −2.463, P = 0.029) respectively. Haplotype analysis demonstrated a significant association between especially LIPC double mutant (−250 A/-514 T) haplotype and presence of CAD. Conclusion: Our findings indicated that -250 G/A polymorphism rather than -514 C/T polymorphism of LIPC gene is more associated with the increased risk of CAD particularly in women with T2DM. PMID:27014654

  15. Analysis of the AHR gene proximal promoter GGGGC-repeat polymorphism in lung, breast, and colon cancer

    SciTech Connect

    Spink, Barbara C.; Bloom, Michael S.; Wu, Susan; Sell, Stewart; Schneider, Erasmus; Ding, Xinxin; Spink, David C.

    2015-01-01

    The aryl hydrocarbon receptor (AhR) regulates expression of numerous genes, including those of the CYP1 gene family. With the goal of determining factors that control AHR gene expression, our studies are focused on the role of the short tandem repeat polymorphism, (GGGGC){sub n}, located in the proximal promoter of the human AHR gene. When luciferase constructs containing varying GGGGC repeats were transfected into cancer cell lines derived from the lung, colon, and breast, the number of GGGGC repeats affected AHR promoter activity. The number of GGGGC repeats was determined in DNA from 327 humans and from 38 samples representing 5 species of non-human primates. In chimpanzees and 3 species of macaques, only (GGGGC){sub 2} alleles were observed; however, in western gorilla, (GGGGC){sub n} alleles with n = 2, 4, 5, 6, 7, and 8 were identified. In all human populations examined, the frequency of (GGGGC){sub n} was n = 4 > 5 ≫ 2, 6. When frequencies of the (GGGGC){sub n} alleles in DNA from patients with lung, colon, or breast cancer were evaluated, the occurrence of (GGGGC){sub 2} was found to be 8-fold more frequent among lung cancer patients in comparison with its incidence in the general population, as represented by New York State neonates. Analysis of matched tumor and non-tumor DNA samples from the same individuals provided no evidence of microsatellite instability. These studies indicate that the (GGGGC){sub n} short tandem repeats are inherited, and that the (GGGGC){sub 2} allele in the AHR proximal promoter region should be further investigated with regard to its potential association with lung cancer susceptibility. - Highlights: • The AHR proximal promoter contains a polymorphism, (GGGGC){sub n}, where n = 4 > 5 ≫ 2, 6 • Matched tumor and non-tumor DNA did not show (GGGGC){sub n} microsatellite instability • AHR promoter activity of a construct with (GGGGC){sub 2} was lower than that of (GGGGC){sub 4} • The frequency of (GGGGC){sub 2} in lung

  16. The functional UGT1A1 promoter polymorphism decreases endometrial cancer risk.

    PubMed

    Duguay, Yannick; McGrath, Monica; Lépine, Johanie; Gagné, Jean-François; Hankinson, Susan E; Colditz, Graham A; Hunter, David J; Plante, Marie; Têtu, Bernard; Bélanger, Alain; Guillemette, Chantal; De Vivo, Immaculata

    2004-02-01

    UDP-glucuronosyltransferase (UGT) 1A1 is involved in the inactivation of estradiol (E(2)) and its oxidized metabolites. These metabolites have been shown to contribute to the development of endometrial cancer in animal studies. Thus UGT1A1 represents a candidate gene in endometrial carcinogenesis. In this study, we established the substrate specificity of UGT1A1 for E(2) and its 2- and 4-hydroxylated metabolites. Intrinsic clearances indicated that UGT1A1 had a preference for the glucuronidation of 2-hydroxyestradiol, a metabolite associated with antiproliferative activity. Expression analysis demonstrated that UGT1A1 is present in the nonmalignant endometrium. Subsequently, we sought to determine whether the common UGT1A1 promoter allele, UGT1A1*28 [A(TA)(7)TAA], which decreases gene transcription, was associated with endometrial cancer risk in a case-control study nested within the Nurses' Health Study (222 cases, 666 matched controls). Conditional logistic regression demonstrated a significant inverse association with the UGT1A1*28 allele and endometrial cancer risk. Compared with women homozygous for the UGT1A1*1 [A(TA)(6)TAA] allele, the adjusted odds ratio (OR) was 0.81 [95% confidence interval (CI), 0.56-1.16] for the UGT1A1*1/*28 genotype and 0.40 (95% CI, 0.21-0.75) for the homozygous UGT1A1*28 genotype (P(trend) = 0.007). There was a suggestion of an interaction by menopausal status [OR = 0.39 (95% CI, 0.18-0.85) for premenopausal women and OR = 0.79 (95% CI, 0.55-1.13) for postmenopausal women who carry the UGT1A1*28 allele (P(interaction) = 0.05)]. These observations suggest that lower expression of UGT1A1 decreases the risk of endometrial cancer by reducing the excretion of 2-hydroxyestradiol, the antiproliferative metabolite of E(2), in the endometrium. PMID:14871858

  17. Hybridization promotes color polymorphism in the aposematic harlequin poison frog, Oophaga histrionica

    PubMed Central

    Medina, Iliana; Wang, Ian J; Salazar, Camilo; Amézquita, Adolfo

    2013-01-01

    Whether hybridization can be a mechanism that drives phenotypic diversity is a widely debated topic in evolutionary biology. In poison frogs (Dendrobatidae), assortative mating has been invoked to explain how new color morphs persist despite the expected homogenizing effects of natural selection. Here, we tested the complementary hypothesis that new morphs arise through hybridization between different color morphs. Specifically, we (1) reconstructed the phylogenetic relationships among the studied populations of a dart-poison frog to provide an evolutionary framework, (2) tested whether microsatellite allele frequencies of one putative hybrid population of the polymorphic frog O. histrionica are intermediate between O. histrionica and O. lehmanni, and (3) conducted mate-choice experiments to test whether putatively intermediate females prefer homotypic males over males from the other two populations. Our findings are compatible with a hybrid origin for the new morph and emphasize the possibility of hybridization as a mechanism generating variation in polymorphic species. Moreover, because coloration in poison frogs is aposematic and should be heavily constrained, our findings suggest that hybridization can produce phenotypic novelty even in systems where phenotypes are subject to strong stabilizing selection. PMID:24340180

  18. CD209 (DC-SIGN) -336A>G promoter polymorphism and severe acute respiratory syndrome in Hong Kong Chinese.

    PubMed

    Chan, Kelvin Yuen Kwong; Xu, Mei-Shu; Ching, Johannes Chi Yun; So, Thomas Man Kit; Lai, Sik-To; Chu, Chung-Ming; Yam, Loretta Y C; Wong, Andrew T Y; Chung, Pui Hong; Chan, Vera Sau Fong; Lin, Chen Lung Steve; Sham, Pak Chung; Leung, Gabriel M; Peiris, Joseph S M; Khoo, Ui-Soon

    2010-07-01

    CD209 (DC-SIGN) is an important C-type lectin which acts a receptor of many pathogens. The single nucleotide polymorphism (SNP) -336A>G in the CD209 promoter has been demonstrated to regulate promoter activity and to be associated with several important infectious diseases, such as human immunodeficiency virus-1 (HIV-1), Mycobacterium tuberculosis, and Dengue fever. CD209 facilitates severe acute respiratory syndrome (SARS)-coronavirus spike protein-bearing pseudotype driven infection of permissive cells in vitro. In keeping with previously published findings, our in vitro studies confirmed that this SNP modulates gene promoter activity. Genetic association analysis of this SNP with clinico-pathologic outcomes in 824 serologic confirmed SARS patients showed that the -336AG/GG genotype SARS patients was associated with lower standardized lactate-dehydrogenase (LDH) levels compared with the -336AA patients (p = 0.014, odds ratio = 0.40). High LDH levels are known to be an independent predictor for poor clinical outcome, probably related to tissue destruction from immune hyperactivity. Hence, SARS patients with the CD209 -336 AA genotype carry a 60% chance of having a poorer prognosis. This association is in keeping with the role of CD209 in modulating immune response to viral infection. The relevance of these findings for other infectious diseases and inflammatory conditions would be worth investigating. PMID:20359516

  19. TNF-α Promoter Polymorphisms Predict the Response to Etanercept More Powerfully than that to Infliximab/Adalimumab in Spondyloarthritis

    PubMed Central

    Liu, Jing; Dong, Zheng; Zhu, Qi; He, Dongyi; Ma, Yanyun; Du, Aiping; He, Fan; Zhao, Dongbao; Xu, Xia; Zhang, Hui; jin, Li; Wang, Jiucun

    2016-01-01

    While previous studies have researched in association analyses between TNFα promoter polymorphisms and responses to TNF blockers in spondyloarthritis patients, their results were conflicting. Therefore, we aimed to determine whether TNFα promoter polymorphisms could predict response to TNF blockers and find the source of heterogeneity. Data were extracted and analyzed from published articles and combined with our unpublished data. We found that the greatest potential sources of heterogeneity in the results were gender ratio, disease type, continents, and TNF blockers. Then Stratification analysis showed that the TNFα −308 G allele and the −238 G allele predicted a good response to TNF blockers (OR = 2.64 [1.48–4.73]; 2.52 [1.46–4.37]). However, G alleles of TNFα −308 and −238 could predict the response to etanercept (OR = 4.02 [2.24–7.23]; 5.17 [2.29–11.67]) much more powerfully than the response to infiliximab/adalimumab (OR = 1.68 [1.02–2.78]; 1.28 [0.57–2.86]). TNFα −857 could not predict the response in either subgroup. Cumulative meta-analysis performed in ankylosing spondylitis patients presented the odds ratio decreased with stricter response criteria. In conclusion, TNFα −308 A/G and −238 A/G are more powerful to predict the response to Etanercept and it is dependent on the criteria of response. PMID:27578555

  20. Possible association of the 5-HTTLPR serotonin transporter promoter gene polymorphism with premature ejaculation in a Turkish population

    PubMed Central

    Ozbek, Emin; Tasci, Ali I; Tugcu, Volkan; Ilbey, Yusuf O; Simsek, Abdulmuttalip; Ozcan, Levent; Polat, Emre C; Koksal, Vedat

    2009-01-01

    We evaluated the genotypes of the serotonin transporter gene (5-HTT) in patients with premature ejaculation (PE) to determine the role of genetic factors in the etiopathogenesis of PE and possibly to identify the patient subgroups. A total of 70 PE patients and 70 controls were included in this study. All men were heterosexual, had no other disorders and were either married or in a stable relationship. PE was defined as ejaculation that occurred within 1 min of vaginal intromission. Genomic DNA from patients and controls was analyzed using polymerase chain reaction, and allelic variations of the promoter region of the serotonin transporter gene (5-HTTLPR) were determined. The 5-HTTLPR (serotonin transporter promoter gene) genotypes in PE patients vs. controls were distributed as follows: L/L 16% vs. 17%, L/S 30% vs. 53% and S/S 54% vs. 28%. We examined the haplotype analysis for three polymorphisms of the 5-HTTLPR gene: LL, LS and SS. The appropriateness of the allele frequencies in the 5-HTTLPR gene was analyzed by the Hardy-Weinberg equilibrium using the χ2-test. The short (S) allele of the 5-HTTLPR gene was significantly more frequent in PE patients than in controls (P < 0.05). We suggest that the 5-HTTLPR gene plays a role in the pathophysiology of all primary PE cases. Further studies are needed to evaluate the relationship between 5-HTTLPR gene polymorphism and patient subgroup (such as primary and secondary PE) responses to selective serotonin reuptake inhibitors as well as ethnic differences. PMID:19252508

  1. Polymorphic core promoter GA-repeats alter gene expression of the early embryonic developmental genes.

    PubMed

    Valipour, E; Kowsari, A; Bayat, H; Banan, M; Kazeminasab, S; Mohammadparast, S; Ohadi, M

    2013-12-01

    Protein complexes that bind to 'GAGA' DNA elements are necessary to replace nucleosomes to create a local chromatin environment that facilitates a variety of site-specific regulatory responses. Three to four elements are required for the disruption of a preassembled nucleosome. We have previously identified human protein-coding gene core promoters that are composed of exceptionally long GA-repeats. The functional implication of those GA-repeats is beginning to emerge in the core promoter of the human SOX5 gene, which is involved in multiple developmental processes. In the current study, we analyze the functional implication of GA-repeats in the core promoter of two additional genes, MECOM and GABRA3, whose expression is largely limited to embryogenesis. We report a significant difference in gene expression as a result of different alleles across those core promoters in the HEK-293 cell line. Across-species homology check for the GABRA3 GA-repeats revealed that those repeats are evolutionary conserved in mouse and primates (p<1 × 10(-8)). The MECOM core promoter GA-repeats are also conserved in numerous species, of which human has the longest repeat and complexity. We propose a novel role for GA-repeat core promoters to regulate gene expression in the genes involved in development and evolution. PMID:24055488

  2. Multifactor dimensionality reduction analysis identifies specific nucleotide patterns promoting genetic polymorphisms

    PubMed Central

    Arehart, Eric; Gleim, Scott; White, Bill; Hwa, John; Moore, Jason H

    2009-01-01

    Background The fidelity of DNA replication serves as the nidus for both genetic evolution and genomic instability fostering disease. Single nucleotide polymorphisms (SNPs) constitute greater than 80% of the genetic variation between individuals. A new theory regarding DNA replication fidelity has emerged in which selectivity is governed by base-pair geometry through interactions between the selected nucleotide, the complementary strand, and the polymerase active site. We hypothesize that specific nucleotide combinations in the flanking regions of SNP fragments are associated with mutation. Results We modeled the relationship between DNA sequence and observed polymorphisms using the novel multifactor dimensionality reduction (MDR) approach. MDR was originally developed to detect synergistic interactions between multiple SNPs that are predictive of disease susceptibility. We initially assembled data from the Broad Institute as a pilot test for the hypothesis that flanking region patterns associate with mutagenesis (n = 2194). We then confirmed and expanded our inquiry with human SNPs within coding regions and their flanking sequences collected from the National Center for Biotechnology Information (NCBI) database (n = 29967) and a control set of sequences (coding region) not associated with SNP sites randomly selected from the NCBI database (n = 29967). We discovered seven flanking region pattern associations in the Broad dataset which reached a minimum significance level of p ≤ 0.05. Significant models (p << 0.001) were detected for each SNP type examined in the larger NCBI dataset. Importantly, the flanking region models were elongated or truncated depending on the nucleotide change. Additionally, nucleotide distributions differed significantly at motif sites relative to the type of variation observed. The MDR approach effectively discerned specific sites within the flanking regions of observed SNPs and their respective identities, supporting the collective

  3. An IL-13 Promoter Polymorphism Associated with Liver Fibrosis in Patients with Schistosoma japonicum

    PubMed Central

    Long, Xin; Chen, Qian; Zhao, Jianping; Rafaels, Nicholas; Mathias, Priyanka; Liang, Huifang; Potee, Joseph; Campbell, Monica; Zhang, Bixiang; Gao, Li; Georas, Steve N.; Vercelli, Donata; Beaty, Terri H.; Ruczinski, Ingo; Mathias, Rasika; Barnes, Kathleen C.; Chen, Xiaoping

    2015-01-01

    The aim of this study was to determine whether two polymorphisms in the gene encoding IL13 previously associated with Schistosoma hematobium (S. hematobium) and S. mansoni infection are associated with S. japonicum infection. Single nucleotide polymorphisms (SNPs) rs1800925 (IL13/-1112C>T) and rs20541 (IL13R130Q) were genotyped in 947 unrelated individuals (307 chronically infected, 339 late-stage with liver fibrosis, 301 uninfected controls) from a schistosomiasis-endemic area of Hubei province in China. Regression models were used to evaluate allelic and haplotypic associations with chronic and late-stage schistosomiasis adjusted for non-genetic covariates. Expression of IL-13 was measured in S. japonicun-infected liver fibrosis tissue and normal liver tissue from uninfected controls by immunohistochemistry (IHC). The role of rs1800925 in IL-13 transcription was further determined by Luciferase report assay using the recombinant PGL4.17-rs180092 plasmid. We found SNP rs1800925T was associated with late-stage schistosomiasis caused by S. japonicum but not chronic schistosomiasis (OR = 1.39, 95%CI = 1.02–1.91, p = 0.03) and uninfected controls (OR = 1.49, 95%CI = 1.03–2.13, p = 0.03). Moreover, the haplotype rs1800925T-rs20541C increased the risk of disease progression to late-stage schistosomiasis (OR = 1.46, p = 0.035), whereas haplotype rs1800925C-rs20541A showed a protective role against development of late-stage schistosomiasis (F = 0.188, OR = 0.61, p = 0.002). Furthermore, S. japonicum-induced fibrotic liver tissue had higher IL13 expression than normal liver tissue. Plasmid PGL4.17-rs1800925T showed a stronger relative luciferase activity than Plasmid PGL4.17-rs1800925C in 293FT, QSG-7701 and HL-7702 cell lines. In conclusion, the functional IL13 polymorphism, rs1800925T, previously associated with risk of schistosomiasis, also contributes to risk of late-stage schistosomiasis caused by S. japonicum. PMID:26258681

  4. An IL-13 promoter polymorphism associated with liver fibrosis in patients with Schistosoma japonicum.

    PubMed

    Long, Xin; Chen, Qian; Zhao, Jianping; Rafaels, Nicholas; Mathias, Priyanka; Liang, Huifang; Potee, Joseph; Campbell, Monica; Zhang, Bixiang; Gao, Li; Georas, Steve N; Vercelli, Donata; Beaty, Terri H; Ruczinski, Ingo; Mathias, Rasika; Barnes, Kathleen C; Chen, Xiaoping

    2015-01-01

    The aim of this study was to determine whether two polymorphisms in the gene encoding IL13 previously associated with Schistosoma hematobium (S. hematobium) and S. mansoni infection are associated with S. japonicum infection. Single nucleotide polymorphisms (SNPs) rs1800925 (IL13/-1112C>T) and rs20541 (IL13R130Q) were genotyped in 947 unrelated individuals (307 chronically infected, 339 late-stage with liver fibrosis, 301 uninfected controls) from a schistosomiasis-endemic area of Hubei province in China. Regression models were used to evaluate allelic and haplotypic associations with chronic and late-stage schistosomiasis adjusted for non-genetic covariates. Expression of IL-13 was measured in S. japonicun-infected liver fibrosis tissue and normal liver tissue from uninfected controls by immunohistochemistry (IHC). The role of rs1800925 in IL-13 transcription was further determined by Luciferase report assay using the recombinant PGL4.17-rs180092 plasmid. We found SNP rs1800925T was associated with late-stage schistosomiasis caused by S. japonicum but not chronic schistosomiasis (OR = 1.39, 95%CI = 1.02-1.91, p = 0.03) and uninfected controls (OR = 1.49, 95%CI = 1.03-2.13, p = 0.03). Moreover, the haplotype rs1800925T-rs20541C increased the risk of disease progression to late-stage schistosomiasis (OR = 1.46, p = 0.035), whereas haplotype rs1800925C-rs20541A showed a protective role against development of late-stage schistosomiasis (F = 0.188, OR = 0.61, p = 0.002). Furthermore, S. japonicum-induced fibrotic liver tissue had higher IL13 expression than normal liver tissue. Plasmid PGL4.17-rs1800925T showed a stronger relative luciferase activity than Plasmid PGL4.17-rs1800925C in 293FT, QSG-7701 and HL-7702 cell lines. In conclusion, the functional IL13 polymorphism, rs1800925T, previously associated with risk of schistosomiasis, also contributes to risk of late-stage schistosomiasis caused by S. japonicum. PMID:26258681

  5. Laryngeal cancer risk and common single nucleotide polymorphisms in nucleotide excision repair pathway genes ERCC1, ERCC2, ERCC3, ERCC4, ERCC5 and XPA.

    PubMed

    Lu, Baocai; Li, Jing; Gao, Qingzu; Yu, Wenfa; Yang, Qinghui; Li, Xiaoyu

    2014-05-25

    Because the molecular mechanisms underlying the development of laryngeal cancer are not well understood, we conducted a case-control study to determine the association between eight common SNPs in NER pathway genes and risk of laryngeal cancer, and the association between genetic polymorphisms and environmental factors. A 1:1 matched case-control study of 176 cases and 176 controls was conducted. Laryngeal cancer cases were more likely to smoke and drink (all P values<0.05). Subjects with the ERCC1 rs11615 CC genotype and C allele had an increased risk of laryngeal cancer. Similarly, individuals with the ERCC5 rs17655 GG genotype and G allele had an increased risk of laryngeal cancer. Gene-gene interaction analysis showed that subjects carrying ERCC1 rs11615 C allele and XPG/ERCC5 rs17655 G allele had a greatly increased risk of breast cancer. Stratified analysis revealed that the interaction between polymorphisms of ERCC1 rs11615 and ERCC5 rs17655 and smoking on cancer risk was statistically significant, and ERCC1 rs11615 polymorphisms also had a significant interaction with drinking habit. In conclusion, our study suggests that ERCC1 rs11615 and ERCC5 rs17655 polymorphisms are associated with increased risk of laryngeal cancer, and that they confer more risk among smokers and drinkers. PMID:24582975

  6. Association of a Common Oxytocin Receptor Gene Polymorphism with Self-Reported ‘Empathic Concern’ in a Large Population of Healthy Volunteers

    PubMed Central

    Reinders, Anette; Siffert, Doris; Stelmach, Patrick; Knop, Dietmar; Horn, Peter Alexander; Siffert, Winfried

    2016-01-01

    Background Previous research has linked genomic variations of the oxytocin receptor (OXTR) gene with individual differences in empathy. The impact of these variations on specific cognitive and emotional aspects of empathy, however, remains to be clarified. Methods We analysed associations of a common OXTR polymorphism (rs53576) with trait empathy in a sample of 421 blood donors (231 M, 190 F; age 18–74) using the Interpersonal Reactivity Index (IRI) as an established multidimensional self-report measure of empathy. Results Female sex was significantly associated with higher empathy scores in all IRI scales (p<0.001) with the exception of the cognitive perspective taking scale (p = 0.09). The overall trait empathy score was significantly associated with rs53576 (p = 0.01), with mean scores increasing from AA to GG genotypes. An analysis of the IRI subscores revealed that the polymorphism was especially associated with the emotional empathic concern scale (p = 0.02). Separate analysis of the male and female subgroup revealed a significant association of the polymorphism with female (p = 0.04), but not with male (p = 0.20) empathic concern. A comparison of effect sizes between the groups showed greater effects for women compared to men although effect size differences did not become significant in our sample. Conclusions Our findings suggest a significant association of the rs53576 OXTR gene polymorphism with trait empathy and especially with emotional aspects of empathy. This association is possibly weaker or absent in men compared to women. PMID:27467763

  7. MDM2 SNP309 promoter polymorphism confers risk for hereditary melanoma.

    PubMed

    Thunell, Lena K; Bivik, Cecilia; Wäster, Petra; Fredrikson, Mats; Stjernström, Annika; Synnerstad, Ingrid; Rosdahl, Inger; Enerbäck, Charlotta

    2014-06-01

    The p53 pathway regulates stress response, and variations in p53, MDM2, and MDM4 may predispose an individual to tumor development. The aim of this study was to study the impact of genetic variation on sporadic and hereditary melanoma. We have analyzed a combination of three functionally relevant variants of the p53 pathway in 258 individuals with sporadic malignant melanomas, 50 with hereditary malignant melanomas, and 799 healthy controls. Genotyping was performed by PCR-restriction fragment length polymorphism, pyrosequencing, and allelic discrimination. We found an increased risk for hereditary melanoma in MDM2 GG homozygotes, which was more pronounced among women (P=0.035). In the event of pairwise combinations of the single nucleotide polymorphisms, a risk elevation was shown for MDM2 GG homozygotes/p53 wild-type Arg in hereditary melanoma (P=0.01). Individuals with sporadic melanomas of the superficial spreading type, including melanoma in situ, showed a slightly higher frequency of the MDM2 GG genotype compared with those with nodular melanomas (P=0.04). The dysplastic nevus phenotype, present in the majority of our hereditary melanoma cases and also in some sporadic cases, further enhanced the effect of the MDM2 GG genotype on melanoma risk (P=0.005). In conclusion, the results show an association between MDM2 SNP309 and an increased risk for hereditary melanoma, especially among women. Analysis of sporadic melanoma also shows an association between MDM2 and the superficial spreading melanoma subtype, as well as an association with the presence of dysplastic nevi in sporadic melanoma. PMID:24625390

  8. The G-765C promoter polymorphism in cyclooxygenase-2 (PTGS2), aspirin utilization and cardiovascular disease risk: the Atherosclerosis Risk in Communities (ARIC) study

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Cyclooxygenase-2 derived prostaglandins modulate cardiovascular disease risk. We sought to determine if the reduced function G-765C promoter polymorphism in PTGS2 was associated with incident coronary heart disease (CHD) or ischemic stroke risk, and if this was modified by aspirin utilization. Usin...

  9. Identification of single nucleotide polymorphisms within the promoter region of the bovine heat shock protein 70 gene and associations with pregnancy

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Objectives were: 1) determine genetic diversity in a promoter segment of the bovine HSP-70 gene, and 2) determine if the identified single nucleotide polymorphisms (SNPs) were related to pregnancy rates. Genomic DNA was collected from 107 Bos taurus/Bos indicus crossbred cows. Specific primers (HSP-...

  10. Association of polymorphisms in the promoter I of bovine acetyl-CoA carboxylase-alpha gene with beef fatty acid composition

    Technology Transfer Automated Retrieval System (TEKTRAN)

    The objective of this study was to identify single nucleotide polymorphisms (SNPs) in the promoter I (PI) region of bovine acetyl-CoA carboxylase-alpha (ACACA) gene and evaluate the extent to which they were associated with lipid-related traits and fatty acid composition of beef. Eight novel SNPs w...

  11. Association of tumor necrosis factor-alpha(TNF-alpha)gene promoter polymorphisms with TNF-alpha response to endotoxin (LPS)in calves.

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Attenuation of TNF-alpha gene expression is a NF-'B-mediated regulatory process essential to avoid deleterious effects of excessive or prolonged synthesis of TNF-alpha, especially in response to gram-negative bacterial infection or LPS. An uncommon G to A transition polymorphism in the promoter regi...

  12. A 5'-regulatory region and two coding region polymorphisms modulate promoter activity and gene expression of the growth suppressor gene ZBED6 in cattle

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Zinc finger, BED-type containing 6 (ZBED6) is an important transcription factor in placental mammals, affecting development, cell proliferation, and growth. Polymorphisms in its promoter and coding regions are likely to impact ZBED6 transcription and growth traits. In this study, a total of three no...

  13. Novel Polymorphism in the FMR1 Gene Resulting in a “Pseudodeletion” of FMR1 in a Commonly Used Fragile X Assay

    PubMed Central

    Daly, Thomas M.; Rafii, Arash; Martin, Rick A.; Zehnbauer, Barbara A.

    2000-01-01

    The fragile X syndrome is the most commonly inherited cause of mental retardation. Genetic diagnosis of this disease relies on the detection of triplet repeat expansion in the FMR1 gene on the X chromosome. Although the majority of disease in fragile X patients is due to mutations involving triplet repeat expansion, deletion of various portions of FMR1 has also been described in association with the fragile X syndrome. Here we describe a rare polymorphism in the noncoding region of FMR1 that mimics detection of a deletion in a commonly used assay for fragile X syndrome, which can result in misdiagnosis of the disease. PMID:11229516

  14. Association of common C-protein (CRP) gene polymorphism with baseline plasma CRP levels and fenofibrate response: The GOLDN Study

    Technology Transfer Automated Retrieval System (TEKTRAN)

    OBJECTIVE-C-reactive protein (CRP) is an inflammatory marker that contributes to the prediction of cardiovascular diseases (CVD). We investigated the influence of CRP polymorphisms on baseline CRP levels and fenofibrate-induced CRP changes in subjects with the metabolic syndrome (MetS). RESEARCH DES...

  15. Physiological and biochemical characterization of Azospirillum brasilense strains commonly used as plant growth-promoting rhizobacteria.

    PubMed

    Di Salvo, Luciana P; Silva, Esdras; Teixeira, Kátia R S; Cote, Rosalba Esquivel; Pereyra, M Alejandra; García de Salamone, Inés E

    2014-12-01

    Azospirillum is a plant growth-promoting rhizobacteria (PGPR) genus vastly studied and utilized as agriculture inoculants. Isolation of new strains under different environmental conditions allows the access to the genetic diversity and improves the success of inoculation procedures. Historically, the isolation of this genus has been performed by the use of some traditional culture media. In this work we characterized the physiology and biochemistry of five different A. brasilense strains, commonly used as cereal inoculants. The aim of this work is to contribute to pose into revision some concepts concerning the most used protocols to isolate and characterize this bacterium. We characterized their growth in different traditional and non-traditional culture media, evaluated some PGPR mechanisms and characterized their profiles of fatty acid methyl esters and carbon-source utilization. This work shows, for the first time, differences in both profiles, and ACC deaminase activity of A. brasilense strains. Also, we show unexpected results obtained in some of the evaluated culture media. Results obtained here and an exhaustive knowledge revision revealed that it is not appropriate to conclude about bacterial species without analyzing several strains. Also, it is necessary to continue developing studies and laboratory techniques to improve the isolation and characterization protocols. PMID:25138314

  16. A Common Polymorphism in the Caspase Recruitment Domain of RIG-I Modifies the Innate Immune Response of Human Dendritic Cells

    PubMed Central

    Hu, Jianzhong; Nistal-Villán, Estanislao; Voho, Anu; Ganee, Arnold; Kumar, Madhu; Ding, Yaomei; Garciá-Sastre, Adolfo; Wetmur, James G.

    2010-01-01

    Infection of human dendritic cells (DCs) by negative-strand RNA viruses, such as Newcastle disease virus, leads to the induction of the IFNβ gene, IFNB1, through the activation of the RNA helicase RIG-I, which is encoded by DDX58. Expression levels of IFNB1 and DDX58 in infected DCs showed positive correlations at the population and the single-cell levels. DDX58 has a common and potentially functional single nucleotide polymorphism, rs10813831 (A/G), encoding an Arg7Cys amino acid change in the RIG-I protein caspase recruitment domain (CARD). Quantitative RT-PCR analysis on Newcastle disease virus-infected primary DCs from 130 individuals revealed a significant association of the Arg7Cys single nucleotide polymorphism with increased IFNB1 and DDX58 transcription. Allelic imbalance analysis ruled out allele-specific DDX58 message levels and suggested that the observed association between Arg7Cys and IFNB1 and DDX58 transcription originated from a functional change in RIG-I due to the amino acid substitution in the CARD. DDX58 transfection experiments in 293T cells confirmed a biological functional difference between RIG-I 7Cys and the more common RIG-I 7Arg. Taken together, these data indicate that the innate immune response to viral infection of human cells is modified by a functional polymorphism in the RIG-I CARD. PMID:20511549

  17. A polymorphism in the leptin gene promoter is associated with anemia in patients with HIV disease

    PubMed Central

    Jeong, Jee-Yeong; Tate, Janet; Bathulapalli, Harini; Anderson, Damon; Steen, Hanno; Fleming, Mark; Mattocks, Kristin; Telenti, Amalio; Fellay, Jacques; Justice, Amy C.; Berliner, Nancy

    2011-01-01

    To study factors associated with anemia and its effect on survival in HIV-infected persons treated with modern combined antiretroviral therapy (cART), we characterized the prevalence of anemia in the Veterans Aging Cohort Study (VACS) and used a candidate gene approach to identify proinflammatory gene single nucleotide polymorphisms (SNPs) associated with anemia in HIV disease. The study comprised 1597 HIV+ and 865 HIV− VACS subjects with DNA, blood, and annotated clinical data available for analysis. Anemia was defined according to World Health Organization criteria (hemoglobin < 13 g/dL and < 12 g/dL in men and women, respectively). The prevalence of anemia in HIV+ and HIV− subjects was 23.1% and 12.9%, respectively. Independent of HIV status, anemia was present in 23.4% and 8% in blacks and whites, respectively. Analysis of our candidate genes revealed that the leptin −2548 G/A SNP was associated with anemia in HIV+, but not HIV−, patients, with the AA and AG genotypes significantly predicting anemia (P < .003 and P < .039, respectively, logistic regression). This association was replicated in an independent cohort of HIV+ women. Our study provides novel insight into the association between genetic variability in the leptin gene and anemia in HIV+ individuals. PMID:21926355

  18. Association Study of FOS-Like Antigen-2 Promoter Polymorphisms With Papillary Thyroid Cancer in Korean Population

    PubMed Central

    Kim, Seung Woo; Kim, Choon Dong; Chung, Joo Ho

    2014-01-01

    Objectives FOS-like antigen-2 (FOSL-2), a member of the FOS gene family, encode leucine zipper proteins that can heterodimerize with proteins of Jun family. Thus, activating protein (AP)-1 transcription factor is formed, has a crucial role in proliferation, differentiation and apoptosis of normal tissue as well as oncogenic transformation and progression. We performed an association study of single nucleotide polymorphisms (SNPs) in the FOSL-2 with papillary thyroid cancer (PTC). We also estimated the relationships between the SNPs and the clinicopathologic characteristics of PTC. Methods One promoter SNPs (rs925255) of FOSL-2 gene were genotyped with direct sequencing method in 94 PTC and 213 controls. PTC patients were dichotomized and compared with respect to clinical parameters of PTC. Genetic data were analyzed using Helixtree, SNPAnalyzer, SNPStats. Multivariate logistic regression analysis was fulfilled to evaluate the genetic effect with adjustment for age and sex. Results SNP (rs925255) in FOSL-2 showed a significant association (codominant 1 model [G/G vs. A/G]: odds ratio [OR], 0.531, 95% confidence interval [CI], 0.293 to 0.96, P=0.036; dominant model: OR, 0.50, 95% CI, 0.28 to 0.89, P=0.015) with PTC. The frequency of allele G in rs925255 was also significantly associated with PTC (OR, 0.59; 95% CI, 0.34 to 0.91; P=0.02). But we fail to prove significant association between this polymorphism (rs925255) and clinico-pathological parameters. Conclusion Our findings suggest that the rs925255 SNP and its allele G show significant association with the PTC in Korean population. PMID:24587880

  19. The Effect of UGT1A1 Promoter Polymorphism in the Development of Hyperbilirubinemia and Cholelithiasis in Hemoglobinopathy Patients

    PubMed Central

    AlFadhli, Suad; Al-Jafer, Hassan; Hadi, Mays; Al-Mutairi, Mashael; Nizam, Rasheeba

    2013-01-01

    Present study was aimed to explore the effect of (TA)n UGT1A1 gene promoter polymorphism on bilirubin metabolism, bilirubinaemia, predisposition to cholelithiasis and subsequent cholecystectomy, in Sickle-Cell Anemia (SCA) and beta-Thalasemia major (bTH) in Kuwaiti subjects compared to other population. This polymorphism was analyzed and correlated to total bilirubin and cholelithiasis in 270 age, gender, ethnically matched subjects (92 bTH, 116 SCA and 62 Controls) using PCR, dHPLC, fragment analysis and direct sequencing. Four genotypes of UGT1A1 were detected in this study (TA6/6, TA6/7, TA6/8 and TA7/7). (TA)6/8 was found only in four individuals; hence it was not included in the analysis. There was a statistically significant association of genotypes with serum total bilirubin levels in both bTH and SCA groups (p<0.001). Subjects with (TA)7/7 had the highest total serum bilirubin level (178.7±3.5 µmole/l). A significant association was observed between allele (TA)7 and cholelithiasis development (p = 0.0001). The 40%, 67.5% and 100% of SCA with (TA)6/6, (TA)6/7 and (TA)7/7 respectively developed cholelithiasis and were subsequently cholecystectomized. Our results confirm UGT1A1 (TA)7 allele as one of the factors accounting for the hyperbilirubinemia and cholelithiasis observed in SCA and bTH. PMID:24204915

  20. Characterization of Chicken MMP13 Expression and Genetic Effect on Egg Production Traits of Its Promoter Polymorphisms.

    PubMed

    Yuan, Zhenjie; Chen, Yuxia; Chen, Qiuyue; Guo, Miao; Kang, Li; Zhu, Guiyu; Jiang, Yunliang

    2016-01-01

    Extracelluar matrix undergoes constant remodeling, cell-cell, and cell-matrix interactions during chicken ovarian follicle growth, which is coordinated by matrix metalloproteinases (MMPs), and their associated endogenous inhibitors (TIMPs). Transcriptome analysis revealed upregulation of MMP13 in sexually mature chicken ovaries. In this study, we found that the expression of MMP13 in chicken ovary was stably elevated from 60 d to 159 d, and was significantly higher at 159 d than at the other three developmental stages (P < 0.05). The expression of MMP13 mRNA increased from SW (small white follicles) to F5 (fifth largest follicles), then decreased to F1 (first largest follicles), and dramatically increased again in POF1 (newly postovulatory follicles) follicles (P < 0.05). The MMP13 protein was localized in stroma cells and primordial follicles of sexually immature chicken ovaries, in the theca cell layers of all sized follicles of sexually mature chicken ovaries. Furthermore, we identified a positive element (positions -1863 to -1036) controlling chicken MMP13 transcription, and, in this region, six single nucleotide polymorphisms were found and genotyped in chicken populations. In the White Recessive Rock population, hens with A(-1356)-C(-1079)/A(-1356)-C(-1079) genotype had earlier "age at first laying" than those with G(-1356)-T(-1079)/G(-1356)-T(-1079) genotype (P < 0.05), and exhibited significantly lower transcriptional activity (P < 0.01). Collectively, chicken MMP13 plays an important role in ovarian follicle growth and regression, and polymorphisms in its promoter region could be used as molecular markers for improving the trait "age at first laying" in chicken breeding. PMID:26966259

  1. Characterization of Chicken MMP13 Expression and Genetic Effect on Egg Production Traits of Its Promoter Polymorphisms

    PubMed Central

    Yuan, Zhenjie; Chen, Yuxia; Chen, Qiuyue; Guo, Miao; Kang, Li; Zhu, Guiyu; Jiang, Yunliang

    2016-01-01

    Extracelluar matrix undergoes constant remodeling, cell–cell, and cell–matrix interactions during chicken ovarian follicle growth, which is coordinated by matrix metalloproteinases (MMPs), and their associated endogenous inhibitors (TIMPs). Transcriptome analysis revealed upregulation of MMP13 in sexually mature chicken ovaries. In this study, we found that the expression of MMP13 in chicken ovary was stably elevated from 60 d to 159 d, and was significantly higher at 159 d than at the other three developmental stages (P < 0.05). The expression of MMP13 mRNA increased from SW (small white follicles) to F5 (fifth largest follicles), then decreased to F1 (first largest follicles), and dramatically increased again in POF1 (newly postovulatory follicles) follicles (P < 0.05). The MMP13 protein was localized in stroma cells and primordial follicles of sexually immature chicken ovaries, in the theca cell layers of all sized follicles of sexually mature chicken ovaries. Furthermore, we identified a positive element (positions –1863 to –1036) controlling chicken MMP13 transcription, and, in this region, six single nucleotide polymorphisms were found and genotyped in chicken populations. In the White Recessive Rock population, hens with A–1356-C–1079/A–1356-C–1079 genotype had earlier “age at first laying” than those with G–1356-T–1079/G–1356-T–1079 genotype (P < 0.05), and exhibited significantly lower transcriptional activity (P < 0.01). Collectively, chicken MMP13 plays an important role in ovarian follicle growth and regression, and polymorphisms in its promoter region could be used as molecular markers for improving the trait “age at first laying” in chicken breeding. PMID:26966259

  2. Association Between IL-10 Gene Promoter Polymorphisms (-592 A/C, -819 T/C, -1082 A/G) and Susceptibility to HBV Infection in an Iranian Population

    PubMed Central

    Moudi, Bita; Heidari, Zahra; Mahmoudzadeh-Sagheb, Hamidreza; Hashemi, Mohammad; Metanat, Malihe; Khosravi, Soheila; Farrokh, Parisa

    2016-01-01

    Background IL-10 can play a vital role in immune response against HBV. Three biallelic SNPs from the transcription start site control the transcription of the IL-10 gene. An association between susceptibility to HBV and IL-10 polymorphisms has been suggested in patients with HBV infection. Objectives The present study was designed to study the association between polymorphisms in interleukin-10 (-1082 A/G, -819 T/C and -592 A/C) promoter gene and chronic hepatitis B virus (HBV) infection. Patients and Methods 221 chronically infected patients and 200 healthy control subjects were enrolled in the study. Three biallelic (-1082 A/G, -819 T/C and -592 A/C) polymorphisms in the IL-10 promoter gene were determined by PCR-RFLP method. Results Persistent HBV infection was associated with IL-10-1082 AG (P = 0.001) and GG (P = 0.004) genotypes and G (P = 0.000) allele. IL-10-819 T/C and -592 A/C genotype and allele frequencies did not show any correlation with the risk of chronic hepatitis B infection. Conclusions These results suggest that polymorphisms in interleukin-10 gene promoter influence clinical outcome of HBV infection and susceptibility to HBV infection. PMID:27148384

  3. Relationships between serotonin transporter promoter polymorphism, platelet serotonin transporter binding and clinical phenotype in suicidal and non-suicidal adolescent inpatients.

    PubMed

    Zalsman, G; Anderson, G M; Peskin, M; Frisch, A; King, R A; Vekslerchik, M; Sommerfeld, E; Michaelovsky, E; Sher, L; Weizman, A; Apter, A

    2005-02-01

    Relationships between the serotonin transporter promoter polymorphism (5-HTTLPR), platelet serotonin transporter (SERT) binding and clinical phenotype were examined in 32 suicidal and 28 non-suicidal Ashkenazi Israeli adolescent psychiatric inpatients. The 5-HTTLPR polymorphism was not associated with transporter binding or with suicidality or other clinical phenotypes. However, in the suicidal group, a significant positive correlation between platelet SERT density and anger scores (n=32, r=.40; p=.027) and a negative correlation between platelet count and trait anxiety (n=32, r=-.42; p=.034) were observed. PMID:15657646

  4. Effects of Common Polymorphism rs11614913 in Hsa-miR-196a2 on Lung Cancer Risk

    PubMed Central

    Wang, Weilu; Liu, Zhihua

    2013-01-01

    Background Emerging evidence suggests that single nucleotide polymorphisms (SNPs) in microRNA-coding genes may participate in the pathogenesis of lung cancer by altering the expression of tumor-related microRNAs. Several studies were investigated in recent years to evaluate the association between hsa-miR-196a2 rs11614913 polymorphism and increased/decreased lung cancer risk. In the present study, we performed a meta-analysis to systematically summarize the possible association. Methodology/Principal Findings We performed a meta-analysis of 4 case-control studies that included 2219 lung-cancer cases and 2232 cancer-free controls. We evaluated the strength of the association using odds ratios (ORs) with 95% confidence intervals (CIs). In the overall analysis, it was found that the rs11614913 polymorphism significantly elevated the risk of lung cancer (CC versus (vs.) TT OR = 1.26, 95% CI 1.07–1.49, P = 0.007; CC/CT vs. TT: OR = 1.13, 95% CI 0.98–1.29, P = 0.007; C vs. T: OR = 1.12, 95% CI 1.03–1.22, P = 0.008). In the subgroup analysis by ethnicity, statistically significantly increased cancer risk was found among Asians (CC vs. TT: OR = 1.30, 95% CI 1.10–1.54, P = 0.003; CT vs. TT: OR = 1.16, 95% CI 1.01–1.34, P = 0.039; CC vs. CT/TT: OR = 1.21, 95% CI 1.04–1.41, P = 0.012; C vs. T: OR = 1.14, 95% CI 1.05–1.25, P = 0.002). For Europeans, a significant association with lung cancer risk was found in recessive model (CC vs. CT/TT: OR = 0.63, 95% CI 0.40–0.98, P = 0.040). No publication bias was found in this study. Conclusions/Significance Our meta-analysis suggests that the rs11614913 polymorphism is significant associated with the increased risk of lung cancer, especially in Asians. Besides, the C allele of rs11614913 polymorphism may contribute to increased lung cancer risk. PMID:23593385

  5. Association of Epstein-Barr virus antibody titers with a human IL-10 promoter polymorphism in Japanese women

    PubMed Central

    Yasui, Yutaka; Hamajima, Nobuyuki; Nakamura, Tsuneya; El-Din, Noha Sharaf; Tajima, Kazuo; Potter, John D

    2008-01-01

    Background Multiple sclerosis (MS) risk, over 10-fold higher in Western than in Asian countries, is associated with elevated IgG antibody titers against Epstein-Barr viral capcid antigen (anti-EBVCA IgG titers). Given the 84% homology of the open reading frame BCRF1 of Epstein-Barr virus (EBV) to human interleukin 10 (hIL-10) and the remarkable Caucasian-vs.-Asian population differences in hIL-10 gene promoter polymorphisms, this strong association of MS risk with anti-EB-VCA IgG titers may be explained by the genetic variations in the hIL-10 gene. Methods We evaluated anti-EB-VCA IgG titers in association with a single nucleotide polymorphism (SNP) in the promoter of hIL-10 at position -819 (hIL-10 T-819C) in a cross-sectional survey of 241 Japanese. Anti-EB-VCA IgG titer and its elevation (≥ 1:160) were evaluated, stratified by sex and hIL-10 T-819C genotype. Results The cytosine-allele frequencies at hIL-10 T-819C were 32.9% in women and 30.9% in men. These are consistent with the published reports of Japanese and Chinese, but substantially lower than those of Caucasians (> 70%). In women, the proportion with elevated anti-EB-VCA IgG titers (≥ 1:160) increased appreciably from 53.7% in the T/T genotype group to 66.7% in the T/C group and to 83.3% in the C/C group (P-trend = 0.037). The titers did not differ by the hIL-10 T-819C genotype in men. Conclusion Anti-EB-VCA IgG titers may increase with the number of cytosine alleles at hIL-10 T-819C in women. This observed gender specific association in Japanese warrants further investigation, especially in Western populations with high MS risk. PMID:18318911

  6. Polymorphisms in the promoter regions of the CXCL1 and CXCL2 genes contribute to increased risk of alopecia areata in the Korean population.

    PubMed

    Kim, S K; Chung, J-H; Park, H J; Kang, S W; Lim, D-J; Byun, S H; Baek, D G; Ko, H Y; Lew, B-L; Baik, H H; Sim, W-Y

    2015-01-01

    Alopecia areata (AA) is a common disease, which causes hair loss in humans. AA has a genetically complex inheritance. This study investigated the possible correlations between single nucleotide polymorphisms (SNPs) in the promoter regions of the chemokine (C-X-C motif) ligand 1 (melanoma growth stimulating activity, alpha) (CXCL1) and chemokine (C-X-C motif) ligand 2 (CXCL2) genes and the development of AA in the Korean population. Two hundred and thirty-five AA patients and 240 control subjects were recruited. The specific SNPs occurring in the promoter regions of the CXCL1 and CXCL2 genes (rs3117604, -429C/T and rs3806792, -264T/C, respectively) were genotyped. All data obtained was evaluated using the SNPStats, SPSS 18.0, and the Haploview v.4.2 software platforms. The Odd's ratios (OR), 95% confidence intervals (CI), and P values were calculated using multiple logistic regression models. Analyses of the genetic sequences obtained revealed a significant correlation between the two SNPs and the development of AA (rs3117604, P = 0.0009 in co-dominant model 1, P = 0.01 in co-dominant model 2, P = 0.004 in the dominant model, P = 0.005 in the log-additive model, P = 0.012 in allele distribution; rs3806792, P = 0.036 in co-dominant model 2, P = 0.0046 in the log-additive model). The TT and CC haplotypes were also observed to show a significant association with increased risk of AA (TT haplotype, P = 0.0018; CC haplotype, P = 0.0349). Our data suggests that the CXCL1 and CXCL2 genes may be associated with AA susceptibility. PMID:26345899

  7. Association between TERT promoter polymorphisms and acute myeloid leukemia risk and prognosis.

    PubMed

    Mosrati, Mohamed Ali; Willander, Kerstin; Falk, Ingrid Jakobsen; Hermanson, Monica; Höglund, Martin; Stockelberg, Dick; Wei, Yuan; Lotfi, Kourosh; Söderkvist, Peter

    2015-09-22

    Telomerase reverse transcriptase gene (TERT) promoter mutations are identified in many malignancies but not in hematological malignancies. Here we analyzed TERT and protection of telomeres 1 gene (POT1) mutations, and four different TERT SNVs in 226 acute myeloid leukemia (AML) patients and 806 healthy individuals in a case referent design, where also overall survival was assessed. A significant association for increased risk of AML was found for TERT SNVs, rs2853669 (OR = 2.45, p = 0.00015) and rs2736100 (OR = 1.5, p = 0.03). The overall survival for patients with CC genotype of rs2853669 was significantly shorter compared to those with TT or TC genotypes (p = 0.036 and 0.029 respectively). The influence of TERT rs2853669 CC on survival was confirmed in multivariable Cox regression analysis as an independent risk biomarker in addition to high risk group, higher age and treatment. No hot spot TERT promoter mutations at -228C > T or -250C > T or POT1 mutations could be identified in this AML cohort. We show that rs2853669 CC may be a risk factor for the development of AML that may also be used as a prognostic marker to identify high risk normal karyotype-AML (NK-AML) patients, for treatment guidance. PMID:26298771

  8. Association between TERT promoter polymorphisms and acute myeloid leukemia risk and prognosis

    PubMed Central

    Mosrati, Mohamed Ali; Willander, Kerstin; Falk, Ingrid Jakobsen; Hermanson, Monica; Höglund, Martin; Stockelberg, Dick; Wei, Yuan; Lotfi, Kourosh; Söderkvist, Peter

    2015-01-01

    Telomerase reverse transcriptase gene (TERT) promoter mutations are identified in many malignancies but not in hematological malignancies. Here we analyzed TERT and protection of telomeres 1 gene (POT1) mutations, and four different TERT SNVs in 226 acute myeloid leukemia (AML) patients and 806 healthy individuals in a case referent design, where also overall survival was assessed. A significant association for increased risk of AML was found for TERT SNVs, rs2853669 (OR = 2.45, p = 0.00015) and rs2736100 (OR = 1.5, p = 0.03). The overall survival for patients with CC genotype of rs2853669 was significantly shorter compared to those with TT or TC genotypes (p = 0.036 and 0.029 respectively). The influence of TERT rs2853669 CC on survival was confirmed in multivariable Cox regression analysis as an independent risk biomarker in addition to high risk group, higher age and treatment. No hot spot TERT promoter mutations at −228C > T or −250C > T or POT1 mutations could be identified in this AML cohort. We show that rs2853669 CC may be a risk factor for the development of AML that may also be used as a prognostic marker to identify high risk normal karyotype -AML (NK-AML) patients, for treatment guidance. PMID:26298771

  9. Topics in Transcriptional Control of Lipid Metabolism: from Transcription Factors to Gene-Promoter Polymorphisms

    PubMed Central

    Bergen, Werner G.; Burnett, Derris D.

    2013-01-01

    The central dogma of biology (DNA>>RNA>>Protein) has remained as an extremely useful scaffold to guide the study of molecular regulation of cellular metabolism. Molecular regulation of cellular metabolism has been pursued from an individual enzyme to a global assessment of protein function at the genomic (DNA), transcriptomic (RNA) and translation (Protein) levels. Details of a key role by inhibitory small RNAs and post-translational processing of cellular proteins on a whole cell/global basis are now just emerging. Below we emphasize the role of transcription factors (TF) in regulation of adipogenesis and lipogenesis. Additionally we have also focused on emerging additional TF that may also have hitherto unrecognized roles in adipogenesis and lipogenesis as compared to our present understanding. It is generally recognized that SNPs in structural genes can affect the final structure/function of a given protein. The implications of SNPs located in the non-transcribed promoter region on transcription have not been examined as extensively at this time. Here we have also summarized some emerging results on promoter SNPs for lipid metabolism and related cellular processes. PMID:25031651

  10. Interleukin-1β Promoter Polymorphism Enhances the Risk of Sleep Disturbance in Alzheimer’s Disease

    PubMed Central

    Chen, Rui; Li, Peng; Wu, Hui-Juan; Zhao, Zheng-Qing; Li, Yan-Peng; Huang, Liu-Qing; Zhuang, Jian-Hua; Zhao, Zhong-Xin

    2016-01-01

    Sleep alleviates Alzheimer’s disease (AD)-related neuropathological processes, whereas sleep disturbance in AD patients is associated with elevated peripheral inflammatory cytokine levels. In the present study, we assessed interleukin (IL)-1β and APOEε4 polymorphisms for association with susceptibility of sleep disturbances in AD patients. A total of 123 pretreated AD patients and 120 age-, gender- and education level-matched healthy controls were recruited for two consecutive full-night polysomnography and measurement of Epworth Sleepiness Scale (ESS) scores for sleep-wake disturbance. Their genomic DNA was analyzed for IL-1β and APOEε4 SNPs using ligase detection reaction (LDR) technology. Blood levels of IL-1β, IL-6, and tumor necrosis factor alpha (TNF-α) were measured using ELISA after lipopolysaccharide (LPS) stimulation. The odds ratio and 95% confidence interval for genotype-specific risk were calculated using an unconditional logistic regression model and adjusted by age, gender, educational levels, body mass index (BMI), and activities of daily living (ADL). Compared to the non-APOEε4/ε4 genotype, APOEε4/ε4 significantly increased the risk of AD (APOEε4/ε4 vs. non-APOEε4/ε4, adjusted OR = 4.33, 95% CI = 1.33–14.10, p = 0.015). Compared to the IL-1β CC genotype (-31), the TT genotype significantly increased the risk of AD (TT vs. CC, adjusted OR = 1.72, 95% CI = 1.13–2.61, p = 0.010). AD patients carrying the APOEε4 allele and the IL-1β TT genotype showed less time in bed, longer sleep latency and REM latency, more awakenings, and a lower SWS percentage than those carrying CC/CT combined genotypes. In addition, blood IL-1β levels were significantly greater in AD patients carrying both the APOEε4 allele and the IL-1β-31TT genotype than in those carrying the APOEε4 allele and the -31 TC or CC genotype. In conclusion, this study provides the first evidence indicating that the IL-1β-31TT genotype and homozygous APOEε4 combined are

  11. Interleukin-1β Promoter Polymorphism Enhances the Risk of Sleep Disturbance in Alzheimer's Disease.

    PubMed

    Yin, You; Liu, Yan; Pan, Xiao; Chen, Rui; Li, Peng; Wu, Hui-Juan; Zhao, Zheng-Qing; Li, Yan-Peng; Huang, Liu-Qing; Zhuang, Jian-Hua; Zhao, Zhong-Xin

    2016-01-01

    Sleep alleviates Alzheimer's disease (AD)-related neuropathological processes, whereas sleep disturbance in AD patients is associated with elevated peripheral inflammatory cytokine levels. In the present study, we assessed interleukin (IL)-1β and APOEε4 polymorphisms for association with susceptibility of sleep disturbances in AD patients. A total of 123 pretreated AD patients and 120 age-, gender- and education level-matched healthy controls were recruited for two consecutive full-night polysomnography and measurement of Epworth Sleepiness Scale (ESS) scores for sleep-wake disturbance. Their genomic DNA was analyzed for IL-1β and APOEε4 SNPs using ligase detection reaction (LDR) technology. Blood levels of IL-1β, IL-6, and tumor necrosis factor alpha (TNF-α) were measured using ELISA after lipopolysaccharide (LPS) stimulation. The odds ratio and 95% confidence interval for genotype-specific risk were calculated using an unconditional logistic regression model and adjusted by age, gender, educational levels, body mass index (BMI), and activities of daily living (ADL). Compared to the non-APOEε4/ε4 genotype, APOEε4/ε4 significantly increased the risk of AD (APOEε4/ε4 vs. non-APOEε4/ε4, adjusted OR = 4.33, 95% CI = 1.33-14.10, p = 0.015). Compared to the IL-1β CC genotype (-31), the TT genotype significantly increased the risk of AD (TT vs. CC, adjusted OR = 1.72, 95% CI = 1.13-2.61, p = 0.010). AD patients carrying the APOEε4 allele and the IL-1β TT genotype showed less time in bed, longer sleep latency and REM latency, more awakenings, and a lower SWS percentage than those carrying CC/CT combined genotypes. In addition, blood IL-1β levels were significantly greater in AD patients carrying both the APOEε4 allele and the IL-1β-31TT genotype than in those carrying the APOEε4 allele and the -31 TC or CC genotype. In conclusion, this study provides the first evidence indicating that the IL-1β-31TT genotype and homozygous APOEε4 combined are

  12. Effect of oral N-acetylcysteine on COPD patients with microsatellite polymorphism in the heme oxygenase-1 gene promoter

    PubMed Central

    Zhang, Jia-Qiang; Zhang, Jian-Qing; Fang, Li-Zhou; Liu, Ling; Fu, Wei-Ping; Dai, Lu-Ming

    2015-01-01

    Background Heme oxygenase-1 (HO-1) plays a protective role as an antioxidant in the lung, and HO-1 gene promoter polymorphism has been shown to be associated with the severity and prognosis of COPD patients. N-acetylcysteine (NAC), an antioxidant/mucous modifier, has shown an uncertain benefit in COPD patients. We hypothesized that this polymorphism could be associated with the effectiveness of oral NAC. Methods A total of 368 patients with COPD were recruited and the polymorphisms of their HO-1 gene promoter were classified into three subclasses according to the number of (GT)n repeats, as previously reported: class S (<27 (GT)n repeats), class M (27–32 (GT)n repeats), and class L (>32 (GT)n repeats). These subjects were then classified as L+ group (with the L allele: L/L, L/M, L/S) and L− group (without the L allele: M/M, M/S, S/S). All the patients were allocated to standard therapy plus NAC 600 mg bid over a 1-year period and were observed over that year. Results The L− group saw improvements in forced expiratory volume in 1 second (FEV1) (from 1.44±0.37 to 1.58±0.38, P=0.04) and FEV1% predicted (from 56.6±19.2 to 59.7±17.2, P=0.03). No improvement was found in forced vital capacity of each group and the decline of forced vital capacity in both of the groups was not statistical significant. The number of yearly COPD exacerbations of the L− group was 1.5±0.66 which was lower than the 2.1±0.53 of the L+ group (P<0.01). For the changes of St George’s Respiratory Questionnaire (SGRQ) score, only the activity score of the L− group was more significant than that of the L+ group (P=0.02). The improvement of the outcome of 6-minute walking distance test in L− group (from 290.1±44.9 meters to 309.7±46.9 m) was higher than that in the L+ group (from 289.7±46.2 m to 300.3±44.2 m) (P=0.03). Conclusion A 600 mg bid oral NAC treatment for 1-year on COPD patients without the L allele can improve the FEV1, FEV1% predicted, the SGRQ activity score, and

  13. Effect of heme oxygenase-1 gene promoter polymorphism on cancer risk by histological subtype: A prospective study in arseniasis-endemic areas in Taiwan.

    PubMed

    Wu, Meei-Maan; Lee, Chih-Hung; Hsu, Ling-I; Cheng, Wen-Fang; Lee, Te-Chang; Wang, Yuang-Hung; Chiou, Hung-Yi; Chen, Chien-Jen

    2016-04-15

    Heme oxygenase (HO)-1 is upregulated by many stressful stimuli, including arsenic. A GT-repeat ((GT)n) polymorphism in the HO-1 gene promoter inversely modulates the levels of HO-1 induction. Previous HO-1 (GT)n polymorphism studies in relation to cancer risk have shown disparate results. We prospectively investigated the associations between HO-1 (GT)n polymorphism and cancer risk related to arsenic from drinking water. Totally, 1,013 participants from community-based cohorts of arseniasis-endemic areas in Taiwan were followed for 13 years. Allelic polymorphisms were classified into long (L, ≥ 27 (GT)n) and short (S, <27 (GT)n). Newly developed cases were identified through linkage with National Cancer Registry of Taiwan. Multivariate Cox proportional hazard methods were used to evaluate effects of the HO-1 polymorphism alone or combined with arsenic exposure. Results showed that participants with the S/S genotype had an increased risk of Bowen's disease (HR = 10.49; 95% CI: 2.77-39.7), invasive skin cancer (HR = 2.99; 95% CI: 1.13-7.87), and lung squamous cell carcinoma (HR = 3.39; 95% CI: 1.15-9.95) versus those with L/S or L/L genotype. The S/S genotype combined with high arsenic exposure (>300 μg/L) had a greater risk of skin cancer compared to the genotype alone. Consistent with previous findings, participants with the S-allele had a reduced risk of lung adenocarcinoma (HR = 0.21; 95% CI: 0.03-0.68) versus those with L/L genotype. There were no significant differences in risk of urothelial carcinoma among the three genotypes. Associations of HO-1 (GT)n polymorphism with cancer risk differs by histological subtype and the polymorphism should be considered a modifier in the risk assessment of arsenic exposure. PMID:26566708

  14. Prognostic significance of interleukin-6 single nucleotide polymorphism genotypes in neuroblastoma: rs1800795 (promoter) and rs8192284 (receptor)

    PubMed Central

    Lagmay, Joanne P.; London, Wendy B.; Gross, Thomas G.; Termuhlen, Amanda; Sullivan, Nicholas; Axel, Amy; Mundy, Bethany; Ranalli, Mark; Canner, Jason; McGrady, Patrick; Hall, Brett

    2009-01-01

    Purpose Neuroblastoma is a childhood cancer of the sympathetic nervous system and many patients present with high risk disease. Risk stratification, based on pathology and tumor-derived biomarkers, has improved prediction of clinical outcomes, but overall survival rates remain unfavorable and new therapeutic targets are needed. Some studies suggest a link between interleukin-6 and more aggressive behavior in neuroblastoma tumor cells. Therefore, we examined the impact of two IL-6 single nucleotide polymorphisms (SNP) on neuroblastoma disease progression. Experimental design DNA samples from 96 high risk neuroblastoma patients were screened for two SNP that are known to regulate the serum levels of IL-6 and the soluble IL-6 receptor (IL-6R), rs1800795 and rs8192284 respectively. The genotype for each SNP was determined in a blinded fashion and independent statistical analysis was performed to determine SNP-related event free survival (EFS) and overall survival (OS) rates. Results The rs1800795 IL-6 promoter SNP is an independent prognostic factor for EFS and OS in -high risk neuroblastoma patients. In contrast, the rs8192284 IL-6 receptor SNP revealed no prognostic value. Conclusions The rs1800795 SNP (-174 IL-6 (G>C) represents a novel and independent prognostic marker for both EFS and OS in high risk neuroblastoma. Since the rs1800795 SNP (-174 IL-6 (G>C) has been shown to correlate with production of IL-6, this cytokine may represent a target for development of new therapies in neuroblastoma. PMID:19671870

  15. Association of neuropeptide Y promoter polymorphism (rs16147) with perceived stress and cardiac vagal outflow in humans.

    PubMed

    Chang, Hsin-An; Fang, Wen-Hui; Chang, Tieh-Ching; Huang, San-Yuan; Chang, Chuan-Chia

    2016-01-01

    Neuropeptide Y (NPY) is involved in resilience to stress, and higher vagal (parasympathetic) activity has been associated with greater stress resilience. Thus, we examined whether rs16147, a functional promoter polymorphism (C>T) of the NPY gene, could influence vagal tone during chronic high stress levels. NPY genotyping, chronic psychological stress level measurement (using the Perceived Stress Scale [PSS]), cardiac autonomic function assessment (using short-term heart rate variability [HRV]) were performed in 1123 healthy, drug-free Han Chinese participants who were divided into low- and high-PSS groups. In the high-PSS group (n = 522), the root mean square of successive heartbeat interval differences and high frequency power (both HRV indices of parasympathetic activity) were significantly increased in T/T homozygotes compared to C/C homozygotes. However, no significant between-genotype difference was found in any HRV variable in the low-PSS group (n = 601). Our results are the first to demonstrate that functional NPY variation alters chronic stress-related vagal control, suggesting a potential parasympathetic role for NPY gene in stress regulation. PMID:27527739

  16. Association of neuropeptide Y promoter polymorphism (rs16147) with perceived stress and cardiac vagal outflow in humans

    PubMed Central

    Chang, Hsin-An; Fang, Wen-Hui; Chang, Tieh-Ching; Huang, San-Yuan; Chang, Chuan-Chia

    2016-01-01

    Neuropeptide Y (NPY) is involved in resilience to stress, and higher vagal (parasympathetic) activity has been associated with greater stress resilience. Thus, we examined whether rs16147, a functional promoter polymorphism (C>T) of the NPY gene, could influence vagal tone during chronic high stress levels. NPY genotyping, chronic psychological stress level measurement (using the Perceived Stress Scale [PSS]), cardiac autonomic function assessment (using short-term heart rate variability [HRV]) were performed in 1123 healthy, drug-free Han Chinese participants who were divided into low- and high-PSS groups. In the high-PSS group (n = 522), the root mean square of successive heartbeat interval differences and high frequency power (both HRV indices of parasympathetic activity) were significantly increased in T/T homozygotes compared to C/C homozygotes. However, no significant between-genotype difference was found in any HRV variable in the low-PSS group (n = 601). Our results are the first to demonstrate that functional NPY variation alters chronic stress-related vagal control, suggesting a potential parasympathetic role for NPY gene in stress regulation. PMID:27527739

  17. Osteopontin Promoter Polymorphism is Associated with Increased Carotid Intima-Media Thickness

    PubMed Central

    de las Fuentes, Lisa; Gu, C. Charles; Mathews, Santhosh J.; Reagan, Joann L.; Ruthmann, Nicholas P.; Waggoner, Alan D.; Lai, Chung-Fang; Towler, Dwight A.; Dávila-Román, Víctor G.

    2008-01-01

    Background Osteopontin (OPN)-transgenic mice exhibit increased carotid artery intima-media thickness (CIMT), smooth muscle cell proliferation, and atheroma formation. Methods An association of the human T-66G promoter variant with CIMT was examined in Caucasian adults grouped according to metabolic syndrome (MetS) criteria: Present (+MetS, n=70) and Absent (−MetS, n=70). Results The G allele frequency was 22%. For the entire cohort, the G group (TG and GG) was associated with significantly lower age/gender-adjusted CIMT compared to the TT group (p=0.008); similar analysis by MetS group found a significant difference only in the −MetS group (p=0.018). Stepwise multivariable regression showed that after age and waist circumference, the T-66G variant was predictive of CIMT (p=0.007). These data suggest that in a normoglycemic environment, human vascular OPN gene expression contributes to arterial structure, an effect diminished in dysmetabolic states. Conclusions Humans with the OPN −66 TT genotype, particularly those without MetS, exhibit thicker CIMT. PMID:18406574

  18. Common Polymorphisms in GSTA1, GSTM1 and GSTT1 Are Associated with Susceptibility to Urinary Bladder Cancer in Individuals from Balkan Endemic Nephropathy Areas of Serbia.

    PubMed

    Matic, Marija; Dragicevic, Biljana; Pekmezovic, Tatjana; Suvakov, Sonja; Savic-Radojevic, Ana; Pljesa-Ercegovac, Marija; Dragicevic, Dejan; Smiljic, Jelena; Simic, Tatjana

    2016-01-01

    Balkan endemic nephropathy (BEN) is a chronic familial form of interstitial nephritis that might eventually lead to end stage renal disease. This nephropathy affects individuals living along of the Danube River and its tributaries in Serbia, Bosnia, Croatia, Bulgaria and Romania. The increased incidence of urinary tract tumors in the BEN areas is well described, but its specific genetic predisposition is still unclear. Certain nephrocarcinogenic compounds, including those associated with BEN, are metabolized by glutathione S-transferase (GST) superfamily of phase II detoxication enzymes. Importantly, the GST-mediated detoxification may result in formation of more toxic compounds. We examined the association of common GST polymorphisms and bladder cancer (BC) risk in individuals from BEN areas in Serbia. A hospital-based case-control study included 201 BC cases (67 from BEN region) and 122 controls. Each polymorphism was identified by a PCR-based method. Individuals from BEN region with low-expression GSTA1 genotype (AB+BB) exhibited a 2.6-fold higher BC risk compared to those with GSTA1 (AA) genotype who were from non-BEN region (OR = 2.60, p = 0.015). In contrast, carriers of GSTM1-active genotype from BEN region had a 2.9-fold increased BC risk compared to those with GSTM1-active genotype from non-BEN region (OR = 2.90, p = 0.010). Likewise, carriers with GSTT1-active genotype from BEN region exhibited 2.1-fold higher BC risk compared to those from non-BEN region with GSTT1-active genotype (OR = 2.10, p = 0.027). Thus, common polymorphisms in GSTA1, GSTM1 and GSTT1 are associated with susceptibility to BC in individuals from BEN areas of Serbia. PMID:27568660

  19. Association of Common Genetic Polymorphisms with Melanoma Patient IL-12p40 Blood Levels, Risk, and Outcomes

    PubMed Central

    Fang, Shenying; Wang, Yuling; Chun, Yun S; Liu, Huey; Ross, Merrick I; Gershenwald, Jeffrey E; Cormier, Janice N; Royal, Richard E; Lucci, Anthony; Schacherer, Christopher W; Reveille, John D; Chen, Wei; Sui, Dawen; Bassett, Roland L; Wang, Li-E; Wei, Qingyi; Amos, Christopher I; Lee, Jeffrey E

    2015-01-01

    Recent investigation has identified association of IL-12p40 blood levels with melanoma recurrence and patient survival. No studies have investigated associations of single-nucleotide polymorphisms (SNPs) with melanoma patient IL-12p40 blood levels or their potential contributions to melanoma susceptibility or patient outcome. In the current study, 818,237 SNPs were available for 1,804 melanoma cases and 1,026 controls. IL-12p40 blood levels were assessed among 573 cases (discovery), 249 cases (case validation), and 299 controls (control validation). SNPs were evaluated for association with log[IL-12p40] levels in the discovery data set and replicated in two validation data sets, and significant SNPs were assessed for association with melanoma susceptibility and patient outcomes. The most significant SNP associated with log[IL-12p40] was in the IL-12B gene region (rs6897260, combined P=9.26 × 10−38); this single variant explained 13.1% of variability in log[IL-12p40]. The most significant SNP in EBF1 was rs6895454 (combined P=2.24 × 10−9). A marker in IL12B was associated with melanoma susceptibility (rs3213119, multivariate P=0.0499; OR=1.50, 95% CI 1.00–2.24), whereas a marker in EBF1 was associated with melanoma-specific survival in advanced-stage patients (rs10515789, multivariate P=0.02; HR=1.93, 95% CI 1.11–3.35). Both EBF1 and IL12B strongly regulate IL-12p40 blood levels, and IL-12p40 polymorphisms may contribute to melanoma susceptibility and influence patient outcome. PMID:25848976

  20. Simultaneous Analysis of SEPT9 Promoter Methylation Status, Micronuclei Frequency, and Folate-Related Gene Polymorphisms: The Potential for a Novel Blood-Based Colorectal Cancer Biomarker

    PubMed Central

    Ravegnini, Gloria; Zolezzi Moraga, Juan Manuel; Maffei, Francesca; Musti, Muriel; Zenesini, Corrado; Simeon, Vittorio; Sammarini, Giulia; Festi, Davide; Hrelia, Patrizia; Angelini, Sabrina

    2015-01-01

    One challenge in colorectal cancer (CRC) is identifying novel biomarkers to be introduced in screening programs. The present study investigated the promoter methylation status of the SEPT9 gene in peripheral blood samples of subjects’ positive fecal occult blood test (FOBT). In order to add new insights, we investigated the association between SEPT9 promoter methylation and micronuclei frequency, and polymorphisms in the folate-related pathway genes. SEPT9 promoter methylation, micronuclei frequency, and genotypes were evaluated on 74 individuals’ FOBT positive. Individuals were subjected to a colonoscopy that provided written informed consent for study participation. SEPT9 promoter methylation status was significantly lower in the CRC group than controls (p = 0.0006). In contrast, the CaCo2 cell-line, analyzed as a tissue specific model of colon adenocarcinoma, showed a significantly higher percentage of SEPT9 promoter methylation compared to the CRC group (p < 0.0001). Linear regression analysis showed an inverse correlation between micronuclei frequency and the decrease in the methylation levels of SEPT9 promoter region among CRC patients (β = −0.926, p = 0.0001). With regard to genotype analysis, we showed the involvement of the DHFR polymorphism (rs70991108) in SEPT9 promoter methylation level in CRC patients only. In particular, the presence of at least one 19 bp del allele significantly correlates with decreased SEPT9 promoter methylation, compared to the 19 bp ins/ins genotype (p = 0.007). While remaining aware of the strengths and limitations of the study, this represents the first evidence of a novel approach for the early detection of CRC, using SEPT9 promoter methylation, micronuclei frequency and genotypes, with the potential to improve CRC risk assessment. PMID:26633373

  1. Simultaneous Analysis of SEPT9 Promoter Methylation Status, Micronuclei Frequency, and Folate-Related Gene Polymorphisms: The Potential for a Novel Blood-Based Colorectal Cancer Biomarker.

    PubMed

    Ravegnini, Gloria; Zolezzi Moraga, Juan Manuel; Maffei, Francesca; Musti, Muriel; Zenesini, Corrado; Simeon, Vittorio; Sammarini, Giulia; Festi, Davide; Hrelia, Patrizia; Angelini, Sabrina

    2015-01-01

    One challenge in colorectal cancer (CRC) is identifying novel biomarkers to be introduced in screening programs. The present study investigated the promoter methylation status of the SEPT9 gene in peripheral blood samples of subjects' positive fecal occult blood test (FOBT). In order to add new insights, we investigated the association between SEPT9 promoter methylation and micronuclei frequency, and polymorphisms in the folate-related pathway genes. SEPT9 promoter methylation, micronuclei frequency, and genotypes were evaluated on 74 individuals' FOBT positive. Individuals were subjected to a colonoscopy that provided written informed consent for study participation. SEPT9 promoter methylation status was significantly lower in the CRC group than controls (p = 0.0006). In contrast, the CaCo2 cell-line, analyzed as a tissue specific model of colon adenocarcinoma, showed a significantly higher percentage of SEPT9 promoter methylation compared to the CRC group (p < 0.0001). Linear regression analysis showed an inverse correlation between micronuclei frequency and the decrease in the methylation levels of SEPT9 promoter region among CRC patients (β = -0.926, p = 0.0001). With regard to genotype analysis, we showed the involvement of the DHFR polymorphism (rs70991108) in SEPT9 promoter methylation level in CRC patients only. In particular, the presence of at least one 19 bp del allele significantly correlates with decreased SEPT9 promoter methylation, compared to the 19 bp ins/ins genotype (p = 0.007). While remaining aware of the strengths and limitations of the study, this represents the first evidence of a novel approach for the early detection of CRC, using SEPT9 promoter methylation, micronuclei frequency and genotypes, with the potential to improve CRC risk assessment. PMID:26633373

  2. Promoters responsive to DNA bending: a common theme in prokaryotic gene expression.

    PubMed Central

    Pérez-Martín, J; Rojo, F; de Lorenzo, V

    1994-01-01

    The early notion of DNA as a passive target for regulatory proteins has given way to the realization that higher-order DNA structures and DNA-protein complexes are at the basis of many molecular processes, including control of promoter activity. Protein binding may direct the bending of an otherwise linear DNA, exacerbate the angle of an intrinsic bend, or assist the directional flexibility of certain sequences within prokaryotic promoters. The important, sometimes essential role of intrinsic or protein-induced DNA bending in transcriptional regulation has become evident in virtually every system examined. As discussed throughout this article, not every function of DNA bends is understood, but their presence has been detected in a wide variety of bacterial promoters subjected to positive or negative control. Nonlinear DNA structures facilitate and even determine proximal and distal DNA-protein and protein-protein contacts involved in the various steps leading to transcription initiation. PMID:8078436

  3. The association of three promoter polymorphisms in interleukin-10 gene with the risk for colorectal cancer and hepatocellular carcinoma: A meta-analysis

    PubMed Central

    Shi, Yan-Hui; Zhao, Dong-Mei; Wang, Yue-Fei; Li, Xue; Ji, Man-Ru; Jiang, Dan-Na; Xu, Bai-Ping; Zhou, Li; Lu, Chang-Zhu; Wang, Bin

    2016-01-01

    Mounting evidence supports a potent inhibitory role of interleukin-10 (IL-10) in tumor carcinogenesis, angiogenesis and metastasis. This meta-analysis was designed to examine the association of three promoter polymorphisms (−592C > A, −819C > T and −1082G > A) in IL-10 gene with the risk for colorectal cancer and hepatocellular carcinoma. Qualification assessment and data collection were completed by two authors independently. The random-effects model using the DerSimonian and Laird method was fitted by the STATA software. Twenty-five articles involving 5933 cases and 9724 controls were meta-analyzed. Overall comparisons of the mutant alleles (−592A, −819T and −1082A) of three promoter polymorphisms with alternative wild alleles failed to reveal any statistical significance for both colorectal cancer and hepatocellular carcinoma (P > 0.05), and the likelihood of heterogeneity was low (I2 < 50%). For −592C > A polymorphism, a significant risk for colorectal cancer was identified when analysis was restricted to East Asians (odds ratio or OR = 1.41, 95% confidence interval or CI: 1.18–1.68, P < 0.001) and retrospective studies (OR = 1.23, 95% CI: 1.09–1.39, P = 0.001). As weighed by the Egger’s test and the fill-and-trim method, there was a low probability of publication bias for all studied polymorphisms. Our findings collectively suggest that the −592C > A polymorphism in IL-10 gene might be a susceptibility locus for colorectal cancer in East Asians. PMID:27489033

  4. The -137G/C Polymorphism in Interleukin-18 Gene Promoter Contributes to Chronic Lymphocytic and Chronic Myelogenous Leukemia Risk in Turkish Patients

    PubMed Central

    Yalçın, Serap; Mutlu, Pelin; Çetin, Türker; Sarper, Meral; Özgür, Gökhan; Avcu, Ferit

    2015-01-01

    Objective: Interleukin-18 (IL-18) is a cytokine that belongs to the IL-1 superfamily and is secreted by various immune and nonimmune cells. Evidence has shown that IL-18 has both anticancer and procancer effects. The aim of this study was to evaluate the relationship between IL-18 gene polymorphisms and susceptibility to chronic lymphocytic leukemias (CLL) and chronic myelogenous leukemias (CML) in Turkish patients. Materials and Methods: The frequencies of polymorphisms (rs61667799(G/T), rs5744227(C/G), rs5744228(A/G), and rs187238(G/C)) were studied in 20 CLL patients, 30 CML patients, and 30 healthy individuals. The genotyping was performed by polymerase chain reaction and DNA sequencing analysis. Results: Significant associations were detected between the IL-18 rs187238(G/C) polymorphism and chronic leukemia. A higher prevalence of the C allele was found in CML cases with respect to controls. The GC heterozygous and CC homozygous genotypes were associated with risk of CML when compared with controls. However, prevalence of the C allele was not significantly high in CLL cases with respect to controls. There was only a significant difference between the homozygous CC genotype of CLL patients and the control group; thus, it can be concluded that the CC genotype may be associated with the risk of CLL. Based on our data, there were no significant associations between the IL-18 rs61667799(G/T), rs5744227(C/G), or rs5744228(A/G) polymorphisms and CLL or CML. Conclusions: IL-18 gene promoter rs187238(G/C) polymorphism is associated with chronic leukemia in the Turkish population. However, due to the limited number of studied patients, these are preliminary results that show the association between -137G/C polymorphism and patients (CLL and CML). Further large-scale studies combined with haplotype and expression analysis are required to validate the current findings. PMID:26376814

  5. Characterization of FeDREB1 promoter involved in cold- and drought-inducible expression from common buckwheat (Fagopyrum esculentum).

    PubMed

    Fang, Z W; Xu, X Y; Gao, J F; Wang, P K; Liu, Z X; Feng, B L

    2015-01-01

    C-repeat-binding factor (CBF)/dehydration-responsive element (DREB) transcription factors play key roles in plant stress responses. However, little information is available on the regulation of CBF/DREB expression. In this study, we isolated and characterized the FeDREB1 promoter sequence from the common buckwheat accession Xinong 9976. To identify the upstream region of the FeDREB1 gene required for promoter activity, we constructed a series of FeDREB1 promoter deletion derivatives. Each deletion construct was analyzed through Agrobacterium-mediated transient transformation in tobacco leaves treated with 4°C cold or drought stress. Promoter-beta-glucuronidase fusion assays revealed that the pCD1 (-270 bp) deletion in the upstream region of FeDREB1 could activate expression of the GUS gene at 4°C. The pCD1 (-270 bp), pCD2 (-530 bp), and pCD3 (-904 bp) deletion induced low-level GUS expression under drought stress. However, the pCD4 (-1278 bp) deletion clearly activated GUS gene expression. Our results suggest that sections pCD1 (-270 bp) and pCD4 (-1278 bp) in the FeDREB1 gene promoter are new sources of induced promoters for adversity-resistance breeding in plant genetic engineering. PMID:26214481

  6. Less Frequent and Less Severe Flu-Like Syndrome in Interferon Beta-1a Treated Multiple Sclerosis Patients with at Least One Allele Bearing the G>C Polymorphism at Position -174 of the IL-6 Promoter Gene

    PubMed Central

    Bertoli, Diego; Serana, Federico; Sottini, Alessandra; Cordioli, Cinzia; Maimone, Davide; Amato, Maria Pia; Centonze, Diego; Florio, Ciro; Puma, Elisa; Capra, Ruggero; Imberti, Luisa

    2015-01-01

    One of the most common adverse event of interferon beta (IFNβ) therapy for multiple sclerosis is flu-like syndrome (FLS), which has been reportedly related to increased levels of cytokines such as interleukin 6 (IL-6) and tumor necrosis factor-alpha (TNF-α). Average cytokine levels can be affected by single nucleotide polymorphism in the gene promoter regions. To investigate whether IL-6 -174 G>C and TNF-α -376 G>A polymorphisms could be correlated to the incidence of FLS, and whether an anti-inflammatory/antipyretic therapy may influence FLS development, a prospective observational study was performed in 190 treatment naïve, multiple sclerosis patients who started IM IFNβ-1a 30mcg once weekly. The identification of IL-6 -174 G>C and TNF-α -376 G>A polymorphisms was achieved by performing an amplification-refractory mutation system. Serum IL-6 levels were measured using enzyme-linked immunosorbent assay in blood samples taken before therapy and then after the first and last IFNβ-1a injection of the follow-up. FLS-related symptoms were recorded by patients once per week during the first 12 weeks of therapy into a self-reported diary. We found that patients carrying at least one copy of the C allele at position -174 in the promoter of IL-6 gene produced lower levels of IL-6 and were less prone to develop FLS, which was also less severe. On the contrary, the polymorphism of TNF-α had no effect on FLS. Patients taking the first dose of anti-inflammatory/antipyretic therapy in the peri-injection period (within 1 hour) experienced a reduced FLS severity. In conclusion, the study of IL-6 -174 G>C polymorphism would allow the identification of patients lacking the C nucleotide on both alleles who are at risk of a more severe FLS, and may be addressed to a timely and stronger anti-inflammatory/antipyretic therapy for a more effective FLS prevention. PMID:26285213

  7. Questions about Common Ailments. Nutrition in Health Promotion Series, Number 26.

    ERIC Educational Resources Information Center

    Crosser, Gail Hoddlebrink; Molleson, Ann L.

    Nutrition is well-recognized as a necessary component of educational programs for physicians. This is to be valued in that of all factors affecting health in the United States, none is more important than nutrition. This can be argued from various perspectives, including health promotion, disease prevention, and therapeutic management. In all…

  8. Common Ground: Practical Ideas To Promote Interdisciplinary Cooperation between Social Studies and Second Language Instructors.

    ERIC Educational Resources Information Center

    McKinnon, Mike

    This document promotes teaching about foreign cultures through the combined efforts of school social studies and foreign language departments. Using the example of Germany and the German language, the document shows how instructors can take an interdisciplinary approach that broadens student exposure to, and thereby learning of, second cultures.…

  9. Impact of interleukin-13 and -18 promoter polymorphisms in health care workers with natural rubber latex allergy.

    PubMed

    Rihs, Hans-Peter; Lotz, Anne; Ruëff, Franziska; Landt, Olfert; Brüning, Thomas; Raulf-Heimsoth, Monika

    2012-01-01

    It is a matter of debate whether single nucleotide polymorphisms (SNP) in the promoter region of interleukin (IL)-13, an IgE regulator, and IL-18, an inducer of immune responses, modulating the respective protein expression, are accompanied by an increased risk of atopy, allergic asthma, and total IgE levels. The suspected associations were noted in health care workers (HCW) with and without latex allergy. IL-13 (-1055C>T) and three IL-18 (-656T>G, -607C>A, -137G>C) SNP were studied in 523 HCW with natural rubber latex (NRL) exposure and diagnosis in the late 1990s. Three hundred and thirty-four HCW displayed NRL sensitization and allergic symptoms, 93 with latex-allergic asthma, and 189 HCW with neither symptoms nor NRL sensitization. SNP analyses were performed by real-time polymerase chain reaction (PCR) using newly developed LightCycler assays. Analysis of IL-13 -1055C>T by analysis of variance (ANOVA) revealed significantly elevated total IgE levels in HCW carrying the CT or TT variant compared with the CC variant. None of the studied SNP showed an association with NRL-specific IgE. The IL-18 variants -656GG and -607CC displayed 99.5% linkage disequilibrium. Frequencies of alleles -656GG and -607CC were elevated in HCW with NRL asthma (48.4%) compared with HCW without symptoms (37.6%). In contrast, IL-18 -137G>C variants displayed an overall homogenous distribution. The association between the IL-13 -1055T allele and elevated total IgE levels confirms the role of a genetic background for total IgE regulation. The studied IL-18 SNP demonstrated no significant association with the clinical outcome, total IgE, or specific IgE in HCW with natural rubber latex allergy. PMID:22686311

  10. Common polymorphisms of cyclooxygenase-2 and prostaglandin E2 receptor and increased risk for acute coronary syndrome in coronary artery disease.

    PubMed

    Szczeklik, Wojciech; Sanak, Marek; Rostoff, Pawel; Piwowarska, Wieslawa; Jakiela, Bogdan; Szczeklik, Andrew

    2008-11-01

    The arachidonic acid metabolites participate in development of coronary artery disease (CAD) and the plaque's instability. We assessed two common genetic polymorphisms: of cyclooxygenase-2 (COX-2) (COX2.8473, rs5275) and prostaglandin EP2 receptor gene (uS5, rs708494) in patients with CAD. Out of 1,368 patients screened by coronary arteriography, two groups fulfilled the entry criteria and were studied: stable coronary disease (sCAD, n = 125) and acute coronary syndromes (ACS, n = 63). They did not differ in the main characteristics. All patients were on aspirin at least seven days prior to the study. In 70 control subjects, the same genotypes were ascertained, expression of cyclooxygenases in peripheral blood monocytes was assessed by flow cytometry, and in-vitro biosynthesis of PGE(2) was measured by mass spectrometry. COX-2 CC homozygotes (variant allele), were more common, while EP2 GG homozygotes (wild-type) were less common in ACS (p = 0.03 and p = 0.017) than in the sCAD group. A combined genotype characterized by the presence of the wild-type COX2.8743T allele and the wild type homozygous EP2uS5 genotype (TT or CT | GG) decreased risk ratio of ACS in CAD patients (relative risk 0.41; 95% confidence interval 0.21-0.81). COX-2 polymorphism in control subjects did not affect the enzyme expression or PGE(2) production by peripheral blood monocytes, but production of PGE(2) increased by 40.1% in the subjects homozygous for EP2 receptor allele uS5A following lipopolysaccharide stimulation. In conclusion, the combined COX-2 (COX2.8473) and the EP2 receptor (uS5) genotypes seem to influence CAD stability, but in peripheral blood monocytes only EP2 receptor modulates PGE(2) production. PMID:18989535

  11. The BCL2 -938C>A Promoter Polymorphism Is Associated with Risk for and Time to Aseptic Loosening of Total Hip Arthroplasty

    PubMed Central

    Fuest, Lena; Kurscheid, Gina; Gehrke, Thorsten; Klenke, Stefanie; Jäger, Marcus; Kauther, Max D.; Bachmann, Hagen S.

    2016-01-01

    Aseptic loosening is a major cause of revision surgery of total hip arthroplasty (THA). Only few host factors affecting aseptic loosening have been identified until now, although they are urgently needed to identify and possibly treat those patients at higher risk for aseptic loosening. To determine whether the functional single nucleotide polymorphism (SNP) c.-938C>A (rs2279115), located in the promoter region of the BCL2 gene has an impact on aseptic loosening of THA we genotyped and analyzed 234 patients suffering from aseptic loosening and 231 patients after primary THA. The polymorphism is associated with risk for aseptic loosening with the CC genotype at highest risk for aseptic loosening, Odds Ratio CC vs. AA 1.93, 95%CI 1.15–3.25, p = 0.013. In contrast, low risk AA genotype carriers that still developed aseptic loosening showed a significantly shorter time to aseptic loosening than patients carrying the C allele (p = 0.004). These results indicate that the BCL2 -938C>A polymorphism influences the occurrence and course of aseptic loosening and suggests this polymorphism as an interesting candidate for prospective studies and analyses in THA registers. PMID:26881923

  12. Association of Myxovirus Resistance Gene Promoter Polymorphism with Response to Combined Interferon Treatment and Progression of Liver Disease in Chronic HCV Egyptian Patients.

    PubMed

    Bader El Din, Noha Gamal; Salum, Ghada M; Anany, Mohamed A; Ibrahim, Marwa Khalil; Dawood, Reham Mohamed; Zayed, Naglaa; El Abd, Yasmine S; El-Shenawy, Reem; El Awady, Mostafa K

    2015-08-01

    To evaluate the frequency of single-nucleotide polymorphism at the -88 myxovirus resistance (MxA) gene promoter region in relation to the status of hepatitis C virus (HCV) progression and response to combined interferon (IFN) in chronic HCV Egyptian patients. One hundred ten subjects were enrolled in the study; 60 HCV genotype 4-infected patients who underwent combined IFN therapy and 50 healthy individuals. All subjects were genotyped for -88 MxA polymorphism by the restriction fragment length polymorphism technique. There was an increasing trend of response to combined IFN treatment as 34.9% of GG, 64.3% of GT, and 66.7% of TT genotypes were sustained responders (P=0.05). The T allele was significantly affecting the response rate more than G allele (P=0.032). Moreover, the hepatic fibrosis score and hepatitis activity were higher in GG genotypes compared with the GT and TT genotypes. The multivariate analysis showed that the MxA GG genotype was an independent factor increasing the no response to IFN therapy (P=0.04, odds ratio [OR] 3.822, 95% confidence interval [CI] 1.056-11.092), also MxA G allele (P=0.0372, OR 2.905, 95% CI 1.066-7.919). MxA -88 polymorphism might be a potential biomarker to predict response to IFN and disease progression in chronic HCV-infected patients. PMID:25868067

  13. Limits of a rapid identification of common Mediterranean sandflies using polymerase chain reaction-restriction fragment length polymorphism

    PubMed Central

    Bounamous, Azzedine; Lehrter, Véronique; Hadj-Henni, Leila; Delecolle, Jean-Claude; Depaquit, Jérôme

    2014-01-01

    A total of 131 phlebotomine Algerian sandflies have been processed in the present study. They belong to the species Phlebotomus bergeroti, Phlebotomus alexandri, Phlebotomus sergenti, Phlebotomus chabaudi, Phlebotomus riouxi, Phlebotomus perniciosus, Phlebotomus longicuspis, Phlebotomus perfiliewi, Phlebotomus ariasi, Phlebotomus chadlii, Sergentomyia fallax, Sergentomyia minuta, Sergentomyia antennata, Sergentomyia schwetzi, Sergentomyia clydei, Sergentomyia christophersi and Grassomyia dreyfussi. They have been characterised by sequencing of a part of the cytochrome b (cyt b), t RNA serine and NADH1 on the one hand and of the cytochrome C oxidase I of the mitochondrial DNA (mtDNA) on the other hand. Our study highlights two sympatric populations within P. sergenti in the area of its type-locality and new haplotypes of P. perniciosus and P. longicuspis without recording the specimens called lcx previously found in North Africa. We tried to use a polymerase chain reaction-restriction fragment length polymorphism method based on a combined double digestion of each marker. These method is not interesting to identify sandflies all over the Mediterranean Basin. PMID:24936911

  14. Limits of a rapid identification of common Mediterranean sandflies using polymerase chain reaction-restriction fragment length polymorphism.

    PubMed

    Bounamous, Azzedine; Lehrter, Véronique; Hadj-Henni, Leila; Delecolle, Jean-Claude; Depaquit, Jérôme

    2014-07-01

    A total of 131 phlebotomine Algerian sandflies have been processed in the present study. They belong to the species Phlebotomus bergeroti, Phlebotomus alexandri, Phlebotomus sergenti, Phlebotomus chabaudi, Phlebotomus riouxi, Phlebotomus perniciosus, Phlebotomus longicuspis, Phlebotomus perfiliewi, Phlebotomus ariasi, Phlebotomus chadlii, Sergentomyia fallax, Sergentomyia minuta, Sergentomyia antennata, Sergentomyia schwetzi, Sergentomyia clydei, Sergentomyia christophersi and Grassomyia dreyfussi. They have been characterised by sequencing of a part of the cytochrome b (cyt b), t RNA serine and NADH1 on the one hand and of the cytochrome C oxidase I of the mitochondrial DNA (mtDNA) on the other hand. Our study highlights two sympatric populations within P. sergenti in the area of its type-locality and new haplotypes of P. perniciosus and P. longicuspis without recording the specimens called lcx previously found in North Africa. We tried to use a polymerase chain reaction-restriction fragment length polymorphism method based on a combined double digestion of each marker. These method is not interesting to identify sandflies all over the Mediterranean Basin. PMID:24936911

  15. A common oxytocin receptor gene (OXTR) polymorphism modulates intranasal oxytocin effects on the neural response to social cooperation in humans

    PubMed Central

    Feng, Chunliang; Lori, Adriana; Waldman, Irwin D.; Binder, Elisabeth B.; Haroon, Ebrahim; Rilling, James K.

    2015-01-01

    Intranasal oxytocin (OT) can modulate social-emotional functioning and related brain activity in humans. Consequently, OT has been discussed as a potential treatment for psychiatric disorders involving social behavioral deficits. However, OT effects are often heterogeneous across individuals. Here we explore individual differences in OT effects on the neural response to social cooperation as a function of the rs53576 polymorphism of the oxytocin receptor gene (OXTR). Previously, we conducted a double-blind, placebo-controlled study in which healthy men and women were randomized to treatment with intranasal OT or placebo. Afterwards, they were imaged with fMRI while playing an iterated Prisoner’s Dilemma Game with same-sex partners. Within the left ventral caudate nucleus, intranasal OT treatment increased activation to reciprocated cooperation in men, but tended to decrease activation in women. Here, we show that these sex differences in OT effects are specific to individuals with the rs53576 GG genotype, and are not found for other genotypes (rs53576 AA/AG). Thus, OT may increase the reward or salience of positive social interactions for male GG homozygotes, while decreasing those processes for female GG homozygotes. These results suggest that rs53576 genotype is an important variable to consider in future investigations of the clinical efficacy of intranasal OT treatment. PMID:26178189

  16. Development of inhibitory antibodies to therapeutic factor VIII in severe hemophilia A is associated with microsatellite polymorphisms in the HMOX1 promoter

    PubMed Central

    Repessé, Yohann; Peyron, Ivan; Dimitrov, Jordan D; Dasgupta, Suryasarathi; Moshai, Elika Farrokhi; Costa, Catherine; Borel-Derlon, Annie; Guillet, Benoit; D’Oiron, Roseline; Aouba, Achille; Rothschild, Chantal; Oldenburg, Johannes; Pavlova, Anna; Kaveri, Srinivas V; Lacroix-Desmazes, Sébastien

    2013-01-01

    Induction of heme oxygenase-1, a stress-inducible enzyme with anti-inflammatory activity, reduces the immunogenicity of therapeutic factor VIII in experimental hemophilia A. In humans, heme oxygenase-1 expression is modulated by polymorphisms in the promoter of the heme oxygenase-1-encoding gene (HMOX1). We investigated the relationship between polymorphisms in the HMOX1 promoter and factor VIII inhibitor development in severe hemophilia A. We performed a case-control study on 99 inhibitor-positive patients and 263 patients who did not develop inhibitors within the first 150 cumulative days of exposure to therapeutic factor VIII. Direct sequencing and DNA fragment analysis were used to study (GT)n polymorphism and single nucleotide polymorphisms located at −1135 and −413 in the promoter of HMOX1. We assessed associations between the individual allele frequencies or genotypes, and inhibitor development. Our results demonstrate that inhibitor-positive patients had a higher frequency of alleles with large (GT)n repeats (L: n≥30), which are associated with lesser heme oxygenase-1 expression (odds ratio 2.31; 95% confidence interval 1.46–3.66; P<0.001]. Six genotypes (L/L, L/M, L/S, M/M, M/S and S/S) of (GT)n repeats were identified (S: n<21; M: 21≤n<30). The genotype group including L alleles (L/L, L/M and L/S) was statistically more frequent among inhibitor-positive than inhibitor-negative patients, as compared to the other genotypes (33.3% versus 17.1%) (odds ratio 2.21, 95% confidence interval 1.30–3.76; P<0.01). To our knowledge, this is the first association identified between HMOX1 promoter polymorphism and development of anti-drug antibodies. Our study paves the way towards modulation of the endogenous anti-inflammatory machinery of hemophilia patients to reduce the risk of inhibitor development PMID:23716558

  17. Using Common Formative Assessments to Promote Student Achievement: A Case Study of Practice, Leadership, and Culture

    ERIC Educational Resources Information Center

    Wall, Patricia T. C.

    2012-01-01

    It is the moral responsibility of educators to work diligently to provide every student with rich, challenging coursework in efforts to prepare them for post high school careers and education. The use of common formative assessments provides teachers with the valuable, timely information they need to make instructional decisions that will better…

  18. Moving Forward: Common Sense Policies to Promote Prosperity for Working Texans

    ERIC Educational Resources Information Center

    Baylor, Don, Jr.

    2006-01-01

    This report proposes several distinct--yet interrelated--policy opportunities that can move more Texans into the middle class. These proposals blend greater state-level investments with common sense policy changes to increase economic well-being for working Texans. While Texas policy makers have recognized the connection between workforce…

  19. A common polymorphism in the 5' UTR of ERCC5 creates an upstream ORF that confers resistance to platinum-based chemotherapy.

    PubMed

    Somers, Joanna; Wilson, Lindsay A; Kilday, John-Paul; Horvilleur, Emilie; Cannell, Ian G; Pöyry, Tuija A A; Cobbold, Laura C; Kondrashov, Alexander; Knight, John R P; Puget, Stéphanie; Grill, Jacques; Grundy, Richard G; Bushell, Martin; Willis, Anne E

    2015-09-15

    We show that a common polymorphic variant in the ERCC5 5' untranslated region (UTR) generates an upstream ORF (uORF) that affects both the background expression of this protein and its ability to be synthesized following exposure to agents that cause bulky adduct DNA damage. Individuals that harbor uORF1 have a marked resistance to platinum-based agents, illustrated by the significantly reduced progression-free survival of pediatric ependymoma patients treated with such compounds. Importantly, inhibition of DNA-PKcs restores sensitivity to platinum-based compounds by preventing uORF1-dependent ERCC5 expression. Our data support a model in which a heritable 5' noncoding mRNA element influences individuals' responses to platinum-based chemotherapy. PMID:26338418

  20. A common polymorphism in the 5′ UTR of ERCC5 creates an upstream ORF that confers resistance to platinum-based chemotherapy

    PubMed Central

    Somers, Joanna; Wilson, Lindsay A.; Kilday, John-Paul; Horvilleur, Emilie; Cannell, Ian G.; Pöyry, Tuija A.A.; Cobbold, Laura C.; Kondrashov, Alexander; Knight, John R.P.; Puget, Stéphanie; Grill, Jacques; Grundy, Richard G.; Bushell, Martin; Willis, Anne E.

    2015-01-01

    We show that a common polymorphic variant in the ERCC5 5′ untranslated region (UTR) generates an upstream ORF (uORF) that affects both the background expression of this protein and its ability to be synthesized following exposure to agents that cause bulky adduct DNA damage. Individuals that harbor uORF1 have a marked resistance to platinum-based agents, illustrated by the significantly reduced progression-free survival of pediatric ependymoma patients treated with such compounds. Importantly, inhibition of DNA-PKcs restores sensitivity to platinum-based compounds by preventing uORF1-dependent ERCC5 expression. Our data support a model in which a heritable 5′ noncoding mRNA element influences individuals’ responses to platinum-based chemotherapy. PMID:26338418

  1. CHARACTERIZATION OF FUSARIUM OXYSPORUM ISOLATES FROM COMMON BEAN AND SUGAR BEET USIG PATHOGENICITY ASSAYS AND RANDOM AMPLIFIED POLYMORPHIC DNA MARKERS.

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Technical Abstract. Fusarium wilt is an economically important fungal disease of common bean and Fusarium yellows of sugar beet in the Central High Plains (CHP) region of the United States with yield losses approaching 30% under appropriate environmental conditions. The objective of this study was ...

  2. The commonly used antimicrobial additive triclosan is a liver tumor promoter.

    PubMed

    Yueh, Mei-Fei; Taniguchi, Koji; Chen, Shujuan; Evans, Ronald M; Hammock, Bruce D; Karin, Michael; Tukey, Robert H

    2014-12-01

    Triclosan [5-chloro-2-(2,4-dichlorophenoxy)phenol; TCS] is a synthetic, broad-spectrum antibacterial chemical used in a wide range of consumer products including soaps, cosmetics, therapeutics, and plastics. The general population is exposed to TCS because of its prevalence in a variety of daily care products as well as through waterborne contamination. TCS is linked to a multitude of health and environmental effects, ranging from endocrine disruption and impaired muscle contraction to effects on aquatic ecosystems. We discovered that TCS was capable of stimulating liver cell proliferation and fibrotic responses, accompanied by signs of oxidative stress. Through a reporter screening assay with an array of nuclear xenobiotic receptors (XenoRs), we found that TCS activates the nuclear receptor constitutive androstane receptor (CAR) and, contrary to previous reports, has no significant effect on mouse peroxisome proliferation activating receptor α (PPARα). Using the procarcinogen diethylnitrosamine (DEN) to initiate tumorigenesis in mice, we discovered that TCS substantially accelerates hepatocellular carcinoma (HCC) development, acting as a liver tumor promoter. TCS-treated mice exhibited a large increase in tumor multiplicity, size, and incidence compared with control mice. TCS-mediated liver regeneration and fibrosis preceded HCC development and may constitute the primary tumor-promoting mechanism through which TCS acts. These findings strongly suggest there are adverse health effects in mice with long-term TCS exposure, especially on enhancing liver fibrogenesis and tumorigenesis, and the relevance of TCS liver toxicity to humans should be evaluated. PMID:25404284

  3. The commonly used antimicrobial additive triclosan is a liver tumor promoter

    PubMed Central

    Yueh, Mei-Fei; Taniguchi, Koji; Chen, Shujuan; Evans, Ronald M.; Hammock, Bruce D.; Karin, Michael; Tukey, Robert H.

    2014-01-01

    Triclosan [5-chloro-2-(2,4-dichlorophenoxy)phenol; TCS] is a synthetic, broad-spectrum antibacterial chemical used in a wide range of consumer products including soaps, cosmetics, therapeutics, and plastics. The general population is exposed to TCS because of its prevalence in a variety of daily care products as well as through waterborne contamination. TCS is linked to a multitude of health and environmental effects, ranging from endocrine disruption and impaired muscle contraction to effects on aquatic ecosystems. We discovered that TCS was capable of stimulating liver cell proliferation and fibrotic responses, accompanied by signs of oxidative stress. Through a reporter screening assay with an array of nuclear xenobiotic receptors (XenoRs), we found that TCS activates the nuclear receptor constitutive androstane receptor (CAR) and, contrary to previous reports, has no significant effect on mouse peroxisome proliferation activating receptor α (PPARα). Using the procarcinogen diethylnitrosamine (DEN) to initiate tumorigenesis in mice, we discovered that TCS substantially accelerates hepatocellular carcinoma (HCC) development, acting as a liver tumor promoter. TCS-treated mice exhibited a large increase in tumor multiplicity, size, and incidence compared with control mice. TCS-mediated liver regeneration and fibrosis preceded HCC development and may constitute the primary tumor-promoting mechanism through which TCS acts. These findings strongly suggest there are adverse health effects in mice with long-term TCS exposure, especially on enhancing liver fibrogenesis and tumorigenesis, and the relevance of TCS liver toxicity to humans should be evaluated. PMID:25404284

  4. Lack of association between rs1800795 (-174 G/C) polymorphism in the promoter region of interleukin-6 gene and susceptibility to type 2 diabetes in Isfahan population

    PubMed Central

    Ghavimi, Reza; Sharifi, Mohammadreza; Mohaghegh, Mohammad Ali; Mohammadian, Hossein; Khadempar, Saedeh; Rezaei, Hamzeh

    2016-01-01

    Background: Type 2 diabetes mellitus (T2DM) is an inflammatory autoimmune disease that mostly affects older adults. The etiology of T2DM includes both genetic and environmental factors. rs1800795 (−174 G/C) single nucleotide polymorphism (SNP) linked with autoimmune disorders predispositions, identified by Genome-Wide Association Study among genes, which immunologically related is considerably over signified. The goal of this study was to evaluate the association between rs1800795 (−174 G/C) polymorphisms in the promoter of interleukin-6 (IL-6) gene with susceptibility to T2DM in a subset of the Iranian population. Materials and Methods: In this case–control study, 120 healthy subjects and 120 patients with T2DM were included. Genomic DNA obtained from whole blood samples and the polymerase chain reaction was used to amplify the fragment of interest contain rs1800795 SNP, restriction fragment length polymorphism method was applied for genotyping of the DNA samples with NlaIII as a restriction enzyme. SPSS for Windows software (version 18.0, SPSS, Chicago, IL, USA) was performed for statistical analysis. Results: No significant differences were found between healthy controls and T2DM patients with respect to the frequency distribution of the cytokine gene polymorphism investigated. Odds ratio, adjusted for sex, age, and smoking status has displayed similar outcomes. Conclusion: These results indicated that the rs1800795 SNP is not a susceptibility gene variant for the development of T2DM in the Isfahan population. Further studies using new data on complex transcriptional interactions between IL-6 polymorphic sites are necessary to determine IL-6 haplotype influence on susceptibility to T2DM. PMID:26962520

  5. Association and Prognostic Significance of the Functional -1562C/T Polymorphism in the Promoter Region of MMP-9 in Turkish Patients with Gastric Cancer.

    PubMed

    Avcı, Nilufer; Ture, Mehmet; Deligonul, Adem; Cubukcu, Erdem; Olmez, Omer Fatih; Sahinturk, Serdar; Topak, Ali; Kurt, Ender; Evrensel, Turkkan; Şahin, Ahmet Bilgehan; Yakut, Tahsin

    2015-09-01

    Matrix metalloproteinases (MMPs) are a group of zinc-dependent peptidases that participate in matrix turnover in solid malignancies. The aim of this study was twofold. First, we sought to investigate under a case-control design the association between the functional -1562C/T polymorphism in the promoter region of MMP-9 and gastric cancer (GC) in a Turkish sample. Second, we examined its prognostic significance in GC patients. A total of 144 subjects were enrolled in the case-control study (79 GC cases and 65 controls). Overall survival (OS) and progression-free survival (PFS) served as the main outcome measures in the longitudinal study. The MMP-9 -1562C/T polymorphism was genotyped using a polymerase chain reaction-restriction fragment length polymorphism method. The odds ratio (OR) of GC for the CC genotype relative to the CT+TT genotypes was not significant (OR = 0.89, 95 % confidence interval [CI] = 0.44-1.82, P = 0.75). These results did not change after allowance for age and sex in multivariable regression analysis (OR = 0.81, 95 % CI = 0.40-1.94, P = 0.84). When the MMP-9 -1562C/T polymorphism was analyzed among GC patients in relation to OS and PFS, we found no significant differences between subjects with the CC and CT+TT genotypes. In conclusion, the results of our study did not point toward a major role of the MMP-9 -1562C/T polymorphism in the pathogenesis and clinical course of GC in Turkish subjects. PMID:26156886

  6. Sequential Infection with Common Pathogens Promotes Human-like Immune Gene Expression and Altered Vaccine Response.

    PubMed

    Reese, Tiffany A; Bi, Kevin; Kambal, Amal; Filali-Mouhim, Ali; Beura, Lalit K; Bürger, Matheus C; Pulendran, Bali; Sekaly, Rafick-Pierre; Jameson, Stephen C; Masopust, David; Haining, W Nicholas; Virgin, Herbert W

    2016-05-11

    Immune responses differ between laboratory mice and humans. Chronic infection with viruses and parasites are common in humans, but are absent in laboratory mice, and thus represent potential contributors to inter-species differences in immunity. To test this, we sequentially infected laboratory mice with herpesviruses, influenza, and an intestinal helminth and compared their blood immune signatures to mock-infected mice before and after vaccination against yellow fever virus (YFV-17D). Sequential infection altered pre- and post-vaccination gene expression, cytokines, and antibodies in blood. Sequential pathogen exposure induced gene signatures that recapitulated those seen in blood from pet store-raised versus laboratory mice, and adult versus cord blood in humans. Therefore, basal and vaccine-induced murine immune responses are altered by infection with agents common outside of barrier facilities. This raises the possibility that we can improve mouse models of vaccination and immunity by selective microbial exposure of laboratory animals to mimic that of humans. PMID:27107939

  7. Prediabetes Is Associated with HNF-4α P2 Promoter Polymorphism rs1884613: A Case-Control Study in Han Chinese Population and an Updated Meta-Analysis

    PubMed Central

    Wang, Changyi; Chen, Sihan; Zhang, Tao; Chen, Zhongwei; Liu, Shengyuan; Peng, Xiaolin; Ma, Jianping; Zhong, Xiaohong; Yan, Yanqiong; Tang, Linlin; Mai, Yifeng; Han, Liyuan

    2014-01-01

    Background. Controversy remains for the association between hepatocyte nuclear factor 4α (HNF-4α) P2 promoter polymorphism rs1884613 and type 2 diabetes (T2D). There was no association test of this polymorphism with prediabetes and T2D in the Chinese population. Moreover, an updated meta-analysis in various ethnic groups is needed to establish the contribution of rs1884613 to T2D risk. Methods. Using the Sequenom MassARRAY platform approach, we genotyped rs1884613 of HNF-4α in the P2 promoter region among 490 T2D patients, 471 individuals with prediabetes, and 575 healthy controls. All the individuals were recruited from 16 community health service centers in Nanshan district in Shenzhen province. Using STATA 11.0 software, meta-analysis was performed to summarize the overall contribution of rs1884613 to T2D risk. Results. Polymorphism rs1884613 was associated with genetic susceptibility to prediabetes in the whole samples (OR = 1.40, 95% CI = 1.16–1.68, P = 0.0001) and the female subgrouped samples (OR = 1.48, 95% CI = 1.14–1.92, P = 0.003) after adjusting for age and body mass index (BMI). In contrast, there was no association of rs1884613 with T2D in the whole samples and male in our case-control study and meta-analysis. Conclusions. Our results suggest that rs1884613 contributes to susceptibility to prediabetes, whereas this polymorphism may not play an important role in the development of T2D. PMID:25400315

  8. Functional analysis of a human tumor necrosis factor alpha (TNF-alpha) promoter polymorphism related to joint damage in rheumatoid arthritis.

    PubMed Central

    Kaijzel, E. L.; van Krugten, M. V.; Brinkman, B. M.; Huizinga, T. W.; van der Straaten, T.; Hazes, J. M.; Ziegler-Heitbrock, H. W.; Nedospasov, S. A.; Breedveld, F. C.; Verweij, C. L.

    1998-01-01

    BACKGROUND: Functional heterogeneity in the tumor necrosis factor alpha (TNF-alpha) gene may be responsible for the TNF-alpha response in infectious and autoimmune diseases. Recently, the TNF-238 promoter polymorphism was observed as being associated with a more destructive disease in rheumatoid arthritis (RA). To determine the relation between TNF-238 and disease progression, the extent of joint destruction in a cohort of 101 RA patients followed for 12 years was analyzed. Furthermore, we have attempted to link this polymorphism to TNF-alpha gene transcription in monocytes and lymphocytes in vitro. PATIENTS, MATERIALS, AND METHODS: The extent of joint destruction determined on X-rays of hands and feet assessed after 0, 3, 6, and 12 years was compared with TNF-238 genotypes. Functional consequences of TNF-alpha gene polymorphisms using reporter gene constructs were analyzed in cells of the monocyte and lymphocyte lineage by means of transient transfection systems. RESULTS: The rate of joint damage in -238GA patients was lower than that in the -238GG patients, independent of HLA-DR4. Damage after 12 years was 76 +/- 30 for the -238GA versus 126 +/- 13 for the -238GG patients as determined by the van der Heijde's modification of Sharp's method. Furthermore, TNF-238A was found to be in linkage disequilibrium with an additional polymorphism at position -376. Functional assays revealed no significant differences in the level of inducible reporter gene expression between the TNF-238/-376 promoter constructs in the cell types tested. CONCLUSION: In a prospective study, we show that the TNF-238GG genotype contributes to progression of joint destruction in RA, independent of the presence of HLA-DR4. However, in vitro transfection assays indicate that TNF-238A by itself or in combination with TNF-376A is not likely to be of direct functional relevance for transcriptional activation. Therefore, these polymorphisms may serve as markers for additional polymorphisms in the TNF

  9. A functional polymorphism in the MAOA gene promoter (MAOA-LPR) predicts central dopamine function and body mass index.

    PubMed

    Ducci, F; Newman, T K; Funt, S; Brown, G L; Virkkunen, M; Goldman, D

    2006-09-01

    Variation in brain monoaminergic activity is heritable and modulates risk of alcoholism and other addictions, as well as food intake and energy expenditure. Monoamine oxidase A deaminates the monoamine neurotransmitters serotonin, dopamine (DA), and noradrenaline. The monoamine oxidase A (MAOA) gene (Xp11.5) contains a length polymorphism in its promoter region (MAOA-LPR) that putatively affects transcriptional efficiency. Our goals were to test (1) whether MAOA-LPR contributes to interindividual variation in monoamine activity, assessed using levels of cerebrospinal fluid (CSF) monoamine metabolites; and (2) whether MAOA-LPR genotype influences alcoholism and/or body mass index (BMI). Male, unrelated criminal alcoholics (N=278) and controls (N=227) were collected from a homogeneous Finnish source population. CSF concentration of 5-hydroxyindoleacetic acid (5-HIAA), homovanillic acid (HVA), and 3-methoxy-4-hydroxyphenylglycol (MHPG) were available from 208 participants. Single allele, hemizygous genotypes were grouped according to inferred effect of the MAOA alleles on transcriptional activity. MAOA-LPR genotypes had a significant effect on CSF HVA concentration (P=0.01) but explained only 3% of the total variance. There was a detectable but nonsignificant genotype effect on 5-HIAA and no effects on MHPG. Specifically, the genotype conferring high MAOA activity was associated with lower HVA levels in both alcoholics and controls, a finding that persisted after accounting for the potential confounds of alcoholism, BMI, height, and smoking. MAOA-LPR genotype predicted BMI (P<0.005), with the high-activity genotype being associated with lower BMI. MAOA-LPR genotypes were not associated with alcoholism or related psychiatric phenotypes in this data set. Our results suggest that MAOA-LPR allelic variation modulates DA turnover in the CNS, but does so in a manner contrary to our prior expectation that alleles conferring high activity would predict higher HVA levels in

  10. A Promoter Polymorphism in the CD59 Complement Regulatory Protein Gene in Donor Lungs Correlates With a Higher Risk for Chronic Rejection After Lung Transplantation.

    PubMed

    Budding, K; van de Graaf, E A; Kardol-Hoefnagel, T; Broen, J C A; Kwakkel-van Erp, J M; Oudijk, E-J D; van Kessel, D A; Hack, C E; Otten, H G

    2016-03-01

    Complement activation leads primarily to membrane attack complex formation and subsequent target cell lysis. Protection against self-damage is regulated by complement regulatory proteins, including CD46, CD55, and CD59. Within their promoter regions, single-nucleotide polymorphisms (SNPs) are present that could influence transcription. We analyzed these SNPs and investigated their influence on protein expression levels. A single SNP configuration in the promoter region of CD59 was found correlating with lower CD59 expression on lung endothelial cells (p = 0.016) and monocytes (p = 0.013). Lung endothelial cells with this SNP configuration secreted more profibrotic cytokine IL-6 (p = 0.047) and fibroblast growth factor β (p = 0.036) on exposure to sublytic complement activation than cells with the opposing configuration, whereas monocytes were more susceptible to antibody-mediated complement lysis (p < 0.0001). Analysis of 137 lung transplant donors indicated that this CD59 SNP configuration correlates with impaired long-term survival (p = 0.094) and a significantly higher incidence of bronchiolitis obliterans syndrome (p = 0.046) in the recipient. These findings support a role for complement in the pathogenesis of this posttransplant complication and are the first to show a deleterious association of a donor CD59 promoter polymorphism in lung transplantation. PMID:26517734