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Sample records for genes controlling susceptibility

  1. XPG Gene Polymorphisms Contribute to Colorectal Cancer Susceptibility: A Two-Stage Case-Control Study

    PubMed Central

    Hua, Rui-Xi; Zhuo, Zhen-Jian; Zhu, Jinhong; Zhang, Shao-Dan; Xue, Wen-Qiong; Zhang, Jiang-Bo; Xu, Hong-Mei; Li, Xi-Zhao; Zhang, Pei-Fen; He, Jing; Jia, Wei-Hua

    2016-01-01

    Previous studies have reported that xeroderma pigmentosum group G (XPG) gene polymorphisms may modulate colorectal cancer (CRC) susceptibility. In this study, we performed a two-stage case-control study to comprehensively investigate the associations of five polymorphisms in the XPG gene with CRC risk in 1,901 cases and 1,976 controls from Southern China, including rs2094258 C>T, rs751402 C>T, rs2296147 T>C, rs1047768 T>C and rs873601 G>A. After combining data from two stages, we found that three of the studied polymorphisms (rs2094258 C>T, rs751402 C>T, and rs873601 G>A) were significantly associated with CRC susceptibility. After adjustment for age and gender, multivariate logistic regression analysis indicated that carriers of the rs2094258 T alleles had an increased CRC risk [CT vs. CC: adjusted odds ratio (OR)=1.17, 95% confidence interval (CI)=1.01-1.36; TT vs. CC: adjusted OR=1.49, 95% CI=1.18-1.89; TT vs. CT/CC: adjusted OR=1.38, 95% CI=1.10-1.72]. Likely, rs873601 A allele also conferred increased CRC susceptibility. In contrast, a protective association was identified between rs751402 C>T polymorphism and the risk of CRC. In summary, our results indicated that these three polymorphisms were found to associate with CRC susceptibility in a Southern Chinese population.

  2. Susceptibility Genes in Thyroid Autoimmunity

    PubMed Central

    Ban, Yoshiyuki; Tomer, Yaron

    2005-01-01

    The autoimmune thyroid diseases (AITD) are complex diseases which are caused by an interaction between susceptibility genes and environmental triggers. Genetic susceptibility in combination with external factors (e.g. dietary iodine) is believed to initiate the autoimmune response to thyroid antigens. Abundant epidemiological data, including family and twin studies, point to a strong genetic influence on the development of AITD. Various techniques have been employed to identify the genes contributing to the etiology of AITD, including candidate gene analysis and whole genome screening. These studies have enabled the identification of several loci (genetic regions) that are linked with AITD, and in some of these loci, putative AITD susceptibility genes have been identified. Some of these genes/loci are unique to Graves' disease (GD) and Hashimoto's thyroiditis (HT) and some are common to both the diseases, indicating that there is a shared genetic susceptibility to GD and HT. The putative GD and HT susceptibility genes include both immune modifying genes (e.g. HLA, CTLA-4) and thyroid specific genes (e.g. TSHR, Tg). Most likely, these loci interact and their interactions may influence disease phenotype and severity. PMID:15712599

  3. Association between Estrogen Receptor Alpha Gene Polymorphisms and Susceptibility to Idiopathic Scoliosis in Bulgarian Patients: A Case-Control Study

    PubMed Central

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

    2015-01-01

    BACKGROUND: The current consensus on idiopathic scoliosis maintains that it has a multifactorial etiology with genetic predisposing factors. AIM: Estrogen receptor alpha gene has been considered as candidate gene of idiopathic scoliosis. MATERIAL AND METHODS: We conducted a case-control study of Bulgarian population samples (eighty patients with idiopathic scoliosis and one hundred-sixty healthy unrelated gender-matched controls) trying to investigate the association between common genetic polymorphisms of estrogen receptor alpha and the susceptibility to idiopathic scoliosis. Molecular detection of the restriction polymorphisms XbaI and PvuII was performed by polymerase chain reaction following by restriction fragment length polymorphism. The statistical analysis was performed by Pearson’s chi-squared test. RESULTS: Our case-control study showed statistically significant association between the PvuII polymorphism and susceptibility to idiopathic scoliosis and curve progression. No genotype or allele of XbaI polymorphism was found to be correlated with the onset or severity of the disease. CONCLUSIONS: The identification of molecular markers with diagnostic and prognostic value could be useful for early detection of children at risk for the development of scoliosis and for prognosis of the risk for a rapid deformity progression. That would facilitate the therapy decisions and early stage treatment of the patient with the least invasive procedures. PMID:27275235

  4. Breast cancer susceptibility genes.

    PubMed

    Lubinski, Jan; Korzen, Marcin; Gorski, Bohdan; Cybulski, Cezary; Debniak, Tadeusz; Jakubowska, Anna; Medrek, Krzysztof; Matyjasik, Joanna; Huzarski, Tomasz; Byrski, Tomasz; Gronwald, Jacek; Masojc, Bartlomiej; Lener, Marcin; Szymanska, Anna; Szymanska-Pasternak, Jolanta; Fernandez, Pablo Serrano; Wokolorczyk, Dominika; Piegat, Andrzej; Ucinski, Michal; Domagala, Pawel; Kladny, Jozef; Gorecka, Barbara; Scott, Rodney; Narod, Steven

    2007-09-01

    In 1999 it has been recognized that 3 BRCA1 abnormalities - 5382insC, C61G and 4153delA - constitute almost 90% of all germline mutations of this gene in Poland. Due to the above findings we started performing the cheap and quick large scale testing for BRCA1 mutations and, these days, we have almost 4,000 carriers diagnosed and under direct or indirect supervision what is probably the largest number in the world. Additionally, the above results pushed us to hypothesize that genetic homogeneity will be seen in Poland in studies of other genes. Actually, the next studies allowed us to identify genes / changes associated with moderate / low breast cancer risk and showed, similarly to BRCA1, high level of genetic homogeneity. This series included BRCA2, C5972T, CHEK2 del5395; 1100delC, I157T or IVS2 + 1G > A, CDKN2A (p16) A148T, XPD Asp312Asn and Lys751Gln, CYP1B1 R48G, A119S and L43V. The results of the above studies led us in 2004 already to hypothesize that >90% of all cancers have genetic (constitutional) background. Two years later we were able to show a panel of markers covering 92% of consecutive breast cancers in Poland, and we formulated the hypothesis that all cancers have a genetic background. These days we are demonstrating for the first time that genetic components to malignancy play a role in all cancers. We are presenting it on examples of late-onset breast cancers from Poland, but it seems to be justified to expect that similar results can be achieved from other malignancies. PMID:17935274

  5. Susceptibility genes in movement disorders.

    PubMed

    Scholz, Sonja; Singleton, Andrew

    2008-05-15

    During the last years, remarkable progress in our understanding of molecular genetic mechanisms underlying movement disorders has been achieved. The successes of linkage studies, followed by positional cloning, have dominated the last decade and several genes underlying monogenic disorders have been discovered. The pathobiological understanding garnered from these mutations has laid the foundation for much of the search for genetic loci that confer risk for, rather than cause, disease. With the introduction of whole genome association studies as a novel tool to investigate genetic variation underlying common, complex diseases, a new era in neurogenomics has just begun. As the field rapidly moves forward several new challenges and critical questions in clinical care have to be addressed. In this review, we summarize recent advances in the discovery of susceptibility loci underlying major movement disorders, explain the newest methodologies and tools employed for finding and characterizing genes and discuss how insights into the molecular genetic basis of neurological disorders will impact therapeutic concepts in patient care.

  6. Protein-truncating variants in moderate-risk breast cancer susceptibility genes: a meta-analysis of high-risk case-control screening studies.

    PubMed

    Aloraifi, Fatima; McCartan, Damian; McDevitt, Trudi; Green, Andrew J; Bracken, Adrian; Geraghty, James

    2015-09-01

    Several "moderate-risk breast cancer susceptibility genes" have been conclusively identified. Pathogenic mutations in these genes are thought to cause a two to fivefold increased risk of breast cancer. In light of the current development and use of multigene panel testing, the authors wanted to systematically obtain robust estimates of the cancer risk associated with loss-of-function mutations within these genes. An electronic search was conducted to identify studies that sequenced the full coding regions of ATM, CHEK2, BRIP1, PALB2, NBS1, and RAD50 in a general and gene-targeted approach. Inclusion was restricted to studies that sequenced the germline DNA in both high-risk cases and geographically matched controls. A meta-analysis was then performed on protein-truncating variants (PTVs) identified in the studies for an association with breast cancer risk. A total of 10,209 publications were identified, of which 64 studies comprising a total of 25,418 cases and 52,322 controls in the 6 interrogated genes were eligible under our selection criteria. The pooled odds ratios for PTVs in the susceptibility genes were at least >2.6. Additionally, mutations in these genes have shown geographic and ethnic variation. This comprehensive study emphasizes the fact that caution should be taken when identifying certain genes as moderate susceptibility with the lack of sufficient data, especially with regard to the NBS1, RAD50, and BRIP1 genes. Further data from case-control sequencing studies, and especially family studies, are warranted. PMID:26250988

  7. Loci controlling lymphocyte production of interferon c after alloantigen stimulation in vitro and their co-localization with genes controlling lymphocyte infiltration of tumors and tumor susceptibility.

    PubMed

    Lipoldová, Marie; Havelková, Helena; Badalova, Jana; Vojtísková, Jarmila; Quan, Lei; Krulova, Magdaléna; Sohrabi, Yahya; Stassen, Alphons P; Demant, Peter

    2010-02-01

    Low infiltration of lymphocytes into cancers is associated with poor prognosis, but the reasons why some patients exhibit a low and others a high infiltration of tumors are unknown. Previously we mapped four loci (Lynf1–Lynf4) controlling lymphocyte infiltration of mouse lung tumors. These loci do not encode any of the molecules that are involved in traffic of lymphocytes. Here we report a genetic relationship between these loci and the control of production of IFNγ in allogeneic mixed lymphocyte cultures (MLC). We found that IFNγ production by lymphocytes of O20/A mice is lower than by lymphocytes of OcB-9/Dem mice (both H2pz) stimulated in MLC by irradiated splenocytes of C57BL/10SnPh (H2b) or BALB/ cHeA (H2d) mice, or by ConA. IFNγ production in MLCs of individual (O20 9 OcB-9)F2mice stimulated by irradiated C57BL/10 splenocytes and genotyped for microsatellite markers revealed four IFNγ-controlling loci (Cypr4-Cypr7), each of which is closely linked with one of the four Lynf loci and with a cluster of susceptibility genes for different tumors. This suggests that inherited differences in certain lymphocyte responses may modify their propensity to infiltrate tumors and their capacity to affect tumor growth.

  8. Antibiotic resistance genes & susceptibility patterns in staphylococci

    PubMed Central

    Duran, Nizami; Ozer, Burcin; Duran, Gulay Gulbol; Onlen, Yusuf; Demir, Cemil

    2012-01-01

    Background & objectives: This study was carried out to evaluate the association between the antibiotic susceptibility patterns and the antibiotic resistance genes in staphylococcal isolates obtained from various clinical samples of patients attending a teaching hospital in Hatay, Turkey. Methods: A total of 298 staphylococci clinical isolates were subjected to antimicrobial susceptibility testing. The genes implicated in resistance to oxacillin (mecA), gentamicin (aac(6’)/aph(2”), aph(3’-IIIa, ant(4’)-Ia), erythromycin (ermA, ermB, ermC, and msrA), tetracyclin (tetK, tetM), and penicillin (blaZ) were amplified using multiplex PCR method. Results: Methicillin resistance rate among 139 Staphlococcus aureus isolates was 16.5 and 25.9 per cent of S. aureus carried mecA gene. Of the 159 CoNS isolates, methicillin resistance rate was 18.9 and 29.6 per cent carried mecA gene. Ninety four isolates identified as gentamicin resistant phenotypically, contained at least one of the gentamicin resistance genes [aac(6’)/aph(2”), aph(3’)-IIIa, ant(4’)-Ia], 17 gentamicin-susceptible isolates were found as positive in terms of one or more resistance genes [aac(6’)/aph(2”), aph(3’)-IIIa, ant(4’)-Ia] by multiplex PCR. A total of 165 isolates were resistant to erythromycin, and contained at least one of the erythromycin resistance genes (ermA, ermB, ermC and msrA). Phenotypically, 106 staphylococcal isolates were resistant to tetracycline, 121 isolates carried either tetK or tetM or both resistance genes. The majority of staphylococci tested possessed the blaZ gene (89.9%). Interpretation & conclusions: The present results showed that the phenotypic antibiotic susceptibility patterns were not similar to those obtained by genotyping done by multiplex PCR. Rapid and reliable methods for antibiotic susceptibility are important to determine the appropriate therapy decisions. Multiplex PCR can be used for confirmation of the results obtained by conventional

  9. Association Between P2RX7 Gene and Hepatocellular Carcinoma Susceptibility: A Case-Control Study in a Chinese Han Population

    PubMed Central

    Duan, Shaobo; Yu, Jie; Han, Zhiyu; Cheng, Zhigang; Liang, Ping

    2016-01-01

    Background Hepatocellular carcinoma (HCC) is one of the most common types of liver cancer. It is hypothesized that P2RX7 genetic polymorphisms have strong association with HCC susceptibility. Therefore, a case-control study was designed and performed to verify the association between P2RX7 gene polymorphisms and HCC susceptibility. Material/Methods A total of 646 subjects were recruited in our study, including 323 HCC patients and 323 healthy controls. Five gene polymorphisms, −762C>T (rs2393799), 946G>A (rs28360457), 1513A>C (rs3751143), 1068G>A (rs1718119), and 1096C>G (rs2230911), were selected. Odds ratio (ORs) and 95% confidence interval (CI) were used to quantify the association between P2RX7 gene polymorphisms and the susceptibility to HCC. All tests were performed using SPSS 20 and a 2-sided P value of less than 0.05 was considered to be statistically significant. Results Our results suggest that allelic frequencies of these 5 SNPs all conformed to Hardy-Weinberg equilibrium (HWE). There was no significant difference in genotype and allele distributions of −762C>T and 1096C>G between the case group and the control group. However, an increased risk of HCC was associated with 946G>A (A vs. G: OR=1.48, 95%CI=1.09–2.01, P=0.013; GA+AA vs. GG: OR=1.46, 95%CI=1.03–2.07, P=0.033). A similar increased risk was associated with 1513A>C polymorphism (C vs. A: OR=1.37, 95%CI=1.05–1.79, P=0.021; AC+CC vs. AA: OR=1.40, 95%CI=1.01–1.93, P=0.041). On the other hand, a decreased risk of HCC was associated with gene polymorphism of 1068G>A (A vs. G: OR=0.68, 95%CI=0.51–0.91, P=0.010; GA+AA vs. GG: OR=0.68, 95%CI=0.49–0.96, P=0.027; AA vs. GG: OR=0.42, 95%CI=0.18–0.99, P=0.048). Conclusions Our results suggest that 3 of the 5 polymorphisms of P2RX7 described above (1513A>C, 946G>A, and 1068G>A) are significantly associated with HCC susceptibility in a Chinese Han population. Studies with larger sample sizes are recommended to confirm whether our results will

  10. The associations between VEGF gene polymorphisms and diabetic retinopathy susceptibility: a meta-analysis of 11 case-control studies.

    PubMed

    Han, Liyuan; Zhang, Lina; Xing, Wenhua; Zhuo, Renjie; Lin, XiaLu; Hao, Yanhua; Wu, Qunhong; Zhao, Jinshun

    2014-01-01

    AIMS. Published data on the associations of VEGF polymorphisms with diabetic retinopathy (DR) susceptibility are inconclusive. A systematic meta-analysis was undertaken to clarify this topic. METHODS. Data were collected from the following electronic databases: PubMed, Embase, OVID, Web of Science, Elsevier Science Direct, Excerpta Medica Database (EMBASE), and Cochrane Library with the last report up to January 10, 2014. ORs and 95% CIs were calculated for VEGF-2578C/A (rs699947), -1154G/A (rs1570360), -460T/C (rs833061), -634G>C (rs2010963), and +936C/T (rs3025039) in at least two published studies. Meta-analysis was performed in a fixed/random effect model by using the software STATA 12.0. RESULTS. A total of 11 studies fulfilling the inclusion criteria were included in this meta-analysis. A significant relationship between VEGF+936C/T (rs3025039) polymorphism and DR was found in a recessive model (OR = 3.19, 95% CI = 1.20-8.41, and P(z) = 0.01) in Asian and overall populations, while a significant association was also found between -460T/C (rs833061) polymorphism and DR risk under a recessive model (OR = 2.12, 95% CI = 1.12-4.01, and P(z) = 0.02). CONCLUSIONS. Our meta-analysis demonstrates that +936C/T (rs3025039) is likely to be associated with susceptibility to DR in Asian populations, and the recessive model of -460T/C (rs833061) is associated with elevated DR susceptibility.

  11. Pathways: Strategies for Susceptibility Genes in SLE

    PubMed Central

    Kelley, James M.; Edberg, Jeffrey C.; Kimberly, Robert P.

    2010-01-01

    Systemic lupus erythematosus (SLE) is a complex autoimmune disorder marked by an inappropriate immune response to nuclear antigens. Recent whole genome association and more focused studies have revealed numerous genes implicated in this disease process, including ITGAM, Fc gamma receptors, complement components, C-reactive protein, and others. One common feature of these molecules is their involvement in the immune opsonins pathway and phagocytic clearing of nuclear antigens and apoptotic debris which provide excessive exposure of lupus-related antigens to immune cells. Analysis of gene-gene interactions in the opsonin pathway and its relationship to SLE may provide a systems-based approach to identify additional candidate genes associated with disease able to account for a larger part of lupus susceptibility. PMID:20144911

  12. Genetic mapping of tumor susceptibility genes involved in mouse plasmacytomagenesis

    SciTech Connect

    Mock, B.A.; Krall, M.M.; Dosik, J.K. )

    1993-10-15

    Plasmacytomas (PCTs) were induced in 47% of BALB/cAnPt mice by the intraperitoneal injection of pristane, in 2% of (BALB/c [times] DBA/2N)F[sub 1], and in 11% of 773 BALB/cAnPt [times] (BALB/cAnPt [times] DBA/2N)F[sub 1]N[sub 2] backcross mice. This result indicates a multigenic mode of inheritance for PCT susceptibility. To locate genes controlling this complex genetic trait, tumor susceptibility in backcross progeny generated from BALB/c and DBA/2N (resistant) mice was correlated with alleles of 83 marker loci. The genotypes of the PCT-susceptible progeny displayed an excess homozygosity for BALB/c alleles with a 32-centimorgan stretch of mouse chromosome 4 (>95% probability of linkage) with minimal recombination (12%) near Gt10. Another susceptibility gene on mouse chromosome 1 may be linked to Fcgr2 (90% probability of linkage); there were excess heterozygotes for Fcgr2 among the susceptible progeny and excess homozygotes among the resistant progeny. Regions of mouse chromosomes 4 and 1 that are correlated with PCT susceptibility share extensive linkage homology with regions of human chromosome 1 that have been associated with cytogenetic abnormalities in multiple myeloma and lymphoid, breast, and endocrine tumors. 68 refs., 2 figs., 1 tab.

  13. Network Analysis of Human Genes Influencing Susceptibility to Mycobacterial Infections.

    PubMed

    Lipner, Ettie M; Garcia, Benjamin J; Strong, Michael

    2016-01-01

    Tuberculosis and nontuberculous mycobacterial infections constitute a high burden of pulmonary disease in humans, resulting in over 1.5 million deaths per year. Building on the premise that genetic factors influence the instance, progression, and defense of infectious disease, we undertook a systems biology approach to investigate relationships among genetic factors that may play a role in increased susceptibility or control of mycobacterial infections. We combined literature and database mining with network analysis and pathway enrichment analysis to examine genes, pathways, and networks, involved in the human response to Mycobacterium tuberculosis and nontuberculous mycobacterial infections. This approach allowed us to examine functional relationships among reported genes, and to identify novel genes and enriched pathways that may play a role in mycobacterial susceptibility or control. Our findings suggest that the primary pathways and genes influencing mycobacterial infection control involve an interplay between innate and adaptive immune proteins and pathways. Signaling pathways involved in autoimmune disease were significantly enriched as revealed in our networks. Mycobacterial disease susceptibility networks were also examined within the context of gene-chemical relationships, in order to identify putative drugs and nutrients with potential beneficial immunomodulatory or anti-mycobacterial effects.

  14. Network Analysis of Human Genes Influencing Susceptibility to Mycobacterial Infections

    PubMed Central

    Lipner, Ettie M.; Garcia, Benjamin J.; Strong, Michael

    2016-01-01

    Tuberculosis and nontuberculous mycobacterial infections constitute a high burden of pulmonary disease in humans, resulting in over 1.5 million deaths per year. Building on the premise that genetic factors influence the instance, progression, and defense of infectious disease, we undertook a systems biology approach to investigate relationships among genetic factors that may play a role in increased susceptibility or control of mycobacterial infections. We combined literature and database mining with network analysis and pathway enrichment analysis to examine genes, pathways, and networks, involved in the human response to Mycobacterium tuberculosis and nontuberculous mycobacterial infections. This approach allowed us to examine functional relationships among reported genes, and to identify novel genes and enriched pathways that may play a role in mycobacterial susceptibility or control. Our findings suggest that the primary pathways and genes influencing mycobacterial infection control involve an interplay between innate and adaptive immune proteins and pathways. Signaling pathways involved in autoimmune disease were significantly enriched as revealed in our networks. Mycobacterial disease susceptibility networks were also examined within the context of gene-chemical relationships, in order to identify putative drugs and nutrients with potential beneficial immunomodulatory or anti-mycobacterial effects. PMID:26751573

  15. Melanoma susceptibility genes and risk assessment.

    PubMed

    Marzuka-Alcalá, Alexander; Gabree, Michele Jacobs; Tsao, Hensin

    2014-01-01

    Familial melanoma accounts for approximately a tenth of all melanoma cases. The most commonly known melanoma susceptibility gene is the highly penetrant CDKN2A (p16INK4a) locus, which is transmitted in an autosomal dominant fashion and accounts for approximately 20-50 % of familial melanoma cases. Mutated p16INK4a shows impaired capacity to inhibit the cyclin D1-CDK4 complex, allowing for unchecked cell cycle progression. Mutations in the second protein coded by CDKN2A, p14ARF, are much less common and result in proteasomal degradation of p53 with subsequent accumulation of DNA damage as the cell progresses through the cell cycle without a functional p53-mediated DNA damage response. Mutations in CDK4 that impair the inhibitory interaction with p16INK4a also increase melanoma risk but these mutations are extremely rare. Genes of the melanin biosynthetic pathway, including MC1R and MITF, have also been implicated in melanomagenesis. MC1R variants were traditionally thought to increase risk for melanoma secondary to intensified UV-mediated DNA damage in the setting of absent photoprotective eumelanin. Accumulation of pheomelanin, which appears to have a carcinogenic effect regardless of UV exposure, may be a more likely mechanism. Impaired SUMOylation of the E318K variant of MITF results in increased transcription of genes that confer melanocytes with a pro-malignant phenotype. Mutations in the tumor suppressor BAP1 enhance the metastatic potential of uveal melanoma and predispose to cutaneous/ocular melanoma, atypical melanocytic tumors, and other internal malignancies (COMMON syndrome). Genome-wide association studies have identified numerous low-risk alleles. Although several melanoma susceptibility genes have been identified, risk assessment tools have been developed only for the most common gene implicated with hereditary melanoma, CDKN2A. MelaPRO, a validated model that relies on Mendelian inheritance and Bayesian probability theories, estimates carrier

  16. Prediction of autism susceptibility genes based on association rules.

    PubMed

    Gong, Lejun; Yan, Yunyang; Xie, Jianming; Liu, Hongde; Sun, Xiao

    2012-06-01

    Autism is a complex neuropsychiatric disorder with high heritability and an unclear etiology. The identification of key genes related to autism may elucidate its etiology. The current study provides an approach to predicting autism susceptibility genes. Genes are first extracted from the biomedical literature, and some autism susceptibility genes are then recognized as seeds by the prior knowledge. As candidates, the remaining genes are predicted by creating association rules between the seeds and candidates. In an evaluated data set, 27 autism susceptibility genes (type "Y") are extracted and 43 possible autism susceptibility genes (type "P") are predicted. The sum of "Y" and "P" genes accounts for 93.3% of the data set that are not contained in the typical database of autism susceptibility genes. Our approach can effectively extract and predict autism susceptibility genes from the biomedical literature. These predicted results complement the typical database of autism susceptibility genes. The web portal for the predicted results, which is freely available at http://biolab.hyit.edu.cn/ar, can be a valuable resource in studies of diseases related to genes.

  17. Novel Cleft Susceptibility Genes in Chromosome 6q

    PubMed Central

    Letra, A.; Menezes, R.; Fonseca, R.F.; Govil, M.; McHenry, T.; Murphy, M.J.; Hennebold, J.D.; Granjeiro, J.M.; Castilla, E.E.; Orioli, I.M.; Martin, R.; Marazita, M.L.; Bjork, B.C.; Vieira, A.R.

    2010-01-01

    Cleft lip/palate is a defect of craniofacial development. In previous reports, chromosome 6q has been suggested as a candidate region for cleft lip/palate. A multipoint posterior probability of linkage analysis of multiplex families from the Philippines attributed an 88% probability of harboring a cleft-susceptibility gene to a narrower region on bands 6q14.2-14.3. We genotyped 2732 individuals from families and unrelated individuals with and without clefts to investigate the existence of possible cleft-susceptibility genes in this region. We found association of PRSS35 and SNAP91 genes with cleft lip/palate in the case-control cohort and in Caucasian families. Haplotype analyses support the individual associations with PRSS35. We found Prss35 expression in the head and palate of mouse embryos at critical stages for palatogenesis, whereas Snap91 was expressed in the adult brain. We provide further evidence of the involvement of chromosome 6q in cleft lip/palate and suggest PRSS35 as a novel candidate gene. PMID:20511563

  18. Prioritization of Disease Susceptibility Genes Using LSM/SVD.

    PubMed

    Gong, Lejun; Yang, Ronggen; Yan, Qin; Sun, Xiao

    2013-12-01

    Understanding the role of genetics in diseases is one of the most important tasks in the postgenome era. It is generally too expensive and time consuming to perform experimental validation for all candidate genes related to disease. Computational methods play important roles for prioritizing these candidates. Herein, we propose an approach to prioritize disease genes using latent semantic mapping based on singular value decomposition. Our hypothesis is that similar functional genes are likely to cause similar diseases. Measuring the functional similarity between known disease susceptibility genes and unknown genes is to predict new disease susceptibility genes. Taking autism as an instance, the analysis results of the top ten genes prioritized demonstrate they might be autism susceptibility genes, which also indicates our approach could discover new disease susceptibility genes. The novel approach of disease gene prioritization could discover new disease susceptibility genes, and latent disease-gene relations. The prioritized results could also support the interpretive diversity and experimental views as computational evidence for disease researchers.

  19. [Susceptibility gene in multiple system atrophy (MSA)].

    PubMed

    Tsuji, Shoji

    2014-01-01

    To elucidate molecular bases of multiple system atrophy (MSA), we first focused on recently identified MSA multiplex families. Though linkage analyses followed by whole genome resequencing, we have identified a causative gene, COQ2, for MSA. We then conducted comprehensive nucleotide sequence analysis of COQ2 of sporadic MSA cases and controls, and found that functionally deleterious COQ2 variants confer a strong risk for developing MSA. COQ2 encodes an enzyme in the biosynthetic pathway of coenzyme Q10. Decreased synthesis of coenzyme Q10 is considered to be involved in the pathogenesis of MSA through decreased electron transport in mitochondria and increased vulnerability to oxidative stress. PMID:25672683

  20. Klotho gene polymorphisms are related to colorectal cancer susceptibility

    PubMed Central

    Liu, Chang; Cui, Wei; Wang, Li; Yan, Lei; Ruan, Xinjian; Liu, Yanfang; Jia, Xiaoyan; Zhang, Xia

    2015-01-01

    Aim: The purpose of this study was to investigate the relationship of Klotho gene G-395A and C1818T polymorphisms with colorectal cancer (CRC) susceptibility. Methods: 125 CRC patients and 125 controls were enrolled in the study. G-395A and C1818T polymorphisms were genotyped with polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) technology. Haploview software was utilized to conduct linkage disequilibrium and haplotype analysis. Odds ratio (OR) and 95% confidence interval (95% CI) were used to analyze the correlation of genotypes and haplotypes with CRC susceptibility. Results: AA and GA genotypes of G-395A polymorphisms were related with CRC risk (AA: OR = 4.161, 95% CI = 1.437-12.053; GA: OR = 1.958, 95% CI = 1.133-3.385). The frequency of A allele was much higher in case group, compared with controls (31.2% vs.17.6%) and the value of OR AND 95% CI suggested that A allele served as a risk factor for CRC (OR = 2.123, 95% CI = 1.393-3.236). Haplotypes analysis indicated that A-C and A-T haplotypes were significantly associated with risk of CRC (OR = 1.822, 95% CI = 1.124-2.954; OR = 2.877, 95% CI = 1.340-6.176). Conclusion: G-395A polymorphism of Klotho gene could increase the risk of CRC. PMID:26261651

  1. Gene-gene interactions in breast cancer susceptibility.

    PubMed

    Turnbull, Clare; Seal, Sheila; Renwick, Anthony; Warren-Perry, Margaret; Hughes, Deborah; Elliott, Anna; Pernet, David; Peock, Susan; Adlard, Julian W; Barwell, Julian; Berg, Jonathan; Brady, Angela F; Brewer, Carole; Brice, Glen; Chapman, Cyril; Cook, Jackie; Davidson, Rosemarie; Donaldson, Alan; Douglas, Fiona; Greenhalgh, Lynn; Henderson, Alex; Izatt, Louise; Kumar, Ajith; Lalloo, Fiona; Miedzybrodzka, Zosia; Morrison, Patrick J; Paterson, Joan; Porteous, Mary; Rogers, Mark T; Shanley, Susan; Walker, Lisa; Ahmed, Munaza; Eccles, Diana; Evans, D Gareth; Donnelly, Peter; Easton, Douglas F; Stratton, Michael R; Rahman, Nazneen

    2012-02-15

    There have been few definitive examples of gene-gene interactions in humans. Through mutational analyses in 7325 individuals, we report four interactions (defined as departures from a multiplicative model) between mutations in the breast cancer susceptibility genes ATM and CHEK2 with BRCA1 and BRCA2 (case-only interaction between ATM and BRCA1/BRCA2 combined, P = 5.9 × 10(-4); ATM and BRCA1, P= 0.01; ATM and BRCA2, P= 0.02; CHEK2 and BRCA1/BRCA2 combined, P = 2.1 × 10(-4); CHEK2 and BRCA1, P= 0.01; CHEK2 and BRCA2, P= 0.01). The interactions are such that the resultant risk of breast cancer is lower than the multiplicative product of the constituent risks, and plausibly reflect the functional relationships of the encoded proteins in DNA repair. These findings have important implications for models of disease predisposition and clinical translation. PMID:22072393

  2. Circuit-wide Transcriptional Profiling Reveals Brain Region-Specific Gene Networks Regulating Depression Susceptibility.

    PubMed

    Bagot, Rosemary C; Cates, Hannah M; Purushothaman, Immanuel; Lorsch, Zachary S; Walker, Deena M; Wang, Junshi; Huang, Xiaojie; Schlüter, Oliver M; Maze, Ian; Peña, Catherine J; Heller, Elizabeth A; Issler, Orna; Wang, Minghui; Song, Won-Min; Stein, Jason L; Liu, Xiaochuan; Doyle, Marie A; Scobie, Kimberly N; Sun, Hao Sheng; Neve, Rachael L; Geschwind, Daniel; Dong, Yan; Shen, Li; Zhang, Bin; Nestler, Eric J

    2016-06-01

    Depression is a complex, heterogeneous disorder and a leading contributor to the global burden of disease. Most previous research has focused on individual brain regions and genes contributing to depression. However, emerging evidence in humans and animal models suggests that dysregulated circuit function and gene expression across multiple brain regions drive depressive phenotypes. Here, we performed RNA sequencing on four brain regions from control animals and those susceptible or resilient to chronic social defeat stress at multiple time points. We employed an integrative network biology approach to identify transcriptional networks and key driver genes that regulate susceptibility to depressive-like symptoms. Further, we validated in vivo several key drivers and their associated transcriptional networks that regulate depression susceptibility and confirmed their functional significance at the levels of gene transcription, synaptic regulation, and behavior. Our study reveals novel transcriptional networks that control stress susceptibility and offers fundamentally new leads for antidepressant drug discovery.

  3. Circuit-wide Transcriptional Profiling Reveals Brain Region-Specific Gene Networks Regulating Depression Susceptibility.

    PubMed

    Bagot, Rosemary C; Cates, Hannah M; Purushothaman, Immanuel; Lorsch, Zachary S; Walker, Deena M; Wang, Junshi; Huang, Xiaojie; Schlüter, Oliver M; Maze, Ian; Peña, Catherine J; Heller, Elizabeth A; Issler, Orna; Wang, Minghui; Song, Won-Min; Stein, Jason L; Liu, Xiaochuan; Doyle, Marie A; Scobie, Kimberly N; Sun, Hao Sheng; Neve, Rachael L; Geschwind, Daniel; Dong, Yan; Shen, Li; Zhang, Bin; Nestler, Eric J

    2016-06-01

    Depression is a complex, heterogeneous disorder and a leading contributor to the global burden of disease. Most previous research has focused on individual brain regions and genes contributing to depression. However, emerging evidence in humans and animal models suggests that dysregulated circuit function and gene expression across multiple brain regions drive depressive phenotypes. Here, we performed RNA sequencing on four brain regions from control animals and those susceptible or resilient to chronic social defeat stress at multiple time points. We employed an integrative network biology approach to identify transcriptional networks and key driver genes that regulate susceptibility to depressive-like symptoms. Further, we validated in vivo several key drivers and their associated transcriptional networks that regulate depression susceptibility and confirmed their functional significance at the levels of gene transcription, synaptic regulation, and behavior. Our study reveals novel transcriptional networks that control stress susceptibility and offers fundamentally new leads for antidepressant drug discovery. PMID:27181059

  4. Human retinoblastoma susceptibility gene: cloning, identification, and sequence.

    PubMed

    Lee, W H; Bookstein, R; Hong, F; Young, L J; Shew, J Y; Lee, E Y

    1987-03-13

    Recent evidence indicates the existence of a genetic locus in chromosome region 13q14 that confers susceptibility to retinoblastoma, a cancer of the eye in children. A gene encoding a messenger RNA (mRNA) of 4.6 kilobases (kb), located in the proximity of esterase D, was identified as the retinoblastoma susceptibility (RB) gene on the basis of chromosomal location, homozygous deletion, and tumor-specific alterations in expression. Transcription of this gene was abnormal in six of six retinoblastomas examined: in two tumors, RB mRNA was not detectable, while four others expressed variable quantities of RB mRNA with decreased molecular size of about 4.0 kb. In contrast, full-length RB mRNA was present in human fetal retina and placenta, and in other tumors such as neuroblastoma and medulloblastoma. DNA from retinoblastoma cells had a homozygous gene deletion in one case and hemizygous deletion in another case, while the remainder were not grossly different from normal human control DNA. The gene contains at least 12 exons distributed in a region of over 100 kb. Sequence analysis of complementary DNA clones yielded a single long open reading frame that could encode a hypothetical protein of 816 amino acids. A computer-assisted search of a protein sequence database revealed no closely related proteins. Features of the predicted amino acid sequence include potential metal-binding domains similar to those found in nucleic acid-binding proteins. These results provide a framework for further study of recessive genetic mechanisms in human cancers.

  5. Lack of association between the CHL1 gene and adolescent idiopathic scoliosis susceptibility in Han Chinese: a case-control study

    PubMed Central

    2014-01-01

    Background A previous genome-wide association study (GWAS) suggested a strong association between the single nucleotide polymorphism (SNP) rs10510181 in the proximity of the gene encoding a cell adhesion molecule with homology to L1CAM (CHL1) and adolescent idiopathic scoliosis (AIS) in Caucasians. To clarify the role of CHL1 in the etiopathogenesis of AIS, we performed a case-control replication study in a Han Chinese population. Methods Five hundred female AIS patients between 10 and 18 years of age, as well as 500 age- and sex-matched controls were included. This study was conducted as a 2-stage case-control analysis: initial screening for the association between AIS and SNPs in and around the CHL1 gene (186 cases and 169 controls) followed by a confirmation test (314 cases and 331 controls). rs10510181 and 4 SNPs (rs2055314, rs331894, rs2272522, and rs2272524) in the CHL1 gene were selected for genotyping. Results Putative associations were shown between AIS and rs10510181, rs2055314, and rs2272522 in stage I. However, the associations were not confirmed in stage II. For rs10510181, the genotype frequencies were GG 28.8%, GA 46.2%, and AA 25.0% in AIS patients and GG 29.8%, GA 48.8%, and AA 21.4% in controls. No significant difference was found in genotype distribution between cases and controls (P = 0.39). Similarly, the genotype and allele distribution were comparable between case and control for rs2055314 and rs2272522. Conclusions There was no statistical association between polymorphisms of the CHL1 gene and idiopathic scoliosis in a Chinese population. PMID:24512353

  6. NBN Gene Polymorphisms and Cancer Susceptibility: A Systemic Review

    PubMed Central

    Berardinelli, Francesco; di Masi, Alessandra; Antoccia, Antonio

    2013-01-01

    The relationship between DNA repair failure and cancer is well established as in the case of rare, high penetrant genes in high cancer risk families. Beside this, in the last two decades, several studies have investigated a possible association between low penetrant polymorphic variants in genes devoted to DNA repair pathways and risk for developing cancer. This relationship would be also supported by the observation that DNA repair processes may be modulated by sequence variants in DNA repair genes, leading to susceptibility to environmental carcinogens. In this framework, the aim of this review is to provide the reader with the state of the art on the association between common genetic variants and cancer risk, limiting the attention to single nucleotide polymorphisms (SNPs) of the NBN gene and providing the various odd ratios (ORs). In this respect, the NBN protein, together with MRE11 and RAD50, is part of the MRN complex which is a central player in the very early steps of sensing and processing of DNA double-strand breaks (DSBs), in telomere maintenance, in cell cycle control, and in genomic integrity in general. So far, many papers were devoted to ascertain possible association between common synonymous and non-synonymous NBN gene polymorphisms and increased cancer risk. However, the results still remain inconsistent and inconclusive also in meta-analysis studies for the most investigated E185Q NBN miscoding variant. PMID:24396275

  7. Gene-Wide Analysis Detects Two New Susceptibility Genes for Alzheimer's Disease

    PubMed Central

    Harold, Denise; Jones, Lesley; Holmans, Peter; Gerrish, Amy; Vedernikov, Alexey; Richards, Alexander; DeStefano, Anita L.; Lambert, Jean-Charles; Ibrahim-Verbaas, Carla A.; Naj, Adam C.; Sims, Rebecca; Jun, Gyungah; Bis, Joshua C.; Beecham, Gary W.; Grenier-Boley, Benjamin; Russo, Giancarlo; Thornton-Wells, Tricia A.; Denning, Nicola; Smith, Albert V.; Chouraki, Vincent; Thomas, Charlene; Ikram, M. Arfan; Zelenika, Diana; Vardarajan, Badri N.; Kamatani, Yoichiro; Lin, Chiao-Feng; Schmidt, Helena; Kunkle, Brian; Dunstan, Melanie L.; Vronskaya, Maria; Johnson, Andrew D.; Ruiz, Agustin; Bihoreau, Marie-Thérèse; Reitz, Christiane; Pasquier, Florence; Hollingworth, Paul; Hanon, Olivier; Fitzpatrick, Annette L.; Buxbaum, Joseph D.; Campion, Dominique; Crane, Paul K.; Baldwin, Clinton; Becker, Tim; Gudnason, Vilmundur; Cruchaga, Carlos; Craig, David; Amin, Najaf; Berr, Claudine; Lopez, Oscar L.; De Jager, Philip L.; Deramecourt, Vincent; Johnston, Janet A.; Evans, Denis; Lovestone, Simon; Letenneur, Luc; Hernández, Isabel; Rubinsztein, David C.; Eiriksdottir, Gudny; Sleegers, Kristel; Goate, Alison M.; Fiévet, Nathalie; Huentelman, Matthew J.; Gill, Michael; Brown, Kristelle; Kamboh, M. Ilyas; Keller, Lina; Barberger-Gateau, Pascale; McGuinness, Bernadette; Larson, Eric B.; Myers, Amanda J.; Dufouil, Carole; Todd, Stephen; Wallon, David; Love, Seth; Rogaeva, Ekaterina; Gallacher, John; George-Hyslop, Peter St; Clarimon, Jordi; Lleo, Alberto; Bayer, Anthony; Tsuang, Debby W.; Yu, Lei; Tsolaki, Magda; Bossù, Paola; Spalletta, Gianfranco; Proitsi, Petra; Collinge, John; Sorbi, Sandro; Garcia, Florentino Sanchez; Fox, Nick C.; Hardy, John; Naranjo, Maria Candida Deniz; Bosco, Paolo; Clarke, Robert; Brayne, Carol; Galimberti, Daniela; Scarpini, Elio; Bonuccelli, Ubaldo; Mancuso, Michelangelo; Siciliano, Gabriele; Moebus, Susanne; Mecocci, Patrizia; Zompo, Maria Del; Maier, Wolfgang; Hampel, Harald; Pilotto, Alberto; Frank-García, Ana; Panza, Francesco; Solfrizzi, Vincenzo; Caffarra, Paolo; Nacmias, Benedetta; Perry, William; Mayhaus, Manuel; Lannfelt, Lars; Hakonarson, Hakon; Pichler, Sabrina; Carrasquillo, Minerva M.; Ingelsson, Martin; Beekly, Duane; Alvarez, Victoria; Zou, Fanggeng; Valladares, Otto; Younkin, Steven G.; Coto, Eliecer; Hamilton-Nelson, Kara L.; Gu, Wei; Razquin, Cristina; Pastor, Pau; Mateo, Ignacio; Owen, Michael J.; Faber, Kelley M.; Jonsson, Palmi V.; Combarros, Onofre; O'Donovan, Michael C.; Cantwell, Laura B.; Soininen, Hilkka; Blacker, Deborah; Mead, Simon; Mosley, Thomas H.; Bennett, David A.; Harris, Tamara B.; Fratiglioni, Laura; Holmes, Clive; de Bruijn, Renee F. A. G.; Passmore, Peter; Montine, Thomas J.; Bettens, Karolien; Rotter, Jerome I.; Brice, Alexis; Morgan, Kevin; Foroud, Tatiana M.; Kukull, Walter A.; Hannequin, Didier; Powell, John F.; Nalls, Michael A.; Ritchie, Karen; Lunetta, Kathryn L.; Kauwe, John S. K.; Boerwinkle, Eric; Riemenschneider, Matthias; Boada, Mercè; Hiltunen, Mikko; Martin, Eden R.; Schmidt, Reinhold; Rujescu, Dan; Dartigues, Jean-François; Mayeux, Richard; Tzourio, Christophe; Hofman, Albert; Nöthen, Markus M.; Graff, Caroline; Psaty, Bruce M.; Haines, Jonathan L.; Lathrop, Mark; Pericak-Vance, Margaret A.; Launer, Lenore J.; Van Broeckhoven, Christine; Farrer, Lindsay A.; van Duijn, Cornelia M.; Ramirez, Alfredo

    2014-01-01

    Background Alzheimer's disease is a common debilitating dementia with known heritability, for which 20 late onset susceptibility loci have been identified, but more remain to be discovered. This study sought to identify new susceptibility genes, using an alternative gene-wide analytical approach which tests for patterns of association within genes, in the powerful genome-wide association dataset of the International Genomics of Alzheimer's Project Consortium, comprising over 7 m genotypes from 25,580 Alzheimer's cases and 48,466 controls. Principal Findings In addition to earlier reported genes, we detected genome-wide significant loci on chromosomes 8 (TP53INP1, p = 1.4×10−6) and 14 (IGHV1-67 p = 7.9×10−8) which indexed novel susceptibility loci. Significance The additional genes identified in this study, have an array of functions previously implicated in Alzheimer's disease, including aspects of energy metabolism, protein degradation and the immune system and add further weight to these pathways as potential therapeutic targets in Alzheimer's disease. PMID:24922517

  8. IL18 Gene Variants Influence the Susceptibility to Chagas Disease.

    PubMed

    Leon Rodriguez, Daniel A; Carmona, F David; Echeverría, Luis Eduardo; González, Clara Isabel; Martin, Javier

    2016-03-01

    Chagas disease is a parasitic disorder caused by the infection with the flagellated protozoan Trypanosoma cruzi. According to the World Health Organization, more than six million people are currently infected in endemic regions. Genetic factors have been proposed to influence predisposition to infection and development of severe clinical phenotypes like chronic Chagas cardiomyopathy (CCC). Interleukin 18 (IL18) encodes a proinflammatory cytokine that has been proposed to be involved in controlling T. cruzi infection. In this study, we analyzed the possible role of six IL18 gene variants (rs5744258, rs360722, rs2043055, rs187238, rs1946518 and rs360719), which cover most of the variation within the locus, in the susceptibility to infection by T. cruzi and/or CCC. In total, 1,171 individuals from a Colombian region endemic for Chagas disease, classified as seronegative (n = 595), seropositive asymptomatic (n = 175) and CCC (n = 401), were genotyped using TaqMan probes. Significant associations with T. cruzi infection were observed when comparing seronegative and seropositive individuals for rs187238 (P = 2.18E-03, OR = 0.77), rs360719 (P = 1.49E-03, OR = 0.76), rs2043055 (P = 2.52E-03, OR = 1.29), and rs1946518 (P = 0.0162, OR = 1.22). However, dependence analyses suggested that the association was mainly driven by the polymorphism rs360719. This variant is located within the promoter region of the IL18 gene, and it has been described that it creates a binding site for the transcription factor OCT-1 affecting IL-18 expression levels. In addition, no evidence of association was observed between any of the analyzed IL18 gene polymorphisms and the development of CCC. In summary, our data suggest that genetic variation within the promoter region of IL18 is directly involved in the susceptibility to infection by T. cruzi, which provides novel insight into disease pathophysiology and adds new perspectives to achieve a more effective disease control.

  9. Single-nucleotide polymorphism in microRNA-binding site of SULF1 target gene as a protective factor against the susceptibility to breast cancer: a case-control study

    PubMed Central

    Zhou, Qiong; Jiang, Yiwei; Yin, Wenjin; Wang, Yaohui; Lu, Jinsong

    2016-01-01

    Purpose Numerous clinical studies have suggested that chemopreventive drugs for breast cancer such as tamoxifen and exemestane can effectively reduce the incidence of estrogen receptor (ER)-positive breast cancer. However, it remains unclear how to identify those who are susceptible to ER-positive breast cancer. Accordingly, there is a great demand for a probe into the predisposing factors so as to provide precise chemoprevention. Recent evidence has indicated that ERα expression can be regulated by microRNAs (miRNAs), such as miR-206, in breast cancer. We assumed that single-nucleotide polymorphisms (SNPs) in the miR-206-binding sites of the target genes may be associated with breast cancer susceptibility with different ER statuses. Methods We genotyped the SNPs that reside in and around the miR-206-binding sites of two target genes – heparan sulfatase 1 (SULF1) and RPTOR-independent companion of mammalian target of rapamycin Complex 2 (RICTOR) – which were related to the progression or metastasis of breast cancer cells in 710 breast cancer patients and 294 controls by the matrix-assisted laser desorption ionization-time of flight mass spectrometry method. Modified odds ratios (ORs) with their 95% confidence intervals (CIs) were calculated by a multivariate logistic regression analysis to evaluate the potential association between the SNPs and breast cancer susceptibility. Results For rs3802278, which is located in the 3′-untranslated region (3′-UTR) of SULF1, the frequency of the AA genotype was less in breast cancer patients than that in the controls as compared to that of the GG + GA genotype not only for ER-positive breast cancer patients (adjusted OR =0.663, P=0.032) but also for hormone receptor-positive breast cancer patients (adjusted OR =0.610, P=0.018). Besides, the frequency of the AA genotype was less than that of the GG genotype between the ER-positive breast cancer patients and the controls (adjusted OR =0.791, P=0.038). For rs66916453

  10. Glucocorticoid Genes and the Developmental Origins of Asthma Susceptibility and Treatment Response

    PubMed Central

    Kho, Alvin T.; Chhabra, Divya; Qiu, Weiliang; Gaedigk, Roger; Vyhlidal, Carrie A.; Leeder, J. Steven; Barraza-Villarreal, Albino; London, Stephanie J.; Gilliland, Frank; Raby, Benjamin A.; Weiss, Scott T.; Tantisira, Kelan G.

    2015-01-01

    Antenatal corticosteroids enhance lung maturation. However, the importance of glucocorticoid genes on early lung development, asthma susceptibility, and treatment response remains unknown. We investigated whether glucocorticoid genes are important during lung development and their role in asthma susceptibility and treatment response. We identified genes that were differentially expressed by corticosteroids in two of three genomic datasets: lymphoblastoid cell lines of participants in the Childhood Asthma Management Program, a glucocorticoid chromatin immunoprecipitation/RNA sequencing experiment, or a murine model; these genes made up the glucocorticoid gene set (GCGS). Using gene expression profiles from 38 human fetal lungs and C57BL/6J murine fetal lungs, we identified developmental genes that were in the top 5% of genes contributing to the top three principal components (PCs) most highly associated with post-conceptional age. Glucocorticoid genes that were enriched in this set of developmental genes were then included in the developmental glucocorticoid gene set (DGGS). We then investigated whether glucocorticoid genes are important during lung development, and their role in asthma susceptibility and treatment response. A total of 232 genes were included in the GCGS. Analysis of gene expression demonstrated that glucocorticoid genes were enriched in lung development (P = 7.02 × 10−26). The developmental GCGS was enriched for genes that were differentially expressed between subjects with asthma and control subjects (P = 4.26 × 10−3) and were enriched after treatment of subjects with asthma with inhaled corticosteroids (P < 2.72 × 10−4). Our results show that glucocorticoid genes are overrepresented among genes implicated in fetal lung development. These genes influence asthma susceptibility and treatment response, suggesting their involvement in the early ontogeny of asthma. PMID:25192440

  11. NRAMP1 and VDR Gene Polymorphisms in Susceptibility to Tuberculosis in Venezuelan Population

    PubMed Central

    Fernández-Mestre, Mercedes; Villasmil, Ángel; Takiff, Howard; Fuentes Alcalá, Zhenia

    2015-01-01

    Natural resistance-associated macrophage protein (Nramp1) and the vitamin D receptor (VDR) are central components of the innate and adaptive immunity against Mycobacterium tuberculosis, and associations between susceptibility to tuberculosis and polymorphisms in the genes NRAMP and VDR have been sought in geographically diverse populations. We investigated associations of NRAMP1 and VDR gene polymorphisms with susceptibility to TB in the Venezuelan population. The results suggest the absence of any association between VDR variants FokI, ApaI, and TaqI and susceptibility to tuberculosis. In contrast, the NRAMP1 3′UTR variants were associated with susceptibility to M. tuberculosis infection, as seen in the comparisons between TST+ and TST− controls, and also with progression to TB disease, as shown in the comparisons between TB patients and TST+ controls. This study confirms the previously described association of the NRAMP1 3′UTR polymorphism with M. tuberculosis infection and disease progression. PMID:26578819

  12. Single Nucleotide Polymorphism in ATM Gene, Cooking Oil Fumes and Lung Adenocarcinoma Susceptibility in Chinese Female Non-Smokers: A Case-Control Study

    PubMed Central

    Shen, Li; Yin, Zhihua; Wu, Wei; Ren, Yangwu; Li, Xuelian; Zhou, Baosen

    2014-01-01

    Background The ataxia-telangiectasia mutated (ATM) gene plays an important role in the DNA double-strand breaks repair pathway. Single nucleotide polymorphisms (SNPs) of DNA repair genes are suspected to influence the risk of lung cancer. This study aimed to investigate the association between the ATM -111G>A (rs189037) polymorphism, environmental risk factors and the risk of lung adenocarcinoma in Chinese female non-smokers. Methods A hospital-based case-control study of 487 lung cancer patients and 516 matched cancer-free controls was conducted. Information concerning demographic and environmental risk factors was obtained for each case and control by a trained interviewer. After informed consent was obtained, 10 ml venous blood was collected from each subject for biomarker testing. Single nucleotide polymorphism was determined by using TaqMan method. Results This study showed that the individuals with ATM rs189037 AA genotype were at an increased risk for lung adenocarcinoma compared with those carrying the GA or GG genotype (adjusted odds ratios (OR) 1.44, 95% confidence interval (CI) 1.02–2.02, P = 0.039). The stratified analysis suggested that increased risk associated with ATM rs189037 AA genotype in individuals who never or seldom were exposed to cooking oil fumes (adjusted OR 1.89, 95%CI 1.03–3.49, P = 0.040). Conclusions ATM rs189037 might be associated with the risk of lung adenocarcinoma in Chinese non-smoking females. Furthermore, ATM rs189037 AA genotype might be a risk factor of lung adenocarcinoma among female non-smokers without cooking oil fume exposure. PMID:24819391

  13. Rheumatoid arthritis susceptibility genes: An overview

    PubMed Central

    Korczowska, Izabela

    2014-01-01

    Rheumatoid arthritis (RA) is a chronic, inflammatory autoimmune disease sustained by genetic factors. Various aspects of the genetic contribution to the pathogenetics and outcome of RA are still unknown. Several genes have been indicated so far in the pathogenesis of RA. Apart from human leukocyte antigen, large genome wide association studies have identified many loci involved in RA pathogenesis. These genes include protein tyrosine phosphatase, nonreceptor type 22, Peptidyl Arginine Deiminase type IV, signal transducer and activator of transcription 4, cytotoxic T-lymphocyte-associated protein 4, tumor necrosis factor-receptor associated factor 1/complement component 5, tumor necrosis factor and others. It is important to determine whether a combination of RA risk alleles are able to identify patients who will develop certain clinical outcomes, such myocardium infarction, severe infection or lymphoma, as well as to identify patients who will respond to biological medication therapy. PMID:25232530

  14. IL18 Gene Variants Influence the Susceptibility to Chagas Disease.

    PubMed

    Leon Rodriguez, Daniel A; Carmona, F David; Echeverría, Luis Eduardo; González, Clara Isabel; Martin, Javier

    2016-03-01

    Chagas disease is a parasitic disorder caused by the infection with the flagellated protozoan Trypanosoma cruzi. According to the World Health Organization, more than six million people are currently infected in endemic regions. Genetic factors have been proposed to influence predisposition to infection and development of severe clinical phenotypes like chronic Chagas cardiomyopathy (CCC). Interleukin 18 (IL18) encodes a proinflammatory cytokine that has been proposed to be involved in controlling T. cruzi infection. In this study, we analyzed the possible role of six IL18 gene variants (rs5744258, rs360722, rs2043055, rs187238, rs1946518 and rs360719), which cover most of the variation within the locus, in the susceptibility to infection by T. cruzi and/or CCC. In total, 1,171 individuals from a Colombian region endemic for Chagas disease, classified as seronegative (n = 595), seropositive asymptomatic (n = 175) and CCC (n = 401), were genotyped using TaqMan probes. Significant associations with T. cruzi infection were observed when comparing seronegative and seropositive individuals for rs187238 (P = 2.18E-03, OR = 0.77), rs360719 (P = 1.49E-03, OR = 0.76), rs2043055 (P = 2.52E-03, OR = 1.29), and rs1946518 (P = 0.0162, OR = 1.22). However, dependence analyses suggested that the association was mainly driven by the polymorphism rs360719. This variant is located within the promoter region of the IL18 gene, and it has been described that it creates a binding site for the transcription factor OCT-1 affecting IL-18 expression levels. In addition, no evidence of association was observed between any of the analyzed IL18 gene polymorphisms and the development of CCC. In summary, our data suggest that genetic variation within the promoter region of IL18 is directly involved in the susceptibility to infection by T. cruzi, which provides novel insight into disease pathophysiology and adds new perspectives to achieve a more effective disease control. PMID:27027876

  15. IL18 Gene Variants Influence the Susceptibility to Chagas Disease

    PubMed Central

    Leon Rodriguez, Daniel A; Carmona, F. David; Echeverría, Luis Eduardo; González, Clara Isabel; Martin, Javier

    2016-01-01

    Chagas disease is a parasitic disorder caused by the infection with the flagellated protozoan Trypanosoma cruzi. According to the World Health Organization, more than six million people are currently infected in endemic regions. Genetic factors have been proposed to influence predisposition to infection and development of severe clinical phenotypes like chronic Chagas cardiomyopathy (CCC). Interleukin 18 (IL18) encodes a proinflammatory cytokine that has been proposed to be involved in controlling T. cruzi infection. In this study, we analyzed the possible role of six IL18 gene variants (rs5744258, rs360722, rs2043055, rs187238, rs1946518 and rs360719), which cover most of the variation within the locus, in the susceptibility to infection by T. cruzi and/or CCC. In total, 1,171 individuals from a Colombian region endemic for Chagas disease, classified as seronegative (n = 595), seropositive asymptomatic (n = 175) and CCC (n = 401), were genotyped using TaqMan probes. Significant associations with T. cruzi infection were observed when comparing seronegative and seropositive individuals for rs187238 (P = 2.18E-03, OR = 0.77), rs360719 (P = 1.49E-03, OR = 0.76), rs2043055 (P = 2.52E-03, OR = 1.29), and rs1946518 (P = 0.0162, OR = 1.22). However, dependence analyses suggested that the association was mainly driven by the polymorphism rs360719. This variant is located within the promoter region of the IL18 gene, and it has been described that it creates a binding site for the transcription factor OCT-1 affecting IL-18 expression levels. In addition, no evidence of association was observed between any of the analyzed IL18 gene polymorphisms and the development of CCC. In summary, our data suggest that genetic variation within the promoter region of IL18 is directly involved in the susceptibility to infection by T. cruzi, which provides novel insight into disease pathophysiology and adds new perspectives to achieve a more effective disease control. PMID:27027876

  16. Evidence for schizophrenia susceptibility alleles in the Indian population: An association of neurodevelopmental genes in case-control and familial samples.

    PubMed

    Jajodia, Ajay; Kaur, Harpreet; Kumari, Kalpana; Gupta, Meenal; Baghel, Ruchi; Srivastava, Ankit; Sood, Mamta; Chadda, Rakesh Kumar; Jain, Sanjeev; Kukreti, Ritushree

    2015-03-01

    Schizophrenia is a severe psychiatric disorder with lifetime prevalence of ~1% worldwide. A genotyping study was conducted using a custom panel of Illumina 1536 SNPs in 840 schizophrenia cases and 876 controls (351 patients and 385 controls from North India; and 436 patients, 401 controls and 143 familial samples with 53 probands containing 37 complete and 16 incomplete trios from South India). Meta-analysis of this population of Indo-European and Dravidian ancestry identified three strongly associated variants with schizophrenia: STT3A (rs548181, p=1.47×10(-5)), NRG1 (rs17603876, p=8.66×10(-5)) and GRM7 (rs3864075, p=4.06×10(-3)). Finally, a meta-analysis was conducted comparing our data with data from the Schizophrenia Psychiatric Genome-Wide Association Study Consortium (PGC-SCZ) that supported rs548181 (p=1.39×10(-7)). In addition, combined analysis of sporadic case-control association and a transmission disequilibrium test in familial samples from South Indian population identified three associations: rs1062613 (p=3.12×10(-3)), a functional promoter variant of HTR3A; rs6710782 (p=3.50×10(-3)), an intronic variant of ERBB4; and rs891903 (p=1.05×10(-2)), an intronic variant of EBF1. The results support the risk variants observed in the earlier published work and suggest a potential role of neurodevelopmental genes in the schizophrenia pathogenesis.

  17. Genetic Susceptibility to Vitiligo: GWAS Approaches for Identifying Vitiligo Susceptibility Genes and Loci.

    PubMed

    Shen, Changbing; Gao, Jing; Sheng, Yujun; Dou, Jinfa; Zhou, Fusheng; Zheng, Xiaodong; Ko, Randy; Tang, Xianfa; Zhu, Caihong; Yin, Xianyong; Sun, Liangdan; Cui, Yong; Zhang, Xuejun

    2016-01-01

    Vitiligo is an autoimmune disease with a strong genetic component, characterized by areas of depigmented skin resulting from loss of epidermal melanocytes. Genetic factors are known to play key roles in vitiligo through discoveries in association studies and family studies. Previously, vitiligo susceptibility genes were mainly revealed through linkage analysis and candidate gene studies. Recently, our understanding of the genetic basis of vitiligo has been rapidly advancing through genome-wide association study (GWAS). More than 40 robust susceptible loci have been identified and confirmed to be associated with vitiligo by using GWAS. Most of these associated genes participate in important pathways involved in the pathogenesis of vitiligo. Many susceptible loci with unknown functions in the pathogenesis of vitiligo have also been identified, indicating that additional molecular mechanisms may contribute to the risk of developing vitiligo. In this review, we summarize the key loci that are of genome-wide significance, which have been shown to influence vitiligo risk. These genetic loci may help build the foundation for genetic diagnosis and personalize treatment for patients with vitiligo in the future. However, substantial additional studies, including gene-targeted and functional studies, are required to confirm the causality of the genetic variants and their biological relevance in the development of vitiligo.

  18. Genetic Susceptibility to Vitiligo: GWAS Approaches for Identifying Vitiligo Susceptibility Genes and Loci

    PubMed Central

    Shen, Changbing; Gao, Jing; Sheng, Yujun; Dou, Jinfa; Zhou, Fusheng; Zheng, Xiaodong; Ko, Randy; Tang, Xianfa; Zhu, Caihong; Yin, Xianyong; Sun, Liangdan; Cui, Yong; Zhang, Xuejun

    2016-01-01

    Vitiligo is an autoimmune disease with a strong genetic component, characterized by areas of depigmented skin resulting from loss of epidermal melanocytes. Genetic factors are known to play key roles in vitiligo through discoveries in association studies and family studies. Previously, vitiligo susceptibility genes were mainly revealed through linkage analysis and candidate gene studies. Recently, our understanding of the genetic basis of vitiligo has been rapidly advancing through genome-wide association study (GWAS). More than 40 robust susceptible loci have been identified and confirmed to be associated with vitiligo by using GWAS. Most of these associated genes participate in important pathways involved in the pathogenesis of vitiligo. Many susceptible loci with unknown functions in the pathogenesis of vitiligo have also been identified, indicating that additional molecular mechanisms may contribute to the risk of developing vitiligo. In this review, we summarize the key loci that are of genome-wide significance, which have been shown to influence vitiligo risk. These genetic loci may help build the foundation for genetic diagnosis and personalize treatment for patients with vitiligo in the future. However, substantial additional studies, including gene-targeted and functional studies, are required to confirm the causality of the genetic variants and their biological relevance in the development of vitiligo. PMID:26870082

  19. Prostate cancer susceptibility loci: finding the genes.

    PubMed

    Ostrander, Elanie A; Johannesson, Bo

    2008-01-01

    Studies to date suggest that PC is a genetically very heterogeneous disease. High-risk families, in which multiple men are affected likely, reflect the contributions of a number of genes, some that are rare and highly penetrant, while others are more common and weakly penetrant. In this review, we have discussed only the first type of loci, and found that the identification of such genomic regions is a formidable problem. Replication between seemingly similar data sets is weak, likely reflecting the older age of onset associated with the disease, the inability to collect affected individuals from more than two generations in a family, and the variation seen in disease presentation, in addition to the underlying locus heterogeneity. Indeed, the definition of PC is ever changing, as diagnostic criteria and tools for pinpointing early lesions improve. Are we making progress? Clearly the answer is yes. The ability to divide large data sets into homogenous subset of families likely to share common genetic under-pinnings has improved power to identify loci and reproducibility between loci is now more common. Indeed, several groups report linkage to loci on chromosomes 1, 17, 19, and 22. Key to our continued success is our ever increasing ability to understand the disease. Identifying the subset of men who are likely to get clinically significant disease is the goal of genetic studies like these, and identifying the underlying loci is the key for developing diagnostics. The willingness of the community to work together has been an important factor in the successes the community has enjoyed to date, and will likely be as important as we move forward to untangle the genetics of this complex and common disorder.

  20. Genetic variation in the immunosuppression pathway genes and breast cancer susceptibility: a pooled analysis of 42,510 cases and 40,577 controls from the Breast Cancer Association Consortium.

    PubMed

    Lei, Jieping; Rudolph, Anja; Moysich, Kirsten B; Behrens, Sabine; Goode, Ellen L; Bolla, Manjeet K; Dennis, Joe; Dunning, Alison M; Easton, Douglas F; Wang, Qin; Benitez, Javier; Hopper, John L; Southey, Melissa C; Schmidt, Marjanka K; Broeks, Annegien; Fasching, Peter A; Haeberle, Lothar; Peto, Julian; Dos-Santos-Silva, Isabel; Sawyer, Elinor J; Tomlinson, Ian; Burwinkel, Barbara; Marmé, Frederik; Guénel, Pascal; Truong, Thérèse; Bojesen, Stig E; Flyger, Henrik; Nielsen, Sune F; Nordestgaard, Børge G; González-Neira, Anna; Menéndez, Primitiva; Anton-Culver, Hoda; Neuhausen, Susan L; Brenner, Hermann; Arndt, Volker; Meindl, Alfons; Schmutzler, Rita K; Brauch, Hiltrud; Hamann, Ute; Nevanlinna, Heli; Fagerholm, Rainer; Dörk, Thilo; Bogdanova, Natalia V; Mannermaa, Arto; Hartikainen, Jaana M; Van Dijck, Laurien; Smeets, Ann; Flesch-Janys, Dieter; Eilber, Ursula; Radice, Paolo; Peterlongo, Paolo; Couch, Fergus J; Hallberg, Emily; Giles, Graham G; Milne, Roger L; Haiman, Christopher A; Schumacher, Fredrick; Simard, Jacques; Goldberg, Mark S; Kristensen, Vessela; Borresen-Dale, Anne-Lise; Zheng, Wei; Beeghly-Fadiel, Alicia; Winqvist, Robert; Grip, Mervi; Andrulis, Irene L; Glendon, Gord; García-Closas, Montserrat; Figueroa, Jonine; Czene, Kamila; Brand, Judith S; Darabi, Hatef; Eriksson, Mikael; Hall, Per; Li, Jingmei; Cox, Angela; Cross, Simon S; Pharoah, Paul D P; Shah, Mitul; Kabisch, Maria; Torres, Diana; Jakubowska, Anna; Lubinski, Jan; Ademuyiwa, Foluso; Ambrosone, Christine B; Swerdlow, Anthony; Jones, Michael; Chang-Claude, Jenny

    2016-01-01

    Immunosuppression plays a pivotal role in assisting tumors to evade immune destruction and promoting tumor development. We hypothesized that genetic variation in the immunosuppression pathway genes may be implicated in breast cancer tumorigenesis. We included 42,510 female breast cancer cases and 40,577 controls of European ancestry from 37 studies in the Breast Cancer Association Consortium (2015) with available genotype data for 3595 single nucleotide polymorphisms (SNPs) in 133 candidate genes. Associations between genotyped SNPs and overall breast cancer risk, and secondarily according to estrogen receptor (ER) status, were assessed using multiple logistic regression models. Gene-level associations were assessed based on principal component analysis. Gene expression analyses were conducted using RNA sequencing level 3 data from The Cancer Genome Atlas for 989 breast tumor samples and 113 matched normal tissue samples. SNP rs1905339 (A>G) in the STAT3 region was associated with an increased breast cancer risk (per allele odds ratio 1.05, 95 % confidence interval 1.03-1.08; p value = 1.4 × 10(-6)). The association did not differ significantly by ER status. On the gene level, in addition to TGFBR2 and CCND1, IL5 and GM-CSF showed the strongest associations with overall breast cancer risk (p value = 1.0 × 10(-3) and 7.0 × 10(-3), respectively). Furthermore, STAT3 and IL5 but not GM-CSF were differentially expressed between breast tumor tissue and normal tissue (p value = 2.5 × 10(-3), 4.5 × 10(-4) and 0.63, respectively). Our data provide evidence that the immunosuppression pathway genes STAT3, IL5, and GM-CSF may be novel susceptibility loci for breast cancer in women of European ancestry.

  1. Postgenomics, uncertain futures, and the familiarization of susceptibility genes

    PubMed Central

    Chilibeck, Gillian; Lock, Margaret; Sehdev, Megha

    2016-01-01

    This paper draws on empirical findings from interview studies in the USA and Canada to interrogate the idea that expanding practices of genetic testing are likely to transform kin and family relations in fundamental ways. We argue that in connection with common adult onset disorders in which susceptibility genes with low predictive power are implicated it is unlikely that family relationships will be radically altered as a result of learning about either individual or family genotypes. Rather, pre-existing family dynamics and ideas about family susceptibilities for disease may be reinforced. The case of the ApoE gene and its relationship to Alzheimer’s disease is used as an illustrative example. We found that “postgenomic” thinking, in which complexity of disease causation is emphasized, is readily apparent in informant narratives. PMID:20570031

  2. Variants in the inflammatory IL6 and MPO genes modulate stroke susceptibility through main effects and gene–gene interactions

    PubMed Central

    Manso, Helena; Krug, Tiago; Sobral, João; Albergaria, Isabel; Gaspar, Gisela; Ferro, José M; Oliveira, Sofia A; Vicente, Astrid M

    2011-01-01

    There is substantial evidence that inflammation within the central nervous system contributes to stroke risk and recovery. Inflammatory conditions increase stroke risk, and the inflammatory response is of major importance in recovery and healing processes after stroke. We investigated the role of inflammatory genes IL1B, IL6, MPO, and TNF in stroke susceptibility and recovery in a population sample of 672 patients and 530 controls, adjusting for demographic, clinical and lifestyle risk factors, and stroke severity parameters. We also considered the likely complexity of inflammatory mechanisms in stroke, by assessing the combined effects of multiple genes. Two interleukin 6 (IL6) and one myeloperoxidase (MPO) single-nucleotide polymorphisms were significantly associated with stroke risk (0.022gene variants of low to moderate effect in stroke risk. An epistatic interaction between the IL6 and MPO genes was also identified in association with stroke susceptibility (P=0.031 after 1,000 permutations). In a subset of 546 patients, one IL6 haplotype was associated with stroke outcome at 3 months (correctedP=0.024), an intriguing finding warranting further validation. Our findings support the association of the IL6 gene and present novel evidence for the involvement of MPO in stroke susceptibility, suggesting a modulation of stroke risk by main gene effects, clinical and lifestyle factors, and gene–gene interactions. PMID:21407237

  3. Susceptibility to ulcerative colitis in Hungarian patients determined by gene-gene interactions

    PubMed Central

    Sarlos, Patricia; Varszegi, Dalma; Csongei, Veronika; Magyari, Lili; Jaromi, Luca; Nagy, Lajos; Melegh, Bela

    2014-01-01

    AIM: To study the inflammatory bowel disease-5 locus (IBD5) and interleukin-23 receptor (IL23R) gene variants in UC patients and test for gene-gene interaction. METHODS: The study population (n = 625) was comprised of 320 unrelated ulcerative colitis (UC) patients with Caucasian origin and 316 age- and gender-matched, healthy controls. Five variants in the IBD5 locus (IGR2198a_1 rs11739135, IGR2096a_1 rs12521868, IGR2230a_1 rs17622208, SLC22A4 rs1050152 and SLC22A5 rs2631367) and two of the IL23R gene (rs1004819, rs2201841) were analysed. PCR and restriction fragment length polymorphism methods were used for genotyping, the SLC22A4 rs1050152 genotypes were determined by direct sequencing. Interactions and specific genotype combinations of the seven variants were tested by binary logistic regression analysis. The IL23R genotypes were stratified by IBD5 genotypes for further interaction analyses. RESULTS: For the IL23R rs1004819 A allele we found significantly higher allele frequency (P = 0.032) in UC patients compared to control subjects. The SNP rs1004819 showed significant association with UC risk for carriers (P = 0.004, OR = 1.606; 95%CI: 1.160-2.223) and the SNP rs2201841 for homozygotes (P = 0.030, OR = 1.983; 95%CI: 1.069-3.678). Individually none of the IBD5 markers conferred risk to UC development. There was no evidence for statistical interaction either between IBD5 loci and IL23R genes using logistic regression analysis. After genotype stratification, we could detect a positive association on the background of rs1004819 A allele for SLC22A4 T, SLC22A5 C, IGR2198a_1 C or IGR2096a_1 T allele, the highest OR was calculated in the presence of SLC22A4 T allele (P = 0.005, OR = 2.015; 95%CI: 1.230-3.300). There was no association with UC for any combinations of rs1004819 and IGR2230a_1. The IL23R rs2201841 homozygous genotype and IBD5 carrier status together did not confer susceptibility for UC. CONCLUSION: The present study has shown that UC susceptibility

  4. CARD15 Gene Polymorphisms Are Associated with Tuberculosis Susceptibility in Chinese Holstein Cows

    PubMed Central

    Liu, Tong; Tu, Wenji; Li, Wengui; Dong, Guodong; Xu, Cong; Qin, Bo; Liu, Kaihua; Yang, Jie; Chai, Jun; Shi, Xianwei; Zhang, Yifang

    2015-01-01

    Bovine tuberculosis (BTB) is a significant veterinary and financial problem in many parts of the world. Associations between specific host genes and susceptibility to mycobacterial infections, such as tuberculosis, have been reported in several species. The objective of this study was to identify and evaluate the relationship of single-nucleotide polymorphisms (SNPs) in the CARD15 gene with susceptibility to BTB in Chinese Holstein cows. DNA samples from 201 Chinese Holstein cows (103 cases and 98 controls) were collected from Kunming City, Yuxi City, and Dali City in China. SNPs in the CARD15 gene were assessed using polymerase chain reaction (PCR) and restriction fragment length polymorphism-polymerase chain reaction (RFLP-PCR). Case-control association testing and statistical analysis identified six SNPs associated with susceptibility to BTB in Chinese Holstein cows. The frequency of genotypes C/T, A/G, A/G, A/G, C/T, and A/G in E4 (-37), 208, 1644, 1648, 1799, and E10 (+107), respectively, was significantly higher in cases than in controls, and also the alleles C, A, A, G, T, and A, respectively, were associated with a greater relative risk in cases than in controls. The distribution of two haplotypes, TGGACA and CAGACA, was significantly different between cases and controls. Overall, this case-control study suggested that E4 (-37)(C/T), 208(A/G), 1644(A/G), 1648(A/G), 1799(C/T), and E10 (+107)(A/G) in the CARD15 gene were significantly associated with susceptibility to BTB in Chinese Holstein cows and that haplotypes TGGACA and CAGACA could be used as genetic markers in marker-assisted breeding programs for breeding cows with high resistance to BTB. PMID:26244859

  5. An integrated genomic analysis of gene-function correlation on schizophrenia susceptibility genes.

    PubMed

    Chu, Tearina T; Liu, Ying

    2010-05-01

    Schizophrenia is a highly complex inheritable disease characterized by numerous genetic susceptibility elements, each contributing a modest increase in risk for the disease. Although numerous linkage or association studies have identified a large set of schizophrenia-associated loci, many are controversial. In addition, only a small portion of these loci overlaps with the large cumulative pool of genes that have shown changes of expression in schizophrenia. Here, we applied a genomic gene-function approach to identify susceptibility loci that show direct effect on gene expression, leading to functional abnormalities in schizophrenia. We carried out an integrated analysis by cross-examination of the literature-based susceptibility loci with the schizophrenia-associated expression gene list obtained from our previous microarray study (Journal of Human Genetics (2009) 54: 665-75) using bioinformatic tools, followed by confirmation of gene expression changes using qPCR. We found nine genes (CHGB, SLC18A2, SLC25A27, ESD, C4A/C4B, TCP1, CHL1 and CTNNA2) demonstrate gene-function correlation involving: synapse and neurotransmission; energy metabolism and defense mechanisms; and molecular chaperone and cytoskeleton. Our findings further support the roles of these genes in genetic influence and functional consequences on the development of schizophrenia. It is interesting to note that four of the nine genes are located on chromosome 6, suggesting a special chromosomal vulnerability in schizophrenia.

  6. Non-major histocompatibility complex rheumatoid arthritis susceptibility genes.

    PubMed

    Kunz, Manfred; Ibrahim, Saleh M

    2011-01-01

    Recent results from genetic and treatment studies have shed new light on chronic inflammatory and autoimmune diseases such as rheumatoid arthritis (RA). In particular, genome-wide association studies (GWAS) have provided supportive evidence that RA is a disease with a strong genetic background. Interestingly, a series of candidate genes have been identified outside of the classical major histocompatibility (MHC) locus, which had long been regarded as the major contributor to the pathogenesis of this disease. Among these genes, PTPN22 plays an outstanding role. CD40, STAT4, PRM1, and TNFAIP3 also seem to be of relevance. Interestingly, there is a significant overlap between RA susceptibility genes and those of other autoimmune diseases such as systemic lupus erythematosus (SLE) and type 1 diabetes, which suggests common pathogenic mechanisms. Genetic analyses may not only provide new insights into the pathogenesis of RA, but may also open new avenues for therapeutic approaches, because overactive immune-signaling pathways might specifically be addressed by biologic therapies. However, the predictive value of many of the recent findings of large-scale genetic analyses in identifying new genetic polymorphisms remains low. We describe the current knowledge about the role of non-MHC genes in the pathogenesis of rheumatoid arthritis. PMID:21542789

  7. Susceptibility genes for schizophrenia: mutant models, endophenotypes and psychobiology.

    PubMed

    O'Tuathaigh, Colm M P; Desbonnet, Lieve; Moran, Paula M; Waddington, John L

    2012-01-01

    Schizophrenia is characterised by a multifactorial aetiology that involves genetic liability interacting with epigenetic and environmental factors to increase risk for developing the disorder. A consensus view is that the genetic component involves several common risk alleles of small effect and/or rare but penetrant copy number variations. Furthermore, there is increasing evidence for broader, overlapping genetic-phenotypic relationships in psychosis; for example, the same susceptibility genes also confer risk for bipolar disorder. Phenotypic characterisation of genetic models of candidate risk genes and/or putative pathophysiological processes implicated in schizophrenia, as well as examination of epidemiologically relevant gene × environment interactions in these models, can illuminate molecular and pathobiological mechanisms involved in schizophrenia. The present chapter outlines both the evidence from phenotypic studies in mutant mouse models related to schizophrenia and recently described mutant models addressing such gene × environment interactions. Emphasis is placed on evaluating the extent to which mutant phenotypes recapitulate the totality of the disease phenotype or model selective endophenotypes. We also discuss new developments and trends in relation to the functional genomics of psychosis which might help to inform on the construct validity of mutant models of schizophrenia and highlight methodological challenges in phenotypic evaluation that relate to such models.

  8. Evidence From Human and Zebrafish That GPC1 Is a Biliary Atresia Susceptibility Gene

    PubMed Central

    Cui, Shuang; Leyva-Vega, Melissa; Tsai, Ellen A.; Eauclaire, Steven F.; Glessner, Joseph T.; Hakonarson, Hakon; Devoto, Marcella; Haber, Barbara A.; Spinner, Nancy B.; Matthews, Randolph P.

    2013-01-01

    BACKGROUND & AIMS Biliary atresia (BA) is a progressive fibroinflammatory disorder of infants involving the extrahepatic and intrahepatic biliary tree. Its etiology is unclear but is believed to involve exposure of a genetically susceptible individual to certain environmental factors. BA occurs exclusively in the neonatal liver, so variants of genes expressed during hepatobiliary development could affect susceptibility. Genome-wide association studies previously identified a potential region of interest at 2q37. We continued these studies to narrow the region and identify BA susceptibility genes. METHODS We searched for copy number variants that were increased among patients with BA (n = 61) compared with healthy individuals (controls; n = 5088). After identifying a candidate gene, we investigated expression patterns of orthologues in zebrafish liver and the effects of reducing expression, with morpholino antisense oligonucleotides, on biliary development, gene expression, and signal transduction. RESULTS We observed a statistically significant increase in deletions at 2q37.3 in patients with BA that resulted in deletion of one copy of GPC1, which encodes glypican 1, a heparan sulfate proteoglycan that regulates Hedgehog signaling and inflammation. Knockdown of gpc1 in zebrafish led to developmental biliary defects. Exposure of the gpc1 morphants to cyclopamine, a Hedgehog antagonist, partially rescued the gpc1-knockdown phenotype. Injection of zebrafish with recombinant Sonic Hedgehog led to biliary defects similar to those of the gpc1 morphants. Liver samples from patients with BA had reduced levels of apical GPC1 in cholangiocytes compared with samples from controls. CONCLUSIONS Based on genetic analysis of patients with BA and zebrafish, GPC1 appears to be a BA susceptibility gene. These findings also support a role for Hedgehog signaling in the pathogenesis of BA. PMID:23336978

  9. Whole Gene Capture Analysis of 15 CRC Susceptibility Genes in Suspected Lynch Syndrome Patients

    PubMed Central

    van Wezel, Tom; Jagmohan-Changur, Shantie C.; Ruano, Dina; van der Klift, Heleen M.; van den Akker, Brendy E. W. M.; Laros, Jeroen F. J.; van Galen, Michiel; Wagner, Anja; Letteboer, Tom G. W.; Gómez-García, Encarna B.; Tops, Carli M. J.; Vasen, Hans F.; Devilee, Peter; Hes, Frederik J.; Morreau, Hans; Wijnen, Juul T.

    2016-01-01

    Background and Aims Lynch Syndrome (LS) is caused by pathogenic germline variants in one of the mismatch repair (MMR) genes. However, up to 60% of MMR-deficient colorectal cancer cases are categorized as suspected Lynch Syndrome (sLS) because no pathogenic MMR germline variant can be identified, which leads to difficulties in clinical management. We therefore analyzed the genomic regions of 15 CRC susceptibility genes in leukocyte DNA of 34 unrelated sLS patients and 11 patients with MLH1 hypermethylated tumors with a clear family history. Methods Using targeted next-generation sequencing, we analyzed the entire non-repetitive genomic sequence, including intronic and regulatory sequences, of 15 CRC susceptibility genes. In addition, tumor DNA from 28 sLS patients was analyzed for somatic MMR variants. Results Of 1979 germline variants found in the leukocyte DNA of 34 sLS patients, one was a pathogenic variant (MLH1 c.1667+1delG). Leukocyte DNA of 11 patients with MLH1 hypermethylated tumors was negative for pathogenic germline variants in the tested CRC susceptibility genes and for germline MLH1 hypermethylation. Somatic DNA analysis of 28 sLS tumors identified eight (29%) cases with two pathogenic somatic variants, one with a VUS predicted to pathogenic and LOH, and nine cases (32%) with one pathogenic somatic variant (n = 8) or one VUS predicted to be pathogenic (n = 1). Conclusions This is the first study in sLS patients to include the entire genomic sequence of CRC susceptibility genes. An underlying somatic or germline MMR gene defect was identified in ten of 34 sLS patients (29%). In the remaining sLS patients, the underlying genetic defect explaining the MMRdeficiency in their tumors might be found outside the genomic regions harboring the MMR and other known CRC susceptibility genes. PMID:27300758

  10. Genetic control of susceptibility of rats to gastric carcinoma.

    PubMed

    Ohgaki, H; Kawachi, T; Matsukura, N; Morino, K; Miyamoto, M; Sugimura, T

    1983-08-01

    Genetic control of the induction of gastric tumors by N-methyl-N'-nitro-N-nitrosoguanidine (MNNG) was studied in susceptible ACI rats, resistant Buffalo rats, and their F1 and F2 offspring. Both sexes of all strains, initially 7 to 9 weeks old, were given MNNG at a concentration of 83 micrograms/ml in their drinking water for 32 weeks and were sacrificed at experimental Week 72. The incidence of gastric adenocarcinoma in ACI rats was 80% in males and 47% in females; in Buffalo rats, the incidence was 18% in males and 0% in females. F1 hybrids showed the same resistance to MNNG as did Buffalo rats; the incidence of gastric adenocarcinoma was 17% in males and 8% in females. These results suggest that resistance to induction of gastric adenocarcinoma by MNNG is a dominant characteristic. The incidence of gastric adenocarcinoma in the F2 generation was 36% in males and 14% in females, which is close to the 3:1 ratio expected from the segregation of a single resistant gene. In ACI and Buffalo strains and their hybrids, males were more susceptible than females to induction of gastric carcinoma by MNNG. Intestinal tumors were observed mainly in the duodenum and jejunum in both strains and their hybrids, and the incidences were as follows: ACI: males, 67% and females 42%; Buffalo: males, 12% and females, 18%; F1: males, 18% and females, 15%; and F2: males, 15% and females, 19%. Thus, there seems to be a common genetic basis for both gastric and intestinal carcinogenesis by MNNG.

  11. Genes Expressed Differentially in Hessian Fly Larvae Feeding in Resistant and Susceptible Plants.

    PubMed

    Chen, Ming-Shun; Liu, Sanzhen; Wang, Haiyan; Cheng, Xiaoyan; El Bouhssini, Mustapha; Whitworth, R Jeff

    2016-01-01

    The Hessian fly, Mayetiola destructor, is a destructive pest of wheat worldwide and mainly controlled by deploying resistant cultivars. In this study, we investigated the genes that were expressed differentially between larvae in resistant plants and those in susceptible plants through RNA sequencing on the Illumina platform. Informative genes were 11,832, 14,861, 15,708, and 15,071 for the comparisons between larvae in resistant versus susceptible plants for 0.5, 1, 3, and 5 days, respectively, after larvae had reached the feeding site. The transcript abundance corresponding to 5401, 6902, 8457, and 5202 of the informative genes exhibited significant differences (p ≤ 0.05) in the respective paired comparisons. Overall, genes involved in nutrient metabolism, RNA and protein synthesis exhibited lower transcript abundance in larvae from resistant plants, indicating that resistant plants inhibited nutrient metabolism and protein production in larvae. Interestingly, the numbers of cytochrome P450 genes with higher transcript abundance in larvae from resistant plants were comparable to, or higher than those with lower transcript abundance, indicating that toxic chemicals from resistant plants may have played important roles in Hessian fly larval death. Our study also identified several families of genes encoding secreted salivary gland proteins (SSGPs) that were expressed at early stage of 1(st) instar larvae and with more genes with higher transcript abundance in larvae from resistant plants. Those SSGPs are candidate effectors with important roles in plant manipulation. PMID:27529231

  12. Toll-like receptors gene polymorphisms may confer increased susceptibility to breast cancer development.

    PubMed

    Theodoropoulos, George E; Saridakis, Vasilios; Karantanos, Theodoros; Michalopoulos, Nikolaos V; Zagouri, Flora; Kontogianni, Panagiota; Lymperi, Maria; Gazouli, Maria; Zografos, George C

    2012-08-01

    Toll-like receptor (TLR) activation may be an important event in tumor cell immune evasion. TLR2 and TLR4 gene polymorphisms have been related to increased susceptibility to cancer development in various organs. 261 patients and 480 health individuals were investigated for genotype and allelic frequencies of a 22-bp nucleotide deletion (-196 to -174del) in the promoter of TLR2 gene as well as two polymorphisms causing amino acid substitutions (Asp299Gly and Thr399Ile) in TLR4 gene. As far as (-196 to -174del) in TLR2 gene is concerned ins/del and del/del genotypes and del allele were significantly more frequent in breast cancer patients compared to healthy controls. Considering Asp299Gly replacement of TLR4 gene, Gly carriers (Asp/Gly & Gly/Gly genotype) and Gly allele were overrepresented among the breast cancer cases. The -174 to -196del of TLR2 gene and Asp299Gly of TLR4 gene polymorphisms may confer an increased susceptibility to breast cancer development.

  13. Genes Expressed Differentially in Hessian Fly Larvae Feeding in Resistant and Susceptible Plants

    PubMed Central

    Chen, Ming-Shun; Liu, Sanzhen; Wang, Haiyan; Cheng, Xiaoyan; El Bouhssini, Mustapha; Whitworth, R. Jeff

    2016-01-01

    The Hessian fly, Mayetiola destructor, is a destructive pest of wheat worldwide and mainly controlled by deploying resistant cultivars. In this study, we investigated the genes that were expressed differentially between larvae in resistant plants and those in susceptible plants through RNA sequencing on the Illumina platform. Informative genes were 11,832, 14,861, 15,708, and 15,071 for the comparisons between larvae in resistant versus susceptible plants for 0.5, 1, 3, and 5 days, respectively, after larvae had reached the feeding site. The transcript abundance corresponding to 5401, 6902, 8457, and 5202 of the informative genes exhibited significant differences (p ≤ 0.05) in the respective paired comparisons. Overall, genes involved in nutrient metabolism, RNA and protein synthesis exhibited lower transcript abundance in larvae from resistant plants, indicating that resistant plants inhibited nutrient metabolism and protein production in larvae. Interestingly, the numbers of cytochrome P450 genes with higher transcript abundance in larvae from resistant plants were comparable to, or higher than those with lower transcript abundance, indicating that toxic chemicals from resistant plants may have played important roles in Hessian fly larval death. Our study also identified several families of genes encoding secreted salivary gland proteins (SSGPs) that were expressed at early stage of 1st instar larvae and with more genes with higher transcript abundance in larvae from resistant plants. Those SSGPs are candidate effectors with important roles in plant manipulation. PMID:27529231

  14. Correlation of genetic polymorphism of vascular endothelial growth factor gene with susceptibility to lung cancer.

    PubMed

    Liu, C; Zhou, X; Gao, F; Qi, Z; Zhang, Z; Guo, Y

    2015-06-01

    The aim of the study is to study the correlation of genetic polymorphism of vascular endothelial growth factor (VEGF) gene with susceptibility to primary lung cancer. A total of 414 patients with primary lung cancer and 338 healthy volunteers were enrolled in this case-control study from September 2008 to October 2011. Gene identification with PCR-RFLP (polymerase chain reaction-based restriction fragment length polymorphism) was used to detect in white blood cells from the subjects the single-nucleotide polymorphisms (SNP) of VEGF gene, including +405G/C, -460 T/C, -1154G/A, -2578C/A sites. Association of genotypes or haplotypes with susceptibility of lung cancer was analyzed with unconditional logistic regression adjusted by gender and age. Smoking was significantly associated with increased risk of lung cancer. Gene phenotypic analysis demonstrated that C allele of +405G/C in VEGF gene was significantly associated increased risk of lung cancer in males (P=0.0094, odds ratio=1.634.3), as that with carrying GCTC haplotype (odds ratio=1.349), whereas carrying GACG had decreased risk for lung cancer (odds ratio=0.044). No relationship existed between 460 T/C, -1154G/A, -2578C/A alleles of VEGF gene and risk of lung cancer. VEGF gene polymorphism may have a role in the development of lung cancer.

  15. Lateral organ boundaries 1 is a disease susceptibility gene for citrus bacterial canker disease

    PubMed Central

    Hu, Yang; Zhang, Junli; Jia, Hongge; Sosso, Davide; Li, Ting; Frommer, Wolf B.; Yang, Bing; White, Frank F.; Wang, Nian; Jones, Jeffrey B.

    2014-01-01

    Citrus bacterial canker (CBC) disease occurs worldwide and incurs considerable costs both from control measures and yield losses. Bacteria that cause CBC require one of six known type III transcription activator-like (TAL) effector genes for the characteristic pustule formation at the site of infection. Here, we show that Xanthomonas citri subspecies citri strain Xcc306, with the type III TAL effector gene pthA4 or with the distinct yet biologically equivalent gene pthAw from strain XccAw, induces two host genes, CsLOB1 and CsSWEET1, in a TAL effector-dependent manner. CsLOB1 is a member of the Lateral Organ Boundaries (LOB) gene family of transcription factors, and CsSWEET1 is a homolog of the SWEET sugar transporter and rice disease susceptibility gene. Both TAL effectors drive expression of CsLOB1 and CsSWEET1 promoter reporter gene fusions when coexpressed in citrus or Nicotiana benthamiana. Artificially designed TAL effectors directed to sequences in the CsLOB1 promoter region, but not the CsSWEET1 promoter, promoted pustule formation and higher bacterial leaf populations. Three additional distinct TAL effector genes, pthA*, pthB, and pthC, also direct pustule formation and expression of CsLOB1. Unlike pthA4 and pthAw, pthB and pthC do not promote the expression of CsSWEET1. CsLOB1 expression was associated with the expression of genes associated with cell expansion. The results indicate that CBC-inciting species of Xanthomonas exploit a single host disease susceptibility gene by altering the expression of an otherwise developmentally regulated gene using any one of a diverse set of TAL effector genes in the pathogen populations. PMID:24474801

  16. Lateral organ boundaries 1 is a disease susceptibility gene for citrus bacterial canker disease.

    PubMed

    Hu, Yang; Zhang, Junli; Jia, Hongge; Sosso, Davide; Li, Ting; Frommer, Wolf B; Yang, Bing; White, Frank F; Wang, Nian; Jones, Jeffrey B

    2014-01-28

    Citrus bacterial canker (CBC) disease occurs worldwide and incurs considerable costs both from control measures and yield losses. Bacteria that cause CBC require one of six known type III transcription activator-like (TAL) effector genes for the characteristic pustule formation at the site of infection. Here, we show that Xanthomonas citri subspecies citri strain Xcc306, with the type III TAL effector gene pthA4 or with the distinct yet biologically equivalent gene pthAw from strain XccA(w), induces two host genes, CsLOB1 and CsSWEET1, in a TAL effector-dependent manner. CsLOB1 is a member of the Lateral Organ Boundaries (LOB) gene family of transcription factors, and CsSWEET1 is a homolog of the SWEET sugar transporter and rice disease susceptibility gene. Both TAL effectors drive expression of CsLOB1 and CsSWEET1 promoter reporter gene fusions when coexpressed in citrus or Nicotiana benthamiana. Artificially designed TAL effectors directed to sequences in the CsLOB1 promoter region, but not the CsSWEET1 promoter, promoted pustule formation and higher bacterial leaf populations. Three additional distinct TAL effector genes, pthA*, pthB, and pthC, also direct pustule formation and expression of CsLOB1. Unlike pthA4 and pthAw, pthB and pthC do not promote the expression of CsSWEET1. CsLOB1 expression was associated with the expression of genes associated with cell expansion. The results indicate that CBC-inciting species of Xanthomonas exploit a single host disease susceptibility gene by altering the expression of an otherwise developmentally regulated gene using any one of a diverse set of TAL effector genes in the pathogen populations. PMID:24474801

  17. Lateral organ boundaries 1 is a disease susceptibility gene for citrus bacterial canker disease.

    PubMed

    Hu, Yang; Zhang, Junli; Jia, Hongge; Sosso, Davide; Li, Ting; Frommer, Wolf B; Yang, Bing; White, Frank F; Wang, Nian; Jones, Jeffrey B

    2014-01-28

    Citrus bacterial canker (CBC) disease occurs worldwide and incurs considerable costs both from control measures and yield losses. Bacteria that cause CBC require one of six known type III transcription activator-like (TAL) effector genes for the characteristic pustule formation at the site of infection. Here, we show that Xanthomonas citri subspecies citri strain Xcc306, with the type III TAL effector gene pthA4 or with the distinct yet biologically equivalent gene pthAw from strain XccA(w), induces two host genes, CsLOB1 and CsSWEET1, in a TAL effector-dependent manner. CsLOB1 is a member of the Lateral Organ Boundaries (LOB) gene family of transcription factors, and CsSWEET1 is a homolog of the SWEET sugar transporter and rice disease susceptibility gene. Both TAL effectors drive expression of CsLOB1 and CsSWEET1 promoter reporter gene fusions when coexpressed in citrus or Nicotiana benthamiana. Artificially designed TAL effectors directed to sequences in the CsLOB1 promoter region, but not the CsSWEET1 promoter, promoted pustule formation and higher bacterial leaf populations. Three additional distinct TAL effector genes, pthA*, pthB, and pthC, also direct pustule formation and expression of CsLOB1. Unlike pthA4 and pthAw, pthB and pthC do not promote the expression of CsSWEET1. CsLOB1 expression was associated with the expression of genes associated with cell expansion. The results indicate that CBC-inciting species of Xanthomonas exploit a single host disease susceptibility gene by altering the expression of an otherwise developmentally regulated gene using any one of a diverse set of TAL effector genes in the pathogen populations.

  18. Susceptibility to ozone-induced inflammation. II. Separate loci control responses to acute and subacute exposures

    SciTech Connect

    Kleeberger, S.R.; Levitt, R.C.; Zhang, L.Y. )

    1993-01-01

    We demonstrated previously that inbred strains of mice are differentially susceptible to acute (3 h) and subacute (48 h) exposures to 2 parts per million (ppm) ozone (O3) and 0.30 ppm O3, respectively. Genetic studies with O3-resistant C3H/HeJ and O3-susceptible C57BL/6J strains have indicated that susceptibility to each of these O3 exposures is under Mendelian (single gene) control. In the present study, we hypothesized that the same gene controls susceptibility to the airway inflammatory responses to 2 ppm and 0.30 ppm O3 exposures. To test this hypothesis, airway inflammation was induced in 10 BXH and 16 BXD recombinant inbred (RI) strains of mice by acute as well as subacute O3 exposures. Airway inflammation was assessed by counting the number of polymorphonuclear leukocytes (PMNs) in bronchoalveolar lavage (BAL) returns obtained immediately after 48-h subacute exposure to 0.30 ppm O3, or 6 h after 3 h acute exposure to 2 ppm O3. Each RI strain was classified as susceptible or resistant to each exposure, based on a comparison of mean numbers of PMNs with those of the respective progenitor strains. For each RI set, a phenotypic strain distribution pattern (SDP) was thus derived for each exposure regimen, and the SDPs were then compared for concordance. Among the BXH RI strains, 4 of 10 responded discordantly to the two exposures: 3 were susceptible to acute exposure and resistant to subacute exposure, whereas 1 was conversely susceptible. Among the BXD RI strains, 4 of 16 were discordant: 1 was susceptible to acute exposure, and resistant to subacute exposure, whereas 3 were conversely susceptible.

  19. Treating psoriasis by targeting its susceptibility gene Rel.

    PubMed

    Fan, Tingting; Wang, Shaowen; Yu, Linjiang; Yi, Huqiang; Liu, Ruiling; Geng, Wenwen; Wan, Xiaochun; Ma, Yifan; Cai, Lintao; Chen, Youhai H; Ruan, Qingguo

    2016-04-01

    Psoriasis is a chronic inflammatory disorder of the skin. Accumulating evidence indicates that the Rel gene, a member of the NF-κB family, is a risk factor for the disease. We sought to investigate whether psoriasis can be prevented by directly targeting the Rel gene transcript, i.e., the c-Rel mRNA. Using chemically-modified c-Rel specific siRNA (siRel) and poly(ethylene glycol)-b-poly(l-lysine)-b-poly(l-leucine) (PEG-PLL-PLLeu) micelles, we successfully knocked down the expression of c-Rel, and showed that the expression of cytokine IL-23, a direct target of c-Rel that can drive the development of IL-17-producing T cells, was markedly inhibited. More importantly, treating mice with siRel not only prevented but also ameliorated imiquimod (IMQ)-induced psoriasis. Mechanistic studies showed that siRel treatment down-regulated the expression of multiple inflammatory cytokines. Taken together, these results indicate that the susceptibility gene Rel can be targeted to treat and prevent psoriasis.

  20. Gene-asbestos interaction in malignant pleural mesothelioma susceptibility.

    PubMed

    Tunesi, Sara; Ferrante, Daniela; Mirabelli, Dario; Andorno, Silvano; Betti, Marta; Fiorito, Giovanni; Guarrera, Simonetta; Casalone, Elisabetta; Neri, Monica; Ugolini, Donatella; Bonassi, Stefano; Matullo, Giuseppe; Dianzani, Irma; Magnani, Corrado

    2015-10-01

    Asbestos exposure is the main risk factor for malignant pleural mesothelioma (MPM), a rare aggressive tumor. Nevertheless, on average less than 10% of subjects highly exposed to asbestos develop MPM, suggesting the possible involvement of other risk factors. To identify the genetic factors that may modulate the risk of MPM, we conducted a gene-environment interaction analysis including asbestos exposure and 15 single nucleotide polymorphisms (SNPs) previously identified through a genome-wide association study on Italian subjects. In the present study, we assessed gene-asbestos interaction on MPM risk using relative excess risk due to interaction and synergy index for additive interaction and V index for multiplicative interaction. Generalized multifactor dimensionality reduction (GMDR) analyses were also performed. Positive deviation from additivity was found for six SNPs (rs1508805, rs2501618, rs4701085, rs4290865, rs10519201, rs763271), and four of them (rs1508805, rs2501618, rs4701085, rs10519201) deviated also from multiplicative models. However, after Bonferroni correction, deviation from multiplicative model was still significant for rs1508805 and rs4701085 only. GMDR analysis showed a strong MPM risk due to asbestos exposure and suggested a possible synergistic effect between asbestos exposure and rs1508805, rs2501618 and rs5756444. Our results suggested that gene-asbestos interaction may play an additional role on MPM susceptibility, given that asbestos exposure appears as the main risk factor.

  1. Treating psoriasis by targeting its susceptibility gene Rel.

    PubMed

    Fan, Tingting; Wang, Shaowen; Yu, Linjiang; Yi, Huqiang; Liu, Ruiling; Geng, Wenwen; Wan, Xiaochun; Ma, Yifan; Cai, Lintao; Chen, Youhai H; Ruan, Qingguo

    2016-04-01

    Psoriasis is a chronic inflammatory disorder of the skin. Accumulating evidence indicates that the Rel gene, a member of the NF-κB family, is a risk factor for the disease. We sought to investigate whether psoriasis can be prevented by directly targeting the Rel gene transcript, i.e., the c-Rel mRNA. Using chemically-modified c-Rel specific siRNA (siRel) and poly(ethylene glycol)-b-poly(l-lysine)-b-poly(l-leucine) (PEG-PLL-PLLeu) micelles, we successfully knocked down the expression of c-Rel, and showed that the expression of cytokine IL-23, a direct target of c-Rel that can drive the development of IL-17-producing T cells, was markedly inhibited. More importantly, treating mice with siRel not only prevented but also ameliorated imiquimod (IMQ)-induced psoriasis. Mechanistic studies showed that siRel treatment down-regulated the expression of multiple inflammatory cytokines. Taken together, these results indicate that the susceptibility gene Rel can be targeted to treat and prevent psoriasis. PMID:26993753

  2. Case-only exome sequencing and complex disease susceptibility gene discovery: study design considerations.

    PubMed

    Wu, Lang; Schaid, Daniel J; Sicotte, Hugues; Wieben, Eric D; Li, Hu; Petersen, Gloria M

    2015-01-01

    Whole exome sequencing (WES) provides an unprecedented opportunity to identify the potential aetiological role of rare functional variants in human complex diseases. Large-scale collaborations have generated germline WES data on patients with a number of diseases, especially cancer, but less often on healthy controls under the same sequencing procedures. These data can be a valuable resource for identifying new disease susceptibility loci if study designs are appropriately applied. This review describes suggested strategies and technical considerations when focusing on case-only study designs that use WES data in complex disease scenarios. These include variant filtering based on frequency and functionality, gene prioritisation, interrogation of different data types and targeted sequencing validation. We propose that if case-only WES designs were applied in an appropriate manner, new susceptibility genes containing rare variants for human complex diseases can be detected.

  3. Susceptibility genes and pharmacogenetics in ocular inflammatory disorders.

    PubMed

    Liu, Baoying; Sen, H Nida; Nussenblatt, Robert

    2012-10-01

    Ocular inflammatory disorders encompass uveitis, scleritis, keratitis, and other ocular diseases where inflammation may play a role. Although age-related macular degeneration (AMD) is clinically characterized by degenerative changes in the macula, accumulating evidence suggests that inflammation plays an important role in its pathogenesis. Pharmacogenetics is the study of the influence of genetic variation and its effects on drug efficacy or toxicity. There are no pharmacogenetic studies in uveitis and very few in AMD therapies. In this review, the authors describe the susceptibility genes related to uveitis and AMD and the important advances in pharmacogenetic research in relation to AMD and uveitis therapy. They propose polygenic and composite models of treatment responses to fulfill individualized drug therapy in intraocular inflammatory disorders. PMID:22974049

  4. Association Between TRAF6 Gene Polymorphisms and Susceptibility of Ischemic Stroke in Southern Chinese Han Population.

    PubMed

    Su, Li; Chen, Ziwen; Yan, Yan; Liang, Baoyun; Xie, Juanjuan; Chen, Qing; Tan, Jinjing; Gu, Lian

    2015-11-01

    The tumor necrosis factor receptor-associated factor 6 (TRAF6) gene encodes a protein that acts downstream of the Toll-like receptor (TLR) pathway. TLRs activate inflammatory cascades and mediate inflammatory injury after cerebral ischemia. However, the role of TFAR6 gene polymorphisms in ischemic stroke (IS) remains unknown. This study aims to investigate the associations of TRAF6 gene polymorphisms with susceptibility to IS and IS-related quantitative traits in Southern Chinese Han population. A total of 816 IS cases and 816 age- and gender-matched controls were included. Two variants of the TRAF6 gene (rs5030411 and rs5030416) were genotyped using the Sequenom MassARRAY iPLEX platform. Our study showed that rs5030416 was significantly associated with increased susceptibility to IS in the additive model [ORadj 1.25(1.04-1.51), P adj = 0.019, P Bc = 0.038] and dominant model [ORadj 1.23(1.04-1.60), P adj = 0.021, P Bc = 0.042] after adjusting by age and sex and applying a Bonferroni correction. No significant association was found between rs5030411 and IS susceptibility (all P > 0.05). The haplotype rs5030416 (allele C)-rs5030411 (allele C) was significantly associated with IS susceptibility (P adj = 0.015). Moreover, a significant association of rs5030411 with TC levels in IS patients under the additive model [β 0.16(0.01-0.30), P adj = 0.034] and recessive model [β 0.45(0.12-0.78), P adj = 0.007] was observed after adjustment by age and sex. This association remained statistically significant under the recessive model (P Bc = 0.042) after Bonferroni correction. Our results suggest that TRAF6 gene polymorphisms may be involved in the pathogenesis of IS.

  5. Early Differential Gene Expression in Haemocytes from Resistant and Susceptible Biomphalaria glabrata Strains in Response to Schistosoma mansoni

    PubMed Central

    Lockyer, Anne E.; Emery, Aidan M.; Kane, Richard A.; Walker, Anthony J.; Mayer, Claus D.; Mitta, Guillaume; Coustau, Christine; Adema, Coen M.; Hanelt, Ben; Rollinson, David; Noble, Leslie R.; Jones, Catherine S.

    2012-01-01

    The outcome of infection in the host snail Biomphalaria glabrata with the digenean parasite Schistosoma mansoni is determined by the initial molecular interplay occurring between them. The mechanisms by which schistosomes evade snail immune recognition to ensure survival are not fully understood, but one possibility is that the snail internal defence system is manipulated by the schistosome enabling the parasite to establish infection. This study provides novel insights into the nature of schistosome resistance and susceptibility in B. glabrata at the transcriptomic level by simultaneously comparing gene expression in haemocytes from parasite-exposed and control groups of both schistosome-resistant and schistosome-susceptible strains, 2 h post exposure to S. mansoni miracidia, using an novel 5K cDNA microarray. Differences in gene expression, including those for immune/stress response, signal transduction and matrix/adhesion genes were identified between the two snail strains and tests for asymmetric distributions of gene function also identified immune-related gene expression in resistant snails, but not in susceptible. Gene set enrichment analysis revealed that genes involved in mitochondrial electron transport, ubiquinone biosynthesis and electron carrier activity were consistently up-regulated in resistant snails but down-regulated in susceptible. This supports the hypothesis that schistosome-resistant snails recognize schistosomes and mount an appropriate defence response, while in schistosome-susceptible snails the parasite suppresses this defence response, early in infection. PMID:23300533

  6. SRGAP1 Is a Candidate Gene for Papillary Thyroid Carcinoma Susceptibility

    PubMed Central

    He, Huiling; Bronisz, Agnieszka; Liyanarachchi, Sandya; Nagy, Rebecca; Li, Wei; Huang, Yungui; Akagi, Keiko; Saji, Motoyasu; Kula, Dorota; Wojcicka, Anna; Sebastian, Nikhil; Wen, Bernard; Puch, Zbigniew; Kalemba, Michal; Stachlewska, Elzbieta; Czetwertynska, Malgorzata; Dlugosinska, Joanna; Dymecka, Kinga; Ploski, Rafal; Krawczyk, Marek; Morrison, Patrick J.; Ringel, Matthew D.; Kloos, Richard T.; Jazdzewski, Krystian; Symer, David E.; Vieland, Veronica J.; Ostrowski, Michael; Jarząb, Barbara

    2013-01-01

    Background: Papillary thyroid carcinoma (PTC) shows high heritability, yet efforts to find predisposing genes have been largely negative. Objectives: The objective of this study was to identify susceptibility genes for PTC. Methods: A genome-wide linkage analysis was performed in 38 families. Targeted association study and screening were performed in 2 large cohorts of PTC patients and controls. Candidate DNA variants were tested in functional studies. Results: Linkage analysis and association studies identified the Slit-Robo Rho GTPase activating protein 1 gene (SRGAP1) in the linkage peak as a candidate gene. Two missense variants, Q149H and A275T, localized in the Fes/CIP4 homology domain segregated with the disease in 1 family each. One missense variant, R617C, located in the RhoGAP domain occurred in 1 family. Biochemical assays demonstrated that the ability to inactivate CDC42, a key function of SRGAP1, was severely impaired by the Q149H and R617C variants. Conclusions: Our findings suggest that SRGAP1 is a candidate gene in PTC susceptibility. SRGAP1 is likely a low-penetrant gene, possibly of a modifier type. PMID:23539728

  7. Knockdown of MLO genes reduces susceptibility to powdery mildew in grapevine

    PubMed Central

    Pessina, Stefano; Lenzi, Luisa; Perazzolli, Michele; Campa, Manuela; Dalla Costa, Lorenza; Urso, Simona; Valè, Giampiero; Salamini, Francesco; Velasco, Riccardo; Malnoy, Mickael

    2016-01-01

    Erysiphe necator is the causal agent of powdery mildew (PM), one of the most destructive diseases of grapevine. PM is controlled by sulfur-based and synthetic fungicides, which every year are dispersed into the environment. This is why PM-resistant varieties should become a priority for sustainable grapevine and wine production. PM resistance can be achieved in other crops by knocking out susceptibility S-genes, such as those residing at genetic loci known as MLO (Mildew Locus O). All MLO S-genes of dicots belong to the phylogenetic clade V, including grapevine genes VvMLO7, 11 and 13, which are upregulated during PM infection, and VvMLO6, which is not upregulated. Before adopting a gene-editing approach to knockout candidate S-genes, the evidence that loss of function of MLO genes can reduce PM susceptibility is necessary. This paper reports the knockdown through RNA interference of VvMLO6, 7, 11 and 13. The knockdown of VvMLO6, 11 and 13 did not decrease PM severity, whereas the knockdown of VvMLO7 in combination with VvMLO6 and VvMLO11 reduced PM severity up to 77%. The knockdown of VvMLO7 and VvMLO6 seemed to be important for PM resistance, whereas a role for VvMLO11 does not seem likely. Cell wall appositions (papillae) were present in both resistant and susceptible lines in response to PM attack. Thirteen genes involved in defense were less upregulated in infected mlo plants, highlighting the early mlo-dependent disruption of PM invasion. PMID:27390621

  8. Knockdown of MLO genes reduces susceptibility to powdery mildew in grapevine.

    PubMed

    Pessina, Stefano; Lenzi, Luisa; Perazzolli, Michele; Campa, Manuela; Dalla Costa, Lorenza; Urso, Simona; Valè, Giampiero; Salamini, Francesco; Velasco, Riccardo; Malnoy, Mickael

    2016-01-01

    Erysiphe necator is the causal agent of powdery mildew (PM), one of the most destructive diseases of grapevine. PM is controlled by sulfur-based and synthetic fungicides, which every year are dispersed into the environment. This is why PM-resistant varieties should become a priority for sustainable grapevine and wine production. PM resistance can be achieved in other crops by knocking out susceptibility S-genes, such as those residing at genetic loci known as MLO (Mildew Locus O). All MLO S-genes of dicots belong to the phylogenetic clade V, including grapevine genes VvMLO7, 11 and 13, which are upregulated during PM infection, and VvMLO6, which is not upregulated. Before adopting a gene-editing approach to knockout candidate S-genes, the evidence that loss of function of MLO genes can reduce PM susceptibility is necessary. This paper reports the knockdown through RNA interference of VvMLO6, 7, 11 and 13. The knockdown of VvMLO6, 11 and 13 did not decrease PM severity, whereas the knockdown of VvMLO7 in combination with VvMLO6 and VvMLO11 reduced PM severity up to 77%. The knockdown of VvMLO7 and VvMLO6 seemed to be important for PM resistance, whereas a role for VvMLO11 does not seem likely. Cell wall appositions (papillae) were present in both resistant and susceptible lines in response to PM attack. Thirteen genes involved in defense were less upregulated in infected mlo plants, highlighting the early mlo-dependent disruption of PM invasion. PMID:27390621

  9. Optimal control in a model of malaria with differential susceptibility

    NASA Astrophysics Data System (ADS)

    Hincapié, Doracelly; Ospina, Juan

    2014-06-01

    A malaria model with differential susceptibility is analyzed using the optimal control technique. In the model the human population is classified as susceptible, infected and recovered. Susceptibility is assumed dependent on genetic, physiological, or social characteristics that vary between individuals. The model is described by a system of differential equations that relate the human and vector populations, so that the infection is transmitted to humans by vectors, and the infection is transmitted to vectors by humans. The model considered is analyzed using the optimal control method when the control consists in using of insecticide-treated nets and educational campaigns; and the optimality criterion is to minimize the number of infected humans, while keeping the cost as low as is possible. One first goal is to determine the effects of differential susceptibility in the proposed control mechanism; and the second goal is to determine the algebraic form of the basic reproductive number of the model. All computations are performed using computer algebra, specifically Maple. It is claimed that the analytical results obtained are important for the design and implementation of control measures for malaria. It is suggested some future investigations such as the application of the method to other vector-borne diseases such as dengue or yellow fever; and also it is suggested the possible application of free software of computer algebra like Maxima.

  10. CREB1 gene polymorphisms combined with environmental risk factors increase susceptibility to major depressive disorder (MDD)

    PubMed Central

    Wang, Peng; Yang, Yanjie; Yang, Xiuxian; Qiu, Xiaohui; Qiao, Zhengxue; Wang, Lin; Zhu, Xiongzhao; Sui, Hong; Ma, Jingsong

    2015-01-01

    Major depressive disorder (MDD) is one of the most severe psychiatric disorders. The objective of this study was to explore the effects of CREB1 gene polymorphisms on risk of developing MDD and the joint effects of gene-environment interactions. Genotyping was performed by Taqman allelic discrimination assay among 586 patients and 586 healthy controls. A significant impact on rs6740584 genotype distribution was found for childhood trauma (P = 0.015). We did not find an association of CREB1 polymorphisms with MDD susceptibility. However, we found a significantly increased risk associated with the interactions of CREB1 polymorphisms and drinking (OR = 11.67, 95% CI = 2.52-54.18; OR = 11.52, 95% CI = 2.55-51.95 for rs11904814; OR = 4.18, 95% CI = 1.87-9.38; OR = 5.02, 95% CI = 2.27-11.14 for rs6740584; OR = 7.58, 95% CI = 2.05-27.98; OR = 7.59, 95% CI = 2.12-27.14 for rs2553206; OR = 8.37, 95% CI = 3.02-23.23; OR = 7.84, 95% CI = 2.93-20.98 for rs2551941). We also noted that CREB polymorphisms combined with family harmony and childhood trauma conferred increased susceptibility for MDD. In conclusion, polymorphisms in the CREB gene may not be independently associated with MDD risk, but they are likely to confer increased susceptibility by interacting with environmental risk factors in the Chinese population. PMID:25755794

  11. Association Between Polymorphisms of DRD2, COMT, DBH, and MAO-A Genes and Migraine Susceptibility

    PubMed Central

    Chen, Hu; Ji, Chun-Xue; Zhao, Lian-Li; Kong, Xiang-Jun; Zeng, Xian-Tao

    2015-01-01

    Abstract Some epidemiological studies have investigated the relationship between genetic polymorphisms of DRD2, COMT, DBH, and MAO-A and migraine susceptibility, but the results are still inconsistent. Thus, our aim was to further assess the association through a meta-analysis. We examined 5 single nucleotide polymorphisms (SNPs) in 4 genes, including DRD2 rs1799732 and rs6275, DBH rs7239728, MAI-A-VNTR, and COMT rs4680, and performed a meta-analysis of 11 published case–control studies including 3138 cases and 4126 controls. Odd ratios (ORs) with 95% confidence intervals (95% CIs) were used to evaluate the association between the 5 genetic polymorphisms and migraine susceptibility. There was no significant relationship between migraine susceptibility and 4 genetic polymorphisms of DRD2 rs1799732 and rs6275, DBH rs7239728, and MAO-A-VNTR. Nevertheless, decreased risk of migraine was observed to be in association with COMT rs4680 polymorphism in overall analysis (AA vs. GG + GA: OR = 0.76, 95% CI = 0.60–0.97, PHet > 0.642, I2 = 0), and in Caucasian group after subgroup analysis (AA vs. GG + GA: OR = 0.75, 95% CI = 0.58–0.96, PHet > 0.433, I2 = 0). Studied polymorphisms of DRD2, DBH, and MAO-A genes may not be associated with migraine susceptibility. However, COMT rs4680 polymorphism may decrease the risk of migraine, especially in Caucasians. The failure to evaluate environmental influence and provide adjusted effect size estimates highlights the need for additional studies in a large number to take these factors into consideration, thus better elucidating the role of the genes tested in migraine. PMID:26632697

  12. Gene expression profiling in the thiamethoxam resistant and susceptible B-biotype sweetpotato whitefly, Bemisia tabaci.

    PubMed

    Xie, Wen; Yang, Xin; Wang, Shao-Ii; Wu, Qing-jun; Yang, Ni-na; Li, Ru-mei; Jiao, Xiao-guo; Pan, Hui-peng; Liu, Bai-ming; Feng, Yun-tao; Xu, Bao-yun; Zhou, Xu-guo; Zhang, You-jun

    2012-01-01

    Thiamethoxam has been used as a major insecticide to control the B-biotype sweetpotato whitefly, Bemisia tabaci (Gennadius) (Hemiptera: Aleyrodidae). Due to its excessive use, a high level of resistance to thiamethoxam has developed worldwide over the past several years. To better understand the molecular mechanisms underlying this resistance in B. tabaci, gene profiles between the thiamethoxam-resistant and thiamethoxam-susceptible strains were investigated using the suppression subtractive hybridization (SSH) library approach. A total of 72 and 52 upand down-regulated genes were obtained from the forward and reverse SSH libraries, respectively. These expressed sequence tags (ESTs) belong to several functional categories based on their gene ontology annotation. Some categories such as cell communication, response to abiotic stimulus, lipid particle, and nuclear envelope were identified only in the forward library of thiamethoxam-resistant strains. In contrast, categories such as behavior, cell proliferation, nutrient reservoir activity, sequence-specific DNA binding transcription factor activity, and signal transducer activity were identified solely in the reverse library. To study the validity of the SSH method, 16 differentially expressed genes from both forward and reverse SSH libraries were selected randomly for further analyses using quantitative realtime PCR (qRT-PCR). The qRT-PCR results were fairly consistent with the SSH results; however, only 50% of the genes showed significantly different expression profiles between the thiamethoxam-resistant and thiamethoxam-susceptible whiteflies. Among these genes, a putative NAD-dependent methanol dehydrogenase was substantially over-expressed in the thiamethoxamresistant adults compared to their susceptible counterparts. The distributed profiles show that it was highly expressed during the egg stage, and was most abundant in the abdomen of adult females. PMID:22957505

  13. Gene Expression Profiling in the Thiamethoxam Resistant and Susceptible B-biotype Sweetpotato Whitefly, Bemisia tabaci

    PubMed Central

    Xie, Wen; Yang, Xin; Wang, Shao-Ii; Wu, Qing-jun; Yang, Ni-na; Li, Ru-mei; Jiao, Xiaoguo; Pan, Hui-peng; Liu, Bai-ming; Feng, Yun-tao; Xu, Bao-yun; Zhou, Xu-guo; Zhang, You-jun

    2012-01-01

    Thiamethoxam has been used as a major insecticide to control the B-biotype sweetpotato whitefly, Bemisia tabaci (Gennadius) (Hemiptera: Aleyrodidae). Due to its excessive use, a high level of resistance to thiamethoxam has developed worldwide over the past several years. To better understand the molecular mechanisms underlying this resistance in B. tabaci, gene profiles between the thiamethoxam-resistant and thiamethoxam-susceptible strains were investigated using the suppression subtractive hybridization (SSH) library approach. A total of 72 and 52 upand down-regulated genes were obtained from the forward and reverse SSH libraries, respectively. These expressed sequence tags (ESTs) belong to several functional categories based on their gene ontology annotation. Some categories such as cell communication, response to abiotic stimulus, lipid particle, and nuclear envelope were identified only in the forward library of thiamethoxam-resistant strains. In contrast, categories such as behavior, cell proliferation, nutrient reservoir activity, sequence-specific DNA binding transcription factor activity, and signal transducer activity were identified solely in the reverse library. To study the validity of the SSH method, 16 differentially expressed genes from both forward and reverse SSH libraries were selected randomly for further analyses using quantitative realtime PCR (qRT-PCR). The qRT-PCR results were fairly consistent with the SSH results; however, only 50% of the genes showed significantly different expression profiles between the thiamethoxam-resistant and thiamethoxam-susceptible whiteflies. Among these genes, a putative NAD-dependent methanol dehydrogenase was substantially over-expressed in the thiamethoxamresistant adults compared to their susceptible counterparts. The distributed profiles show that it was highly expressed during the egg stage, and was most abundant in the abdomen of adult females. PMID:22957505

  14. Association Study between Polycystic Ovarian Syndrome and the Susceptibility Genes Polymorphisms in Hui Chinese Women

    PubMed Central

    Ha, Lingxia; Shi, Yuhua; Zhao, Junli; Li, Tao; Chen, Zi-Jiang

    2015-01-01

    Introduction Polycystic ovary syndrome (PCOS) is one of the most common endocrine-metabolic disorders. Evidence of familial aggregation analysis and different clinical traits among different regions and ethnicities indicated that the pathogenesis of PCOS is associated with multiple genetic and environmental factors. Our previous research had identified three susceptibility loci (rs2479106, DENND1A; rs13405728, LHCGR; rs13429458, THADA) for PCOS in Han Chinese women. The overall aim of this study was to investigate the relationship between three susceptibility gene polymorphisms and PCOS in Hui ethnic women. Methods 151 patients with PCOS (case group) and 99 healthy women (control group) were recruited from the Reproductive Medicine Center of the General Hospital of Ningxia Medical University. Clinical data and serum hormone characteristics of case and control groups were collected and analyzed. The three susceptibility single-nucleotide polymorphisms have been replicated in both case and control groups. Gene polymorphisms were detected by direct sequencing after polymerase chain reaction. Results The Body Mass Index, LH, LH/FSH ratio and total testosterone were significantly elevated in PCOS patients compared to control group (P<0.05). The frequencies of genotype and allele in rs13405728 were significantly different between the PCOS and the control groups (P<0.05). Of the SNP rs13405728, the PCOS cases with TT genotype stayed at a higher level of total testosterone, TG and LDL than those with the CC and CT genotypes. In contrary, there was no statistical difference between the two groups for SNP rs13429458 and rs2479106 (P>0.05). Conclusion The present study suggested that the SNP rs13405728 in the LHCGR gene was associated with PCOS in Hui ethnic women, and its TT genotype characterized with higher level of TT, TG and LDL. PMID:25978310

  15. SPINK1 Is a Susceptibility Gene for Fibrocalculous Pancreatic Diabetes in Subjects from the Indian Subcontinent

    PubMed Central

    Hassan, Zahid; Mohan, Viswananthan; Ali, Liaquat; Allotey, Rebecca; Barakat, Khalid; Faruque, M. Omar; Deepa, Raj; McDermott, Michael F.; Jackson, Alan E.; Cassell, Paul; Curtis, David; Gelding, Susan V.; Vijayaravaghan, Shanti; Gyr, Niklaus; Whitcomb, David C.; Khan, A. K. Azad; Hitman, Graham A.

    2002-01-01

    Fibrocalculous pancreatic diabetes (FCPD) is a secondary cause of diabetes due to chronic pancreatitis. Since the N34S variant of the SPINK1 trypsin inhibitor gene has been found to partially account for genetic susceptibility to chronic pancreatitis, we used a family-based and case-control approach in two separate ethnic groups from the Indian subcontinent, to determine whether N34S was associated with susceptibility to FCPD. Clear excess transmission of SPINK1 N34S to the probands with FCPD in 69 Bangladeshi families was observed (P<.0001; 20 transmissions and 2 nontransmissions). In the total study group (Bangladeshi and southern Indian) the N34S variant was present in 33% of 180 subjects with FCPD, 4.4% of 861 nondiabetic subjects (odds ratio 10.8; P<.0001 compared with FCPD), 3.7% of 219 subjects with type 2 diabetes, and 10.6% of 354 subjects with early-onset diabetes (aged <30 years) (P=.02 compared with the ethnically matched control group). These results suggest that the N34S variant of SPINK1 is a susceptibility gene for FCPD in the Indian subcontinent, although, by itself, it is not sufficient to cause disease. PMID:12187509

  16. Outbreak of vancomycin-susceptible Enterococcus faecium containing the wild-type vanA gene.

    PubMed

    Szakacs, Tom A; Kalan, Lindsay; McConnell, Michael J; Eshaghi, Alireza; Shahinas, Dea; McGeer, Allison; Wright, Gerry D; Low, Donald E; Patel, Samir N

    2014-05-01

    Accurate detection of vancomycin-resistant enterococci (VRE) is essential in preventing transmission in health care settings. Chromogenic media are widely used for screening VRE because of fast turnaround times (TAT) and high sensitivity. We report an outbreak of Enterococcus faecium bearing vanA yet susceptible to vancomycin (vancomycin-variable Enterococcus [VVE]). Between October 2009 to March 2011, clinical and screening specimens (n=14,747) were screened for VRE using VRE-selective medium and/or PCR. VVE isolates were genotyped to determine relatedness. Plasmids from these isolates were characterized by sequencing. Overall, 52 VVE isolates were identified, comprising 15% of all VRE isolates identified. Isolates demonstrated growth on Brilliance VRE agar (Oxoid) at 24 h of incubation but did not grow on brain heart infusion agar with 6 μg/ml vancomycin (Oxoid) or bile esculin azide agar with 6 μg/ml vancomycin (Oxoid) and were susceptible to vancomycin. Genotyping of 20 randomly selected VVE isolates revealed that 15/20 were identical, while 5 were highly related. PCR of the VVE transposon confirmed the presence of vanHAXY gene cluster; however, vanS (sensor) and vanR (regulator) genes were absent. The outbreak was controlled through routine infection control measures. We report an emergence of a fit strain of E. faecium containing vanA yet susceptible to vancomycin. Whether this new strain represents VRE has yet to be determined; however, unique testing procedures are required for reliable identification of VVE. PMID:24523464

  17. Outbreak of vancomycin-susceptible Enterococcus faecium containing the wild-type vanA gene.

    PubMed

    Szakacs, Tom A; Kalan, Lindsay; McConnell, Michael J; Eshaghi, Alireza; Shahinas, Dea; McGeer, Allison; Wright, Gerry D; Low, Donald E; Patel, Samir N

    2014-05-01

    Accurate detection of vancomycin-resistant enterococci (VRE) is essential in preventing transmission in health care settings. Chromogenic media are widely used for screening VRE because of fast turnaround times (TAT) and high sensitivity. We report an outbreak of Enterococcus faecium bearing vanA yet susceptible to vancomycin (vancomycin-variable Enterococcus [VVE]). Between October 2009 to March 2011, clinical and screening specimens (n=14,747) were screened for VRE using VRE-selective medium and/or PCR. VVE isolates were genotyped to determine relatedness. Plasmids from these isolates were characterized by sequencing. Overall, 52 VVE isolates were identified, comprising 15% of all VRE isolates identified. Isolates demonstrated growth on Brilliance VRE agar (Oxoid) at 24 h of incubation but did not grow on brain heart infusion agar with 6 μg/ml vancomycin (Oxoid) or bile esculin azide agar with 6 μg/ml vancomycin (Oxoid) and were susceptible to vancomycin. Genotyping of 20 randomly selected VVE isolates revealed that 15/20 were identical, while 5 were highly related. PCR of the VVE transposon confirmed the presence of vanHAXY gene cluster; however, vanS (sensor) and vanR (regulator) genes were absent. The outbreak was controlled through routine infection control measures. We report an emergence of a fit strain of E. faecium containing vanA yet susceptible to vancomycin. Whether this new strain represents VRE has yet to be determined; however, unique testing procedures are required for reliable identification of VVE.

  18. Progress in searching for susceptibility gene for inflammatory bowel disease by positional cloning

    PubMed Central

    Zheng, Chang-Qing; Hu, Gang-Zheng; Zeng, Zhao-Shu; Lin, Lian-Jie; Gu, Gin-Ge

    2003-01-01

    Inflammatory bowel disease (IBD) includes two clinical subtypes: Crohn disease (CD) and ulcerative colitis (UC). The general prevalence is about 1.0%-2.0% in Western countries. It is predominantly regarded as a multifactorial disorder involving environmental factors and polygenic defects. The view was confirmed by a lot of evidences from clinical attributions and animal models, especially from epidemiological investigations. So the etiological study of IBD has been focused on searching for susceptibility genes by positional cloning, which consists of two steps: linkage analysis and association analysis. Linkage analysis has been an important method of searching for susceptibility genes to polygenic diseases as well as single-gene disorders. IBD, as a polygenic disease, has been widely investigated by linkage analysis for susceptibility gene since 1996. The paper reviewed 38 articles, which covered almost all original researches in relation to IBD and linkage analysis. So far, several loci, such as 16q, 12q, 6p and 3p, have been identified by the studies. The most striking is 16q12 (IBD1), which linked only with CD not UC in the majority of studies. Association analysis, as one essential step for positional cloning, is usually carried out by genotyping candidate genes selected by means of linkage analysis or other methods, for figuring out the frequencies of alleles and comparing the frequencies between IBD group and healthy control group to identify the specific allele. It has been established that IBD is implicated in immune disorder. So the studies were centered on the genes of NOD2/CARD15, HLA-II, cytokine, cytokine receptor and adhesion molecule. This paper reviewed 14 original articles on association between NOD2 and IBD that have been published since 2001. All results, with the exception of one report from a Japanese group, provide evidences that the three kinds of variants of NOD2 are susceptibility factors for IBD. This article also comprehensively analyzed

  19. Common variants in the CYP2C19 gene are associated with susceptibility to endometriosis

    PubMed Central

    Painter, Jodie N; Nyholt, Dale R; Krause, Lutz; Zhao, Zhen Z; Chapman, Brett; Zhang, Christine; Medland, Sarah; Martin, Nicholas G; Kennedy, Stephen; Treloar, Susan; Zondervan, Krina; Montgomery, Grant W

    2014-01-01

    Objective To follow-up previous studies highlighting a possible role for cytochrome P450, family 2, subfamily C, 19 (CYP2C19) in susceptibility to endometriosis by searching for additional variants in the CYP2C19 gene that may be associated with the disease. Design Case-control study. Setting Academic research. Subject(s) Cases = 2,271 women with surgically confirmed endometriosis; Controls = 939 women with self-report of no endometriosis and 1,770 unscreened population samples. Intervention(s) Sequencing of the CYP2C19 region and follow-up of 80 SNPs in two case-control samples. Main outcome measure(s) Allele frequency differences between cases and controls. Results Sequencing of the CYP2C19 gene region resulted in the detection of a large number of known and novel SNPs. Genotyping of 80 polymorphic SNPs in 901 endometriosis cases and 939 controls resulted in study-wide significant association signals for SNPs in moderate or complete LD with rs4244285, a functional SNP in exon 5 that abrogates CYP2C19 function through the creation of an alternative splice site. Evidence of association was also detected for another functional SNP in the CYP2C19 promoter, rs12248560, highlighted in our previous study. Conclusion(s) Functional variants in CYP2C19 may contribute to endometriosis susceptibility in both familial and sporadic cases. PMID:24796765

  20. Identification of AF4/FMR2 family, member 3 (AFF3) as a novel rheumatoid arthritis susceptibility locus and confirmation of two further pan-autoimmune susceptibility genes.

    PubMed

    Barton, Anne; Eyre, Steve; Ke, Xiayi; Hinks, Anne; Bowes, John; Flynn, Edward; Martin, Paul; Wilson, Anthony G; Morgan, Ann W; Emery, Paul; Steer, Sophia; Hocking, Lynne J; Reid, David M; Harrison, Pille; Wordsworth, Paul; Thomson, Wendy; Worthington, Jane

    2009-07-01

    The concept of susceptibility genes common to different autoimmune diseases is now firmly established with previous studies demonstrating overlap of loci conferring susceptibility to type 1 diabetes (T1D) with both Coeliac disease and multiple sclerosis. Rheumatoid arthritis (RA) is an archetypal autoimmune disease and we, therefore, targeted putative T1D susceptibility loci for genotyping in UK RA cases and unrelated controls. A novel RA susceptibility locus at AFF3 was identified with convincing evidence for association in a combined sample cohort of 6819 RA cases and 12 650 controls [OR 1.12 95% confidence intervals (CI) 1.07-1.17, P = 2.8 x 10(-7)]. Association of two previously described loci (CTLA-4 and 4q27) with RA was also replicated (OR 0.87, 95% CI 0.82-0.94, P = 1.1 x 10(-4) and OR 0.86, 95% CI 0.79-0.94, P = 5.4 x 10(-4), respectively). These findings take the number of established RA susceptibility loci to 13, only one of which has not been associated with other autoimmune diseases. PMID:19359276

  1. Identification of AF4/FMR2 family, member 3 (AFF3) as a novel rheumatoid arthritis susceptibility locus and confirmation of two further pan-autoimmune susceptibility genes

    PubMed Central

    Barton, Anne; Eyre, Steve; Ke, Xiayi; Hinks, Anne; Bowes, John; Flynn, Edward; Martin, Paul; Wilson, Anthony G.; Morgan, Ann W.; Emery, Paul; Steer, Sophia; Hocking, Lynne J.; Reid, David M.; Harrison, Pille; Wordsworth, Paul; Thomson, Wendy; Worthington, Jane

    2009-01-01

    The concept of susceptibility genes common to different autoimmune diseases is now firmly established with previous studies demonstrating overlap of loci conferring susceptibility to type 1 diabetes (T1D) with both Coeliac disease and multiple sclerosis. Rheumatoid arthritis (RA) is an archetypal autoimmune disease and we, therefore, targeted putative T1D susceptibility loci for genotyping in UK RA cases and unrelated controls. A novel RA susceptibility locus at AFF3 was identified with convincing evidence for association in a combined sample cohort of 6819 RA cases and 12 650 controls [OR 1.12 95% confidence intervals (CI) 1.07–1.17, P = 2.8 × 10−7]. Association of two previously described loci (CTLA-4 and 4q27) with RA was also replicated (OR 0.87, 95% CI 0.82–0.94, P = 1.1 × 10−4 and OR 0.86, 95% CI 0.79–0.94, P = 5.4 × 10−4, respectively). These findings take the number of established RA susceptibility loci to 13, only one of which has not been associated with other autoimmune diseases. PMID:19359276

  2. Polymorphisms in the Interleukin 18 Receptor 1 Gene and Tuberculosis Susceptibility among Chinese

    PubMed Central

    Zhu, Donglin; An, Huiru; Yang, Yourong; Liang, Yan; Zhao, Weiguo; Ding, Wenjun; Wu, Xueqiong

    2014-01-01

    Tuberculosis (TB), an infectious disease caused by infection of Mycobacterium tuberculosis, is a major public health challenge globally. Genetic epidemiological evidence suggests a genetic basis for TB, but the molecular mechanism for a genetic predisposition to TB remains largely unknown. Thirty-five tag single-nucleotide polymorphisms (SNPs) across 11 candidate cytokines and related genes, including IL-12/IFN-γ axis genes (IL12B, IL12RB1, IL18R1, IL27, IFNGR1, IFNGR2 and STAT1), the TNF gene locus (TNF and LTA), IL10, and CCL2, were genotyped using Sequenom's iPLEX assays in 1,032 patients with TB and 1,008 controls of Chinese Han origin. We did not find that any of the 35 tag SNPs individually or as haplotypes was significantly associated with susceptibility to TB, on the basis of multivariable logistic regression analysis with adjustment for age and sex. However, stratification analyses showed that, in those with age 46 years or older, carrying the rs1974675 T allele in the IL18R1 gene had a significantly decreased susceptibility to TB occurrence compared with carrying the C/C genotype (OR = 0.57, P = 5.0×10−4). Further analysis indicated that a SNP in absolute linkage disequilibrium with rs1974675, rs3755276, is located within a CpG dinucleotide and showed hypomethylation in controls than in patients (19.6% vs. 31.4%; P = 1.0×10−4) and genotype-specific DNA methylation at the IL18R1 promoter and IL18R1 mRNA levels. In addition, DNA methylation levels were significantly inversely correlated with mRNA levels. Thus, decreased mRNA levels of IL18R1 due to rs3755276 may partially mediate the increased susceptibility to TB risk. PMID:25360588

  3. A polymorphism in the nuclear receptor coactivator 7 gene and breast cancer susceptibility.

    PubMed

    Süllner, Julia; Lattrich, Claus; Häring, Julia; Görse, Regina; Ortmann, Olaf; Treeck, Oliver

    2012-01-01

    The nuclear receptor coactivator 7 (NCoA7) gene codes for an estrogen receptor-associated protein that plays a significant role in the cellular response to estrogens. Given that NCoA7 is expressed in the mammary gland, alterations in this gene may affect breast cancer risk. In this study, we compared the genotype and allele frequencies of the missense single nucleotide polymorphism (SNP) rs1567, located in the coding region of the NCoA7 gene and resulting in an amino acid exchange from asparagine to glutamine, in 305 women with sporadic breast cancer and 346 women without any malignancy. Statistical analysis of the observed frequencies did not reveal a significant difference between the cancer and control groups, nor did a comparison between histological breast cancer subgroups. In conclusion, the results of our phenotype-genotype association study indicate that NCoA7 SNP rs1567 does not affect breast cancer susceptibility. PMID:22740868

  4. A polymorphism in the nuclear receptor coactivator 7 gene and breast cancer susceptibility

    PubMed Central

    SÜLLNER, JULIA; LATTRICH, CLAUS; HÄRING, JULIA; GÖRSE, REGINA; ORTMANN, OLAF; TREECK, OLIVER

    2012-01-01

    The nuclear receptor coactivator 7 (NCoA7) gene codes for an estrogen receptor-associated protein that plays a significant role in the cellular response to estrogens. Given that NCoA7 is expressed in the mammary gland, alterations in this gene may affect breast cancer risk. In this study, we compared the genotype and allele frequencies of the missense single nucleotide polymorphism (SNP) rs1567, located in the coding region of the NCoA7 gene and resulting in an amino acid exchange from asparagine to glutamine, in 305 women with sporadic breast cancer and 346 women without any malignancy. Statistical analysis of the observed frequencies did not reveal a significant difference between the cancer and control groups, nor did a comparison between histological breast cancer subgroups. In conclusion, the results of our phenotype-genotype association study indicate that NCoA7 SNP rs1567 does not affect breast cancer susceptibility. PMID:22740868

  5. Gene polymorphisms in African buffalo associated with susceptibility to bovine tuberculosis infection.

    PubMed

    le Roex, Nikki; Koets, Ad P; van Helden, Paul D; Hoal, Eileen G

    2013-01-01

    Bovine tuberculosis (BTB) is a chronic, highly infectious disease that affects humans, cattle and numerous species of wildlife. In developing countries such as South Africa, the existence of extensive wildlife-human-livestock interfaces poses a significant risk of Mycobacterium bovis transmission between these groups, and has far-reaching ecological, economic and public health impacts. The African buffalo (Syncerus caffer), acts as a maintenance host for Mycobacterium bovis, and maintains and transmits the disease within the buffalo and to other species. In this study we aimed to investigate genetic susceptibility of buffalo for Mycobacterium bovis infection. Samples from 868 African buffalo of the Cape buffalo subspecies were used in this study. SNPs (n = 69), with predicted functional consequences in genes related to the immune system, were genotyped in this buffalo population by competitive allele-specific SNP genotyping. Case-control association testing and statistical analyses identified three SNPs associated with BTB status in buffalo. These SNPs, SNP41, SNP137 and SNP144, are located in the SLC7A13, DMBT1 and IL1α genes, respectively. SNP137 remained significantly associated after permutation testing. The three genetic polymorphisms identified are located in promising candidate genes for further exploration into genetic susceptibility to BTB in buffalo and other bovids, such as the domestic cow. These polymorphisms/genes may also hold potential for marker-assisted breeding programmes, with the aim of breeding more BTB-resistant animals and herds within both the national parks and the private sector.

  6. Genetic and Functional Evidence Supports LPAR1 as a Susceptibility Gene for Hypertension.

    PubMed

    Xu, Ke; Ma, Lu; Li, Yang; Wang, Fang; Zheng, Gu-Yan; Sun, Zhijun; Jiang, Feng; Chen, Yundai; Liu, Huirong; Dang, Aimin; Chen, Xi; Chun, Jerold; Tian, Xiao-Li

    2015-09-01

    Essential hypertension is a complex disease affected by genetic and environmental factors and serves as a major risk factor for cardiovascular diseases. Serum lysophosphatidic acid correlates with an elevated blood pressure in rats, and lysophosphatidic acid interacts with 6 subtypes of receptors. In this study, we assessed the genetic association of lysophosphatidic acid receptors with essential hypertension by genotyping 28 single-nucleotide polymorphisms from genes encoding for lysophosphatidic acid receptors, LPAR1, LPAR2, LPAR3, LPAR4, LPAR5, and LPAR6 and their flanking sequences, in 3 Han Chinese cohorts consisting of 2630 patients and 3171 controls in total. We identified a single-nucleotide polymorphism, rs531003 in the 3'-flanking genomic region of LPAR1, associated with hypertension (the Bonferroni corrected P=1.09×10(-5), odds ratio [95% confidence interval]=1.23 [1.13-1.33]). The risk allele C of rs531003 is associated with the increased expression of LPAR1 and the susceptibility of hypertension, particularly in those with a shortage of sleep (P=4.73×10(-5), odds ratio [95% confidence interval]=1.75 [1.34-2.28]). We further demonstrated that blood pressure elevation caused by sleep deprivation and phenylephrine-induced vasoconstriction was both diminished in LPAR1-deficient mice. Together, we show that LPAR1 is a novel susceptibility gene for human essential hypertension and that stress, such as shortage of sleep, increases the susceptibility of patients with risk allele to essential hypertension.

  7. Iron homeostasis and fire blight susceptibility in transgenic pear plants overexpressing a pea ferritin gene.

    PubMed

    Djennane, Samia; Cesbron, Colette; Sourice, Sophie; Cournol, Raphael; Dupuis, Fabrice; Eychenne, Magali; Loridon, Karine; Chevreau, Elisabeth

    2011-05-01

    The bacterial pathogen Erwinia amylovora causes the devastating disease known as fire blight in some rosaceous plants including apple and pear. One of the pathogenicity factors affecting fire blight development is the production of a siderophore, desferrioxamine, which overcomes the limiting conditions in plant tissues and also protects bacteria against active oxygen species. In this paper we examine the effect of an iron chelator protein encoded by the pea ferritin gene on the fire blight susceptibility of pear (Pyrus communis). Transgenic pear clones expressing this gene controlled either by the constitutive promoter CaMV 35S or by the inducible promoter sgd24 promoter were produced. The transgenic clones produced were analysed by Q-RT-PCR to determine the level of expression of the pea transgene. A pathogen-inducible pattern of expression of the pea transgene was observed in sgd24-promoter transformants. Adaptation to iron deficiency in vitro was tested in some transgenic clones and different iron metabolism parameters were measured. No strong effect on iron and chlorophyll content, root reductase activity and fire blight susceptibility was detected in the transgenic lines tested. No transformants showed a significant reduction in susceptibility to fire blight in greenhouse conditions when inoculated with E. amylovora.

  8. Polymorphisms in the XPC gene and gastric cancer susceptibility in a Southern Chinese population

    PubMed Central

    Hua, Rui-Xi; Zhuo, Zhen-Jian; Shen, Guo-Ping; Zhu, Jinhong; Zhang, Shao-Dan; Xue, Wen-Qiong; Li, Xi-Zhao; Zhang, Pei-Fen; He, Jing; Jia, Wei-Hua

    2016-01-01

    Previous studies have reported that XPC gene polymorphisms may modify the individual susceptibility to gastric cancer. In this case–control study with a total of 1,142 cases and 1,173 controls, four potentially functional polymorphisms were genotyped in the XPC gene (rs2228001 A>C, rs2228000 C>T, rs2607775 C>G, and rs1870134 G>C) by Taqman assays and their associations were analyzed with the risk of gastric cancer in a Southern Chinese population. No significant association between any of XPC polymorphisms and gastric cancer risk was detected except for a borderline association with the rs2228000 CT/TT genotype (crude odds ratio =0.86, 95% confidence interval =0.73–1.02, P=0.088) when compared to the rs2228000 CC genotype. Further stratified analysis revealed that the protective effect of rs2228000 CT/TT on the risk of gastric cancer was only significant among subjects older than 58 years. In summary, results indicated that genetic variations in XPC gene may play a weak effect on gastric cancer susceptibility in Southern Chinese population, which warrants further confirmation in larger prospective studies with different ethnic populations.

  9. Polymorphisms in the XPC gene and gastric cancer susceptibility in a Southern Chinese population.

    PubMed

    Hua, Rui-Xi; Zhuo, Zhen-Jian; Shen, Guo-Ping; Zhu, Jinhong; Zhang, Shao-Dan; Xue, Wen-Qiong; Li, Xi-Zhao; Zhang, Pei-Fen; He, Jing; Jia, Wei-Hua

    2016-01-01

    Previous studies have reported that XPC gene polymorphisms may modify the individual susceptibility to gastric cancer. In this case-control study with a total of 1,142 cases and 1,173 controls, four potentially functional polymorphisms were genotyped in the XPC gene (rs2228001 A>C, rs2228000 C>T, rs2607775 C>G, and rs1870134 G>C) by Taqman assays and their associations were analyzed with the risk of gastric cancer in a Southern Chinese population. No significant association between any of XPC polymorphisms and gastric cancer risk was detected except for a borderline association with the rs2228000 CT/TT genotype (crude odds ratio =0.86, 95% confidence interval =0.73-1.02, P=0.088) when compared to the rs2228000 CC genotype. Further stratified analysis revealed that the protective effect of rs2228000 CT/TT on the risk of gastric cancer was only significant among subjects older than 58 years. In summary, results indicated that genetic variations in XPC gene may play a weak effect on gastric cancer susceptibility in Southern Chinese population, which warrants further confirmation in larger prospective studies with different ethnic populations. PMID:27660469

  10. Polymorphisms in the XPC gene and gastric cancer susceptibility in a Southern Chinese population

    PubMed Central

    Hua, Rui-Xi; Zhuo, Zhen-Jian; Shen, Guo-Ping; Zhu, Jinhong; Zhang, Shao-Dan; Xue, Wen-Qiong; Li, Xi-Zhao; Zhang, Pei-Fen; He, Jing; Jia, Wei-Hua

    2016-01-01

    Previous studies have reported that XPC gene polymorphisms may modify the individual susceptibility to gastric cancer. In this case–control study with a total of 1,142 cases and 1,173 controls, four potentially functional polymorphisms were genotyped in the XPC gene (rs2228001 A>C, rs2228000 C>T, rs2607775 C>G, and rs1870134 G>C) by Taqman assays and their associations were analyzed with the risk of gastric cancer in a Southern Chinese population. No significant association between any of XPC polymorphisms and gastric cancer risk was detected except for a borderline association with the rs2228000 CT/TT genotype (crude odds ratio =0.86, 95% confidence interval =0.73–1.02, P=0.088) when compared to the rs2228000 CC genotype. Further stratified analysis revealed that the protective effect of rs2228000 CT/TT on the risk of gastric cancer was only significant among subjects older than 58 years. In summary, results indicated that genetic variations in XPC gene may play a weak effect on gastric cancer susceptibility in Southern Chinese population, which warrants further confirmation in larger prospective studies with different ethnic populations. PMID:27660469

  11. Correlation between single nucleotide polymorphisms in hypoxia-related genes and susceptibility to acute high-altitude pulmonary edema.

    PubMed

    Wu, A L; Xiong, Y S; Li, Z Q; Liu, Y G; Quan, Q; Wu, L J

    2015-01-01

    This study aimed to explore the relationship between genetic changes and high-altitude pulmonary edema (HAPE) susceptibility, and to screen for the key single nucleotide polymorphism (SNP) loci in the HAPE-susceptibility gene, by investigating the SNPs occurring in hypoxia-related genes in HAPE-susceptible and control (non-susceptible) populations. This research was conducted on Han recruits, who travelled to the Lhasa plateau (altitude, 3658 m). Ten loci located on ten genes extracted from the HAPE and healthy populations were amplified by polymerase chain reaction, and subsequently sequenced. The investigated genes included those coding for aldosterone synthase 2 (CYP11B2), angiotensin-converting enzyme (ACE), heat-shock protein 70 (HSP70), nuclear factor kappa B (NF-κB), surfactant protein A2 (SP-A2), plasminogen activator inhibitor-1 (PAI-1), nitric oxide synthetase (NOS), vascular endothelial growth factor (VEGF), prolyl hydroxylase (EGLN1), and zinc finger protein A20. The gene distribution of each SNP loci and its correlation with HAPE was analyzed. Statistical analyses of the genotype frequencies of the SNPs revealed significant differences in the ACE (rs4309), EGLN1 (rs480902), SP-A2 (rs1965708), HSP70 (rs1008438), PAI-1 (rs1799889), and NOS (rs199983) expressions between the HAPE and healthy control groups (P < 0.05); therefore, these SNP loci were believed to indicate HAPE susceptibility. HAPE is correlated with multiple- SNP loci. A correlation analysis between genetic polymorphism and HAPE susceptibility revealed that 6 hypoxia-related genes were key sites accounting for HAPE. These findings could help assess the risk of HAPE in populations expressing different genotypes, in order to reduce the occurrence of HAPE. PMID:26436397

  12. Identification of MAMDC1 as a Candidate Susceptibility Gene for Systemic Lupus Erythematosus (SLE)

    PubMed Central

    Hellquist, Anna; Zucchelli, Marco; Lindgren, Cecilia M.; Saarialho-Kere, Ulpu; Järvinen, Tiina M.; Koskenmies, Sari; Julkunen, Heikki; Onkamo, Päivi; Skoog, Tiina; Panelius, Jaana; Räisänen-Sokolowski, Anne; Hasan, Taina; Widen, Elisabeth; Gunnarson, Iva; Svenungsson, Elisabet; Padyukov, Leonid; Assadi, Ghazaleh; Berglind, Linda; Mäkelä, Ville-Veikko; Kivinen, Katja; Wong, Andrew; Cunningham Graham, Deborah S.; Vyse, Timothy J.; D'Amato, Mauro; Kere, Juha

    2009-01-01

    Background Systemic lupus erythematosus (SLE) is a complex autoimmune disorder with multiple susceptibility genes. We have previously reported suggestive linkage to the chromosomal region 14q21-q23 in Finnish SLE families. Principal Findings Genetic fine mapping of this region in the same family material, together with a large collection of parent affected trios from UK and two independent case-control cohorts from Finland and Sweden, indicated that a novel uncharacterized gene, MAMDC1 (MAM domain containing glycosylphosphatidylinositol anchor 2, also known as MDGA2, MIM 611128), represents a putative susceptibility gene for SLE. In a combined analysis of the whole dataset, significant evidence of association was detected for the MAMDC1 intronic single nucleotide polymorphisms (SNP) rs961616 (P –value = 0.001, Odds Ratio (OR) = 1.292, 95% CI 1.103–1.513) and rs2297926 (P –value = 0.003, OR = 1.349, 95% CI 1.109–1.640). By Northern blot, real-time PCR (qRT-PCR) and immunohistochemical (IHC) analyses, we show that MAMDC1 is expressed in several tissues and cell types, and that the corresponding mRNA is up-regulated by the pro-inflammatory cytokines tumour necrosis factor alpha (TNF-α) and interferon gamma (IFN-γ) in THP-1 monocytes. Based on its homology to known proteins with similar structure, MAMDC1 appears to be a novel member of the adhesion molecules of the immunoglobulin superfamily (IgCAM), which is involved in cell adhesion, migration, and recruitment to inflammatory sites. Remarkably, some IgCAMs have been shown to interact with ITGAM, the product of another SLE susceptibility gene recently discovered in two independent genome wide association (GWA) scans. Significance Further studies focused on MAMDC1 and other molecules involved in these pathways might thus provide new insight into the pathogenesis of SLE. PMID:19997561

  13. Association of single nucleotide polymorphisms in cell cycle regulatory genes with oral cancer susceptibility.

    PubMed

    Murali, Abitha; Nalinakumari, K R; Thomas, Shaji; Kannan, S

    2014-09-01

    Alterations in the regulation of the cell cycle are strongly linked to tumorigenesis, so genetic variants in genes critical to control of the cycle are good candidates to have their association with susceptibility to oral cancer assessed. In this hospital-based, case-control study of 445 patients who had been newly-diagnosed with oral cancer and 449 unaffected controls, we used a multigenic approach to examine the associations among a panel of 10 selected polymorphisms in the pathway of the cell cycle that were possibly susceptible to oral cancer. Six of 9 single nucleotide polymorphisms in the cell cycle showed significant risks for oral cancer, the highest risk being evident for p27 (rs34329; Odds ratio 3.05, 95% CI 2.12 to 4.40). A significant risk of oral cancer was also evident for individual polymorphisms of cyclin E (rs1406), cyclin H (rs3093816), cyclin D1-1 (rs647451), cyclin D2 (rs3217901) and Rb1-2 (rs3092904). The risk of oral cancer increased significantly as the number of unfavourable genotypes in the pathway increased, and so the results point to a stronger combined effect of polymorphisms in important cell cycle regulatory genes on predisposition to oral cancer. PMID:24947332

  14. Identification of genetic loci that control mammary tumor susceptibility through the host microenvironment

    SciTech Connect

    Zhang, Pengju; Lo, Alvin; Huang, Yurong; Huang, Ge; Liang, Guozhou; Mott, Joni; Karpen, Gary H.; Blakely, Eleanor A.; Bissell, Mina J.; Barcellos-Hoff, Mary Helen; Snijders, Antoine M.; Mao, Jian-Hua

    2015-03-09

    The interplay between host genetics, tumor microenvironment and environmental exposure in cancer susceptibility remains poorly understood. Here we assessed the genetic control of stromal mediation of mammary tumor susceptibility to low dose ionizing radiation (LDIR) using backcrossed F1 into BALB/c (F1Bx) between cancer susceptible (BALB/c) and resistant (SPRET/EiJ) mouse strains. Tumor formation was evaluated after transplantation of non-irradiated Trp53-/- BALB/c mammary gland fragments into cleared fat pads of F1Bx hosts. Genome-wide linkage analysis revealed 2 genetic loci that constitute the baseline susceptibility via host microenvironment. However, once challenged with LDIR, we discovered 13 additional loci that were enriched for genes involved in cytokines, including TGFβ1 signaling. Surprisingly, LDIR-treated F1Bx cohort significantly reduced incidence of mammary tumors from Trp53-/- fragments as well as prolonged tumor latency, compared to sham-treated controls. We demonstrated further that plasma levels of specific cytokines were significantly correlated with tumor latency. Using an ex vivo 3-D assay, we confirmed TGFβ1 as a strong candidate for reduced mammary invasion in SPRET/EiJ, which could explain resistance of this strain to mammary cancer risk following LDIR. Our results open possible new avenues to understand mechanisms of genes operating via the stroma that affect cancer risk from external environmental exposures.

  15. The influence of T cell receptor and cytokine genes on sarcoidosis susceptibility in African Americans.

    PubMed

    Rybicki, B A; Maliarik, M J; Malvitz, E; Sheffer, R G; Major, M; Popovich, J; Iannuzzi, M C

    1999-09-01

    The pathogenesis of sarcoidosis, a multisystem granulomatous disorder, is mediated through immunoregulatory pathways. While sarcoidosis clusters in families, inherited risk factors remain undefined. In search of possible sarcoidosis susceptibility genes, we examined anonymous polymorphic genetic markers tightly linked to six different candidate gene regions on chromosomes 2q13, 5q31, 6p23-25, 7p14-15, 14q11 and 22q11. These candidate regions contain T cell receptor, interleukin (IL) and interferon regulatory factor (IRF) genes. Our study population consisted of 105 African-American sarcoidosis cases and 95 unrelated healthy controls. The allelic frequency distribution of two out of the six markers, IL-1 alpha marker (p = 0.010) on 2q13 and the F13A marker (p = 0.0006) on 6p23-25, was statistically significantly different in cases compared with controls. The two alleles most strongly associated with sarcoidosis were IL-1 alpha*137 (Odds Ratio (OR) = 2.60; 95% confidence interval (CI) = 1.36-4.98) and F13A*188 (OR = 2.42; 95% CI = 1.37-4.30). Individuals that had both of these alleles were at a six-fold increased risk for sarcoidosis (OR = 6.19; 95% CI = 2.54-15.10). Restricting the analysis to cases with at least one first or second-degree relative affected with sarcoidosis increased the OR to 15.38. IL-1 levels are elevated in sarcoidosis and the F13A marker is tightly linked to a gene that codes for a newly identified interferon regulatory factor protein (IRF-4), which is thought to play a role in T cell effector functions. Our results suggest genetic susceptibility to sarcoidosis may be conferred by more than one immune-related gene that act synergistically on disease risk.

  16. Testing the burden of rare variation in arrhythmia-susceptibility genes provides new insights into molecular diagnosis for Brugada syndrome.

    PubMed

    Le Scouarnec, Solena; Karakachoff, Matilde; Gourraud, Jean-Baptiste; Lindenbaum, Pierre; Bonnaud, Stéphanie; Portero, Vincent; Duboscq-Bidot, Laëtitia; Daumy, Xavier; Simonet, Floriane; Teusan, Raluca; Baron, Estelle; Violleau, Jade; Persyn, Elodie; Bellanger, Lise; Barc, Julien; Chatel, Stéphanie; Martins, Raphaël; Mabo, Philippe; Sacher, Frédéric; Haïssaguerre, Michel; Kyndt, Florence; Schmitt, Sébastien; Bézieau, Stéphane; Le Marec, Hervé; Dina, Christian; Schott, Jean-Jacques; Probst, Vincent; Redon, Richard

    2015-05-15

    The Brugada syndrome (BrS) is a rare heritable cardiac arrhythmia disorder associated with ventricular fibrillation and sudden cardiac death. Mutations in the SCN5A gene have been causally related to BrS in 20-30% of cases. Twenty other genes have been described as involved in BrS, but their overall contribution to disease prevalence is still unclear. This study aims to estimate the burden of rare coding variation in arrhythmia-susceptibility genes among a large group of patients with BrS. We have developed a custom kit to capture and sequence the coding regions of 45 previously reported arrhythmia-susceptibility genes and applied this kit to 167 index cases presenting with a Brugada pattern on the electrocardiogram as well as 167 individuals aged over 65-year old and showing no history of cardiac arrhythmia. By applying burden tests, a significant enrichment in rare coding variation (with a minor allele frequency below 0.1%) was observed only for SCN5A, with rare coding variants carried by 20.4% of cases with BrS versus 2.4% of control individuals (P = 1.4 × 10(-7)). No significant enrichment was observed for any other arrhythmia-susceptibility gene, including SCN10A and CACNA1C. These results indicate that, except for SCN5A, rare coding variation in previously reported arrhythmia-susceptibility genes do not contribute significantly to the occurrence of BrS in a population with European ancestry. Extreme caution should thus be taken when interpreting genetic variation in molecular diagnostic setting, since rare coding variants were observed in a similar extent among cases versus controls, for most previously reported BrS-susceptibility genes.

  17. Charting the molecular links between driver and susceptibility genes in colorectal cancer.

    PubMed

    Arroyo, Rodrigo; Duran-Frigola, Miquel; Berenguer, Clara; Soler-López, Montserrat; Aloy, Patrick

    2014-03-21

    Despite significant advances in the identification of specific genes and pathways important in the onset and progression of colorectal cancer (CRC), mechanistic insight into the relationship between driver and susceptibility genes is needed. In this paper, we systematically explore physical interactions between causative and putative CRC susceptibility genes to reveal the molecular mechanisms involved in tumor biology. In total, we identify 622 high-confidence protein-protein interactions between 42 CRC causative and 65 candidate susceptibility genes. Among the latter, 28 are located in the CRCS9 loci, related to the etiology of CRC, and 17 are co-expressed with well-established CRC drivers, which makes them excellent candidates for further functional studies. Moreover, we find a high degree of functional coherence between connected driver and susceptibility genes, which indicates that our network-based strategy is useful to gain insight into the underlying mechanisms of those proteins with unknown roles in CRC.

  18. Vitamin D receptor (VDR) gene polymorphisms and susceptibility to systemic lupus erythematosus clinical manifestations.

    PubMed

    de Azevêdo Silva, J; Monteiro Fernandes, K; Trés Pancotto, J A; Sotero Fragoso, T; Donadi, E A; Crovella, S; Sandrin-Garcia, P

    2013-10-01

    Systemic lupus erythematosus (SLE) is an autoimmune disorder with heterogeneous clinical manifestations and target tissue damage. Currently, several genes have been associated with SLE susceptibility, including vitamin D receptor (VDR), which is a mediator of immune responses through the action of vitamin D. Polymorphisms in the VDR gene can impair the vitamin D (D3) function role, and since SLE patients show deficient D3 blood levels, it leads to a possible connection to the disease's onset. In our study we searched for an association between VDR polymorphisms and risk of developing SLE, as well as the disease's clinical manifestations. We enrolled 158 SLE patients and 190 Southeast Brazilian healthy controls, genotyped for five Tag single nucleotide polymorphisms (SNPs), covering most of the VDR gene region. We found an association between VDR SNPs and SLE for the following clinical manifestations: rs11168268 and cutaneous alterations (p=0.036), rs3890733 (p=0.003) rs3890733 and arthritis (p=0.001), rs2248098 and immunological alterations (p=0.040), rs4760648 and antibody anti-dsDNA (p=0.036). No association was reported between VDR polymorphisms and SLE susceptibility.

  19. Autoinflammatory gene polymorphisms and susceptibility to UK juvenile idiopathic arthritis

    PubMed Central

    2013-01-01

    Background To investigate the autoinflammatory hereditary periodic fever syndrome genes MVK and TNFRSF1A, and the NLRP1 and IL1 genes, for association with juvenile idiopathic arthritis (JIA). Methods For MVK, TNFRSF1A and NLRP1 pair-wise tagging SNPs across each gene were selected and for IL1A SNPs from a prior meta-analysis were included. 1054 UK Caucasian JIA patients were genotyped by Sequenom iPlex MassARRAY and allele and genotype frequencies compared with 5380 unrelated healthy UK Caucasian controls. Results Four SNPs were significantly associated with UK JIA: rs2071374 within intron 4 of IL1A (ptrend=0.006), rs2228576 3’ of TNFRSF1A (ptrend=0.009) and 2 SNPs, rs11836136 and rs7957619, within MVK (ptrend=0.006, ptrend=0.005 respectively). In all cases the association appeared to be driven by the systemic-onset JIA (SoJIA) subtype. Genotype data for the two MVK SNPs was available in a validation cohort of 814 JIA (oligoarticular and RF negative polyarticular) cases and 3058 controls from the US. Replication was not confirmed, however, further suggesting that this association is specific to SoJIA. Conclusions These findings extend the observations of the relevance of studying monogenic loci as candidates for complex diseases. We provide novel evidence of association of MVK and TNFRSF1A with UK JIA, specifically driven by association with SoJIA and further confirm that the IL1A SNP association with SoJIA is subtype specific. Replication is required in independent cohorts. PMID:23547563

  20. Re-evaluation of putative rheumatoid arthritis susceptibility genes in the post-genome wide association study era and hypothesis of a key pathway underlying susceptibility.

    PubMed

    Barton, Anne; Thomson, Wendy; Ke, Xiayi; Eyre, Steve; Hinks, Anne; Bowes, John; Gibbons, Laura; Plant, Darren; Wilson, Anthony G; Marinou, Ioanna; Morgan, Ann; Emery, Paul; Steer, Sophia; Hocking, Lynne; Reid, David M; Wordsworth, Paul; Harrison, Pille; Worthington, Jane

    2008-08-01

    Rheumatoid arthritis (RA) is an archetypal, common, complex autoimmune disease with both genetic and environmental contributions to disease aetiology. Two novel RA susceptibility loci have been reported from recent genome-wide and candidate gene association studies. We, therefore, investigated the evidence for association of the STAT4 and TRAF1/C5 loci with RA using imputed data from the Wellcome Trust Case Control Consortium (WTCCC). No evidence for association of variants mapping to the TRAF1/C5 gene was detected in the 1860 RA cases and 2930 control samples tested in that study. Variants mapping to the STAT4 gene did show evidence for association (rs7574865, P = 0.04). Given the association of the TRAF1/C5 locus in two previous large case-control series from populations of European descent and the evidence for association of the STAT4 locus in the WTCCC study, single nucleotide polymorphisms mapping to these loci were tested for association with RA in an independent UK series comprising DNA from >3000 cases with disease and >3000 controls and a combined analysis including the WTCCC data was undertaken. We confirm association of the STAT4 and the TRAF1/C5 loci with RA bringing to 5 the number of confirmed susceptibility loci. The effect sizes are less than those reported previously but are likely to be a more accurate reflection of the true effect size given the larger size of the cohort investigated in the current study.

  1. TLR9 Gene Region Polymorphisms and Susceptibility to Tuberculosis in Vietnam

    PubMed Central

    Graustein, AD; Horne, DJ; Arentz, M; Bang, ND; Chau, TTH; Thwaites, GE; Caws, M; Thuong, NTT; Dunstan, SJ; Hawn, TR

    2015-01-01

    Summary Humans exposed to Mycobacterium tuberculosis (Mtb) show variation in susceptibility to infection and differences in tuberculosis (TB) disease outcome. Toll-like receptor 9 (TLR9) is a pattern recognition receptor that mediates recognition of Mtb and modulates Mtb-specific T-cell responses. Using a case-population design, we evaluated whether single nucleotide polymorphisms (SNPs) in the TLR9 gene region are associated with susceptibility to pulmonary or meningeal TB as well as neurologic presentation and mortality in the meningeal TB group. In a discovery cohort (n = 352 cases, 382 controls), three SNPs were associated with TB (all forms, p<0.05) while three additional SNPs neared significance (0.05controls), one was significant (rs352142) while another neared significance (rs352143). When the cohorts were combined, rs352142 was most strongly associated with meningeal tuberculosis (dominant model; p=0.0002, OR 2.36, CI 1.43-3.87) while rs352143 was associated with pulmonary tuberculosis (recessive model; p=0.006, OR 5.3, CI 1.26-31.13). None of the SNPs were associated with mortality. This is the first demonstration of an association between a TLR9 gene region SNP and tuberculous meningitis. In addition, this extends previous findings that support associations of TLR9 SNPs with pulmonary tuberculosis. PMID:25616954

  2. Interaction among nitric oxide (NO)-related genes in migraine susceptibility.

    PubMed

    Gonçalves, Flavia M; Luizon, Marcelo R; Speciali, Jose G; Martins-Oliveira, Alisson; Dach, Fabiola; Tanus-Santos, Jose E

    2012-11-01

    The pathogenic mechanisms involved in migraine are complex and not completely clarified. Because there is evidence for the involvement of nitric oxide (NO) in migraine pathophysiology, candidate gene approaches focusing on genes affecting the endothelial function have been studied including the genes encoding endothelial NO synthase (eNOS), inducible NO synthase (iNOS), and vascular endothelial growth factor (VEGF). However, investigations on gene-gene interactions are warranted to better elucidate the genetic basis of migraine. This study aimed at characterizing interactions among nine clinically relevant polymorphisms in eNOS (T(-786)C/rs2070744, the 27 bp VNTR in intron 4, the Glu298Asp/rs1799983, and two additional tagSNPs rs3918226 and rs743506), iNOS (C(-1026)A/rs2779249 and G2087A/rs2297518), and VEGF (C(-2578)A/rs699947 and G(-634)C/rs2010963) in migraine patients and control group. Genotypes were determined by real-time polymerase chain reaction using the Taqman(®) allele discrimination assays or PCR and fragment separation by electrophoresis in 99 healthy women without migraine (control group) and in 150 women with migraine divided into two groups: 107 with migraine without aura and 43 with aura. The multifactor dimensionality reduction method was used to detect and characterize gene-gene interactions. We found a significant interaction between eNOS rs743506 and iNOS 2087G/A polymorphisms in migraine patients compared to control group (P < 0.05), suggesting that this combination affect the susceptibility to migraine. Further studies are needed to determine the molecular mechanisms explaining this interaction.

  3. Multiple type 2 diabetes susceptibility genes following genome-wide association scan in UK samples

    PubMed Central

    Zeggini, Eleftheria; Weedon, Michael N.; Lindgren, Cecilia M.; Frayling, Timothy M.; Elliott, Katherine S.; Lango, Hana; Timpson, Nicholas J.; Perry, John R.B.; Rayner, Nigel W.; Freathy, Rachel M.; Barrett, Jeffrey C.; Shields, Beverley; Morris, Andrew P.; Ellard, Sian; Groves, Christopher J.; Harries, Lorna W.; Marchini, Jonathan L.; Owen, Katharine R.; Knight, Beatrice; Cardon, Lon R.; Walker, Mark; Hitman, Graham A.; Morris, Andrew D.; Doney, Alex S.F.; McCarthy, Mark I.; Hattersley, Andrew T.

    2013-01-01

    The molecular mechanisms involved in the development of type 2 diabetes are poorly understood. Starting from genome-wide genotype data for 1,924 diabetic cases and 2,938 population controls generated by the Wellcome Trust Case Control Consortium, we set out to detect replicated diabetes association signals through analysis of 3,757 additional cases and 5,346 controls, and by integration of our findings with equivalent data from other international consortia. We detected diabetes susceptibility loci in and around the genes CDKAL1, CDKN2A/CDKN2B and IGF2BP2 and confirmed the recently described associations at HHEX/IDE and SLC30A8. Our findings provide insights into the genetic architecture of type 2 diabetes, emphasizing the contribution of multiple variants of modest effect. The regions identified underscore the importance of pathways influencing pancreatic beta cell development and function in the etiology of type 2 diabetes. PMID:17463249

  4. HLA-D region genes and rheumatoid arthritis (RA): importance of DR and DQ genes in conferring susceptibility to RA.

    PubMed Central

    Singal, D P; Green, D; Reid, B; Gladman, D D; Buchanan, W W

    1992-01-01

    The distribution of HLA-D region antigens was studied in three groups (I, IIa, and IIb) of patients with rheumatoid arthritis (RA): group I comprised 43 patients with mild, non-progressive RA, controlled by non-steroidal anti-inflammatory drugs without progression or erosions; group II comprised 94 patients with severe disease, who had earlier been treated with non-steroidal anti-inflammatory drugs and all had incomplete response requiring treatment with gold (sodium aurothiomalate). Of these, 46 patients (group IIa) responded to gold and the disease was well controlled, and the remaining 48 patients (group IIb) did not respond to gold and developed gold induced toxic reactions, including thrombocytopenia or proteinuria, or both. HLA-D region antigens were defined by serological and molecular (Southern blot analysis and oligonucleotide typing) techniques. The results show that DR4 was significantly increased in all three groups of patients. The prevalence of DR1, or DR1 in DR4 negative patients, and DR3 and DR4 associated DQw7 specificities, however, showed differences in these three groups of patients. The prevalence of DR1 and of DR1 in DR4 negative patients was increased only in patients with mild (group I) RA, but not in patients with severe (groups IIa and IIb) disease. On the other hand, the prevalence of DR4 associated DQw7 was significantly increased in patients with severe disease, but not in patients with mild RA. In addition, DR3 was significantly increased only in patients with severe disease who developed gold induced toxic reactions (group IIb). These data suggest that the HLA-D region genes which cause susceptibility to mild RA may be different from those causing susceptibility to severe RA. The results suggest that both DR and DQ (A, B) genes may be important in conferring susceptibility to RA: DR in mild disease and DQ in severe RA. Images PMID:1371662

  5. Genetic polymorphisms in the carbonic anhydrase VI gene and dental caries susceptibility.

    PubMed

    Li, Z-Q; Hu, X-P; Zhou, J-Y; Xie, X-D; Zhang, J-M

    2015-06-01

    We investigated the role of 7 single nucleotide polymorphisms in the carbonic anhydrase (CA) VI gene (rs2274328, rs17032907, rs11576766, rs2274333, rs10864376, rs3765964, and rs6680186) and the possible association between these polymorphisms and dental caries susceptibility in a Northwestern Chinese population. We collected samples from 164 high caries experience and 191 very low caries experience and conducted a case-control study according to the number of decayed, missing, and filled teeth index and genotyped the 7 polymorphisms using a 384-well plate format with the Sequenom MassARRAY platform. Individuals carrying the rs17032907 TT genotype were more likely to have an increased risk of dental caries compared with carriers of the C/C genotype in the co-dominant model, with an odds ratio (95% confidence interval) of 2.144 (1.096-4.195). We also found that the haplotype (ACA) (rs2274328, rs17032907 and rs11576766) was associated with a low number of decayed, missing, and filled teeth index with an odds ratio (95% confidence interval) of 0.635 (0.440-0.918). However, we found no association between dental caries susceptibility and the rs2274328, rs11576766, rs2274333, rs10864376, rs3765964, and rs6680186 polymorphisms and other haplotypes. The rs17032907 genetic variant and the haplotype (ACA) of CA VI may be associated with dental caries susceptibility.

  6. COMPARATIVE MICROARRAY EXPRESSION ANALYSIS OF SELECTED CANCER RELEVANT GENES IN HYPERTENSIVE RESISTANT VERSUS SUSCEPTIBLE RODENT STRAINS

    EPA Science Inventory

    Hypertension and cancer are prevalent diseases. Epidemiological studies suggest that hypertension may increase the long term risk of cancer. Identification of resistance and/or susceptibility genes using rodent models could provide important insights into the management and treat...

  7. Lipoprotein lipase gene mutations and the genetic susceptibility of preeclampsia.

    PubMed

    Kim, Y J; Williamson, R A; Chen, K; Smith, J L; Murray, J C; Merrill, D C

    2001-11-01

    In the pathogenesis of preeclampsia, endothelial cell activation or dysfunction is a central theme, and marked dyslipidemia may contribute to endothelial cell dysfunction. The objective of this study was to evaluate the association between preeclampsia and mutations within the lipoprotein lipase (LPL) gene. DNA was extracted from whole blood or cheek swabs of 250 preeclamptic patients, 265 control subjects, and 106 offspring of preeclamptic patients (all white). Control subjects were women who had undergone >/=2 term pregnancies unaffected by preeclampsia. All samples were genotyped for 3 LPL polymorphisms with the use of polymerase chain reaction of known allelic variants. The 3 mutations studied were the following: (1) Asp9Asn substitution in exon 2, (2) T-to-G substitution at position -93 of the proximal promotor region (-93T/G), and (3) Asn291Ser substitution in exon 6. Results were analyzed with an chi(2) contingency table. The prevalences of the Asp9Asn mutation, -93T/G promotor mutation, and Asn291Ser mutation were not significantly different among the preeclamptic patients and control subjects (Asp9Asn: patients, 2.8%; control subjects, 4.0%; -93T/G: patients, 4.5%; control subjects, 5.5%; Asn291Ser: patients, 4.0%; control subject, 3.0%). In addition, there was no difference in the frequency of any of the mutations in the offspring of preeclamptic women compared with that observed in the control population. Between a small group of patients with nulliparous HELLP syndrome (a variant of severe preeclampsia: hemolysis, elevated liver enzyme, low platelets) patients (n=12) and control subjects, there was a significant difference in the prevalence of the Asn291Ser mutation (16.7% versus 3.0%, P=0.01). In this large white population, the Asp9Asn mutation, -93T/G promotor mutation, and Asn291Ser mutation were not associated with an increased risk for preeclampsia. In a small subgroup of patients, the Asn291Ser mutation was associated with an increased risk for

  8. Possible association of VISA gene polymorphisms with susceptibility to systemic lupus erythematosus in Chinese population.

    PubMed

    Liu, Xiaowen; Jiao, Yulian; Wen, Xin; Wang, Laicheng; Ma, Chunyan; Gao, Xuejun; Chen, Zi-Jiang; Zhao, Yueran

    2011-10-01

    Virus-induced signaling adapter (VISA), an important adaptor protein linking both RIG-I and MDA-5 to downstream signaling events, may mediates the activation of NF kappaB and IRFs and the induction of type I IFN. As the evidence has showed that Toll-like receptors (TLRs), I-IFN and IFN-inducible genes contribute to the pathogenesis of systemic lupus erythematosus (SLE), the aim of the current study was to investigate the possible associations between the VISA gene and SLE. Four single nucleotide polymorphisms (SNPs), rs17857295, rs2326369, rs7262903, and rs7269320, in VISA gene were genotyped in 123 SLE patients and 95 healthy controls. Genotyping was performed using direct sequencing the purified PCR products. Associations were analyzed by using the chi-square test and Fisher's exact test. Haplotype analysis was performed using haploview and PHASE2.1. None of the four SNPs was found to be associated with SLE. The four-SNPs haplotype analysis showed different effect between cases and controls. While the SNPs, rs17857295 and rs2326369, were found to be associated with the renal nephritis and arthritis of SLE patient, respectively. The SNPs rs7269320 showed associations with different manifestations. Our data reveal that polymorphisms in the VISA gene may be related to disease susceptibility and manifestations of SLE.

  9. The Association Study of Calmodulin 1 Gene Polymorphisms with Susceptibility to Adolescent Idiopathic Scoliosis

    PubMed Central

    Zhang, Yu; Gu, Zuchao; Qiu, Guixing

    2014-01-01

    Objective. Idiopathic scoliosis is the most common pediatric spinal deformity affecting 1% to 3% of the population, and adolescent idiopathic scoliosis (AIS) accounts for approximately 80% of these cases; however, the etiology and pathogenesis of AIS are still uncertain. The current study aims to identify the relationship between calmodulin 1 (CALM1) gene and AIS predisposition, to identify the relationship between the genotypes of the SNPs and the clinical phenotypes of AIS. Methods. 146 AIS patients and 146 healthy controls were enrolled into this case-control study. 12 single nucleotide polymorphisms (SNPs) candidates in CALM1 gene were selected to determine the relationship between CALM1 gene and AIS predisposition. Case-only study was performed to determine the effects of these variants on the severity of the condition. Results. Three SNPs from 12 candidates were found to be associated with AIS predisposition. The ORs were observed as 0.549 (95% CI 0.3519–0.8579, P = 0.0079), 0.549 (95% CI 0.3519–0.8579, P = 0.0079), and 1.6139 (95% CI 1.0576–2.4634, P = 0.0257) for rs2300496, rs2300500, and rs3231718, respectively. There was no statistical difference between main curve, severity, and genotype distributions of all of 12 SNPs. Conclusion. Genetic variants of CALM1 gene are associated with AIS susceptibility. PMID:24551838

  10. Functional variants of sphingosine-1-phosphate receptor 1 gene associate with asthma susceptibility

    PubMed Central

    Sun, Xiaoguang; Ma, Shwu-Fan; Wade, Michael S.; Flores, Carlos; Pino-Yanes, Maria; Moitra, Jaideep; Ober, Carole; Kittles, Rick; Husain, Aliya N.; Ford, Jean G.; Garcia, Joe G. N.

    2012-01-01

    Background The genetic mechanisms underlying asthma remain unclear. Increased permeability of the microvasculature is a feature of asthma and the sphingosine-1-phosphate receptor, S1PR1, is an essential participant regulating lung vascular integrity and responses to lung inflammation. Objective We explored the contribution of polymorphisms in the S1PR1 gene (S1PR1) to asthma susceptibility. Methods A combination of gene re-sequencing for SNP discovery, case-control association, functional evaluation of associated SNPs, and protein immunochemistry studies was utilized. Results Immunohistochemistry studies demonstrated significantly decreased S1PR1 protein expression in pulmonary vessels in asthmatic lungs compared to non-asthmatic individuals (p<0.05). Direct DNA sequencing of 27 multiethnic samples identified 39 S1PR1 variants (18 novel SNPs). Association studies were performed based on genotyping results from cosmopolitan tagging SNPs in three case-control cohorts from Chicago and New York totaling 1061 subjects (502 cases and 559 controls). Promoter SNP rs2038366 (−1557G/T) was found to be associated with asthma (p=0.03) in European Americans. In African Americans, an association was found for both asthma and severe asthma for intronic SNP rs3753194 (c.−164+170A/G) (p=0.006 and p=0.040, respectively) and for promoter SNP rs59317557 (−532C/G) with severe asthma (p=0.028). Consistent with predicted in silico functionality, alleles of promoter SNPs rs2038366 (−1557G/T) and rs59317557 (−532C/G) influenced the activity of a luciferase S1PR1 reporter vector in transfected endothelial cells exposed to growth factors (EGF, PDGF, VEGF) known to be increased in asthmatic airways. Conclusion These data provide strong support for a role for S1PR1 gene variants in asthma susceptibility and severity. Clinical Implications Our results indicate S1PR1 is a novel asthma candidate gene and an attractive target for future therapeutic strategies. Capsule summary This study

  11. Association of GSTM1 and GSTT1 genes with the susceptibility to male infertility: result from a meta-analysis.

    PubMed

    Ying, Hou-Qun; Qi, Yue; Pu, Xiao-Ying; Liu, Shuo-Ran; A, Zhou-Cun

    2013-07-01

    The deletion polymorphisms of the glutathione S-transferase M1 (GSTM1) and glutathione S-transferase T1 (GSTT1) genes were considered as candidates for genetic susceptibility factors of male infertility. Previous studies concerning the relationship between the null genotype of the two genes and male infertility have been reported in recent years. However, the results remain elusive. A meta-analysis was performed to estimate the relationship between the deletion polymorphism of the GSTM1 or GSTT1 gene, and male infertility in this study. Sixteen studies concerning the GSTM1 gene, including 2174 cases and 1861 controls, and 13 case-control studies on the GSTT1 gene with a total number of 1992 cases and 1617 controls were processed. The results showed that the null genotype of the GSTM1 gene was associated with male infertility in the overall populations (P=0.003, OR=1.40, 95%CI=1.12-1.75), especially in Caucasian (P=0.012, OR=1.50, 95%CI=1.09-2.07) as well as Chinese (P=0.001, OR=1.55, 95%CI=1.19-2.03). The null genotype of the GSTT1 gene was strongly related to male infertility only in Chinese (P=0.000, OR=1.70, 95%CI=1.34-2.14). These results indicated that the null genotype of the GSTM1 gene might contribute to the susceptibility of male infertility, whereas the null genotype of the GSTT1 gene may be a genetic susceptibility factor of male infertility for the Chinese.

  12. Identification of candidate lung cancer susceptibility genes in mouse using oligonucleotide arrays

    PubMed Central

    Lemon, W; Bernert, H; Sun, H; Wang, Y; You, M

    2002-01-01

    We applied microarray gene expression profiling to lungs from mouse strains having variable susceptibility to lung tumour development as a means to identify, within known quantitative trait loci (QTLs), candidate genes responsible for susceptibility or resistance to lung cancer. At least eight chromosomal regions of mice have been mapped and verified to be linked with lung tumour susceptibility or resistance. In this study, high density oligonucleotide arrays were used to measure the relative expression levels of >36 000 genes and ESTs in lung tissues of A/J, BALB/cJ, SM/J, C3H/HeJ, and C57BL/6J mice. A number of differentially expressed genes were found in each of the lung cancer susceptibility QTLs. Bioinformatic analysis of the differentially expressed genes located within QTLs produced 28 susceptibility candidates and 22 resistance candidates. These candidates may be extremely helpful in the ultimate identification of the precise genes responsible for lung tumour susceptibility or resistance in mice and, through follow up, humans. Complete data sets are available at http://thinker.med.ohio-state.edu. PMID:12205107

  13. Susceptibility to arsenic-induced hyperkeratosis and oxidative stress genes myeloperoxidase and catalase.

    PubMed

    Ahsan, Habibul; Chen, Yu; Kibriya, Muhammad G; Islam, Mohammad N; Slavkovich, Vesna N; Graziano, Joseph H; Santella, Regina M

    2003-11-10

    Chronic exposure to inorganic arsenic is known to cause non-melanocytic skin and internal cancers in humans. We examined whether genetic susceptibility, as determined by single nucleotide polymorphisms -463G-->A and -262C-->T in the oxidative stress genes myeloperoxidase (MPO) and catalase (CAT), respectively, are associated with the risk of arsenic-induced hyperkeratotic skin lesions-precursors of skin cancer-in a case-control study in Bangladesh. Carriers of the susceptible MPO and CAT genotypes were at elevated risk (OR 2.1 and 95% CI 0.7-6.2 for MPO; OR 1.9 and 95% CI 0.8-4.7 for CAT) of hyperkeratosis after adjustment for arsenic exposure and other covariates. Subjects carrying the high-risk MPO genotype and with high arsenic exposure were at almost six times (OR 5.8; 95% CI 1.1-30.1) elevated risk of developing hyperkeratosis as compared to those carrying the low-risk genotype and with low arsenic exposure. Similarly, highly exposed subjects carrying the high-risk CAT genotype were at more than four times (OR 4.6; 95% CI 1.4-15.6) elevated risk of developing hyperkeratosis as compared to those carrying the low-risk genotype and with low arsenic exposure. Our findings, although based on small numbers, suggest that the oxidative stress genes MPO and CAT may influence the risk of arsenic-induced premalignant hyperkeratotic skin lesions.

  14. HLA-A gene polymorphisms contribute to osteoporosis susceptibility in postmenopausal Han Chinese women.

    PubMed

    Li, S M; Guo, H; Yang, H J; Lv, M Q; Zhou, D X

    2015-08-28

    Osteoporosis is a common disease characterized by low bone mineral density, deterioration in bone microarchitecture, and increased fracture risk and is more prevalent in postmenopausal women. HLA is a complex gene family; previous studies have shown that it plays an important role in the pathogenesis of osteoporosis among Japanese and Greek populations. Prompted by these findings, this study was designed to explore the associations between HLA-A gene polymorphisms and postmenopausal osteoporosis in the Han Chinese population. The polymerase chain reaction-sequence-based typing method was used for DNA genotyping at the HLA-A locus in 70 patients with postmenopausal osteoporosis and 73 healthy controls. We identified 17 HLA-A alleles in patients with postmenopausal osteoporosis and 20 HLA-A alleles in control subjects. Furthermore, we found that the frequency of the HLA-A* 02:07 allele was significantly higher in patients with postmenopausal osteoporosis than in control subjects (P = 0.023), and the relative risk was 4.065 (95% confidence interval = 1.109-14.893). Our study provides supportive evidence for the contribution of HLA-A gene polymorphisms to the susceptibility to postmenopausal osteoporosis and suggests that HLA-A* 02:07 is likely an important genetic risk factor for postmenopausal osteoporosis in the Han Chinese population.

  15. Method of controlling gene expression

    DOEpatents

    Peters, Norman K.; Frost, John W.; Long, Sharon R.

    1991-12-03

    A method of controlling expression of a DNA segment under the control of a nod gene promoter which comprises administering to a host containing a nod gene promoter an amount sufficient to control expression of the DNA segment of a compound of the formula: ##STR1## in which each R is independently H or OH, is described.

  16. A major QTL controls susceptibility to spinal curvature in the curveback guppy

    PubMed Central

    2011-01-01

    Background Understanding the genetic basis of heritable spinal curvature would benefit medicine and aquaculture. Heritable spinal curvature among otherwise healthy children (i.e. Idiopathic Scoliosis and Scheuermann kyphosis) accounts for more than 80% of all spinal curvatures and imposes a substantial healthcare cost through bracing, hospitalizations, surgery, and chronic back pain. In aquaculture, the prevalence of heritable spinal curvature can reach as high as 80% of a stock, and thus imposes a substantial cost through production losses. The genetic basis of heritable spinal curvature is unknown and so the objective of this work is to identify quantitative trait loci (QTL) affecting heritable spinal curvature in the curveback guppy. Prior work with curveback has demonstrated phenotypic parallels to human idiopathic-type scoliosis, suggesting shared biological pathways for the deformity. Results A major effect QTL that acts in a recessive manner and accounts for curve susceptibility was detected in an initial mapping cross on LG 14. In a second cross, we confirmed this susceptibility locus and fine mapped it to a 5 cM region that explains 82.6% of the total phenotypic variance. Conclusions We identify a major QTL that controls susceptibility to curvature. This locus contains over 100 genes, including MTNR1B, a candidate gene for human idiopathic scoliosis. The identification of genes associated with heritable spinal curvature in the curveback guppy has the potential to elucidate the biological basis of spinal curvature among humans and economically important teleosts. PMID:21269476

  17. Identification of genetic loci that control mammary tumor susceptibility through the host microenvironment

    DOE PAGESBeta

    Zhang, Pengju; Lo, Alvin; Huang, Yurong; Huang, Ge; Liang, Guozhou; Mott, Joni; Karpen, Gary H.; Blakely, Eleanor A.; Bissell, Mina J.; Barcellos-Hoff, Mary Helen; et al

    2015-03-09

    The interplay between host genetics, tumor microenvironment and environmental exposure in cancer susceptibility remains poorly understood. Here we assessed the genetic control of stromal mediation of mammary tumor susceptibility to low dose ionizing radiation (LDIR) using backcrossed F1 into BALB/c (F1Bx) between cancer susceptible (BALB/c) and resistant (SPRET/EiJ) mouse strains. Tumor formation was evaluated after transplantation of non-irradiated Trp53-/- BALB/c mammary gland fragments into cleared fat pads of F1Bx hosts. Genome-wide linkage analysis revealed 2 genetic loci that constitute the baseline susceptibility via host microenvironment. However, once challenged with LDIR, we discovered 13 additional loci that were enriched for genesmore » involved in cytokines, including TGFβ1 signaling. Surprisingly, LDIR-treated F1Bx cohort significantly reduced incidence of mammary tumors from Trp53-/- fragments as well as prolonged tumor latency, compared to sham-treated controls. We demonstrated further that plasma levels of specific cytokines were significantly correlated with tumor latency. Using an ex vivo 3-D assay, we confirmed TGFβ1 as a strong candidate for reduced mammary invasion in SPRET/EiJ, which could explain resistance of this strain to mammary cancer risk following LDIR. Our results open possible new avenues to understand mechanisms of genes operating via the stroma that affect cancer risk from external environmental exposures.« less

  18. Genetic susceptibility to heroin addiction; a candidate-gene association study

    PubMed Central

    Levran, O.; Londono, D.; O’Hara, K.; Nielsen, D. A.; Peles, E.; Rotrosen, J.; Casadonte, P.; Linzy, S.; Randesi, M.; Ott, J.; Adelson, M.; Kreek, M. J.

    2010-01-01

    Heroin addiction is a chronic complex disease with a substantial genetic contribution. This study was designed to identify genetic variants that are associated with susceptibility to develop heroin addiction, by analyzing 1350 variants in 130 candidate genes. All subjects had Caucasian ancestry. The sample consisted of 412 former severe heroin addicts in methadone treatment, and 184 healthy controls with no history of drug abuse. Nine variants, in six genes, showed the lowest nominal P values in the association tests (P < 0.01). These variants were in non-coding regions of the genes encoding the mu (OPRM1; rs510769, rs3778151), kappa (OPRK1; rs6473797), and delta opioid receptors, (OPRD1; rs2236861, rs2236857 and rs3766951), the neuropeptide galanin (GAL; rs694066), the serotonin receptor subtype 3B (HTR3B; rs3758987) and the casein kinase 1 isoform epsilon (CSNK1E; rs1534891). Several haplotypes and multi-locus genotype patterns showed nominally significant associations (e.g. OPRM1; P = 0.0006 and CSNK1E; P = 0.0007). Analysis of a combined effect of OPRM1 and OPRD1 showed that rs510769 and rs2236861 increase the risk of heroin addiction (P = 0.0005). None of these associations remained significant after adjustment for multiple testing. This study suggests the involvement of several genes and variants in heroin addiction that is worthy of future study. PMID:18518925

  19. FGF receptor genes and breast cancer susceptibility: results from the Breast Cancer Association Consortium

    PubMed Central

    Agarwal, D; Pineda, S; Michailidou, K; Herranz, J; Pita, G; Moreno, L T; Alonso, M R; Dennis, J; Wang, Q; Bolla, M K; Meyer, K B; Menéndez-Rodríguez, P; Hardisson, D; Mendiola, M; González-Neira, A; Lindblom, A; Margolin, S; Swerdlow, A; Ashworth, A; Orr, N; Jones, M; Matsuo, K; Ito, H; Iwata, H; Kondo, N; Hartman, M; Hui, M; Lim, W Y; T-C Iau, P; Sawyer, E; Tomlinson, I; Kerin, M; Miller, N; Kang, D; Choi, J-Y; Park, S K; Noh, D-Y; Hopper, J L; Schmidt, D F; Makalic, E; Southey, M C; Teo, S H; Yip, C H; Sivanandan, K; Tay, W-T; Brauch, H; Brüning, T; Hamann, U; Dunning, A M; Shah, M; Andrulis, I L; Knight, J A; Glendon, G; Tchatchou, S; Schmidt, M K; Broeks, A; Rosenberg, E H; van't Veer, L J; Fasching, P A; Renner, S P; Ekici, A B; Beckmann, M W; Shen, C-Y; Hsiung, C-N; Yu, J-C; Hou, M-F; Blot, W; Cai, Q; Wu, A H; Tseng, C-C; Van Den Berg, D; Stram, D O; Cox, A; Brock, I W; Reed, M W R; Muir, K; Lophatananon, A; Stewart-Brown, S; Siriwanarangsan, P; Zheng, W; Deming-Halverson, S; Shrubsole, M J; Long, J; Shu, X-O; Lu, W; Gao, Y-T; Zhang, B; Radice, P; Peterlongo, P; Manoukian, S; Mariette, F; Sangrajrang, S; McKay, J; Couch, F J; Toland, A E; Yannoukakos, D; Fletcher, O; Johnson, N; Silva, I dos Santos; Peto, J; Marme, F; Burwinkel, B; Guénel, P; Truong, T; Sanchez, M; Mulot, C; Bojesen, S E; Nordestgaard, B G; Flyer, H; Brenner, H; Dieffenbach, A K; Arndt, V; Stegmaier, C; Mannermaa, A; Kataja, V; Kosma, V-M; Hartikainen, J M; Lambrechts, D; Yesilyurt, B T; Floris, G; Leunen, K; Chang-Claude, J; Rudolph, A; Seibold, P; Flesch-Janys, D; Wang, X; Olson, J E; Vachon, C; Purrington, K; Giles, G G; Severi, G; Baglietto, L; Haiman, C A; Henderson, B E; Schumacher, F; Le Marchand, L; Simard, J; Dumont, M; Goldberg, M S; Labrèche, F; Winqvist, R; Pylkäs, K; Jukkola-Vuorinen, A; Grip, M; Devilee, P; Tollenaar, R A E M; Seynaeve, C; García-Closas, M; Chanock, S J; Lissowska, J; Figueroa, J D; Czene, K; Eriksson, M; Humphreys, K; Darabi, H; Hooning, M J; Kriege, M; Collée, J M; Tilanus-Linthorst, M; Li, J; Jakubowska, A; Lubinski, J; Jaworska-Bieniek, K; Durda, K; Nevanlinna, H; Muranen, T A; Aittomäki, K; Blomqvist, C; Bogdanova, N; Dörk, T; Hall, P; Chenevix-Trench, G; Easton, D F; Pharoah, P D P; Arias-Perez, J I; Zamora, P; Benítez, J; Milne, R L

    2014-01-01

    Background: Breast cancer is one of the most common malignancies in women. Genome-wide association studies have identified FGFR2 as a breast cancer susceptibility gene. Common variation in other fibroblast growth factor (FGF) receptors might also modify risk. We tested this hypothesis by studying genotyped single-nucleotide polymorphisms (SNPs) and imputed SNPs in FGFR1, FGFR3, FGFR4 and FGFRL1 in the Breast Cancer Association Consortium. Methods: Data were combined from 49 studies, including 53 835 cases and 50 156 controls, of which 89 050 (46 450 cases and 42 600 controls) were of European ancestry, 12 893 (6269 cases and 6624 controls) of Asian and 2048 (1116 cases and 932 controls) of African ancestry. Associations with risk of breast cancer, overall and by disease sub-type, were assessed using unconditional logistic regression. Results: Little evidence of association with breast cancer risk was observed for SNPs in the FGF receptor genes. The strongest evidence in European women was for rs743682 in FGFR3; the estimated per-allele odds ratio was 1.05 (95% confidence interval=1.02–1.09, P=0.0020), which is substantially lower than that observed for SNPs in FGFR2. Conclusion: Our results suggest that common variants in the other FGF receptors are not associated with risk of breast cancer to the degree observed for FGFR2. PMID:24548884

  20. Common Polymorphisms in the NFKBIA Gene and Cancer Susceptibility: A Meta-Analysis

    PubMed Central

    Zhang, Meng; Huang, Junjie; Tan, Xiuxiu; Bai, Jian; Wang, Hao; Ge, Yukun; Xiong, Hu; Shi, Jizhou; Lu, Wei; Lv, Zhaojie; Liang, Chaozhao

    2015-01-01

    Background NFKBIA encodes the inhibitors of nuclear factor-κB (NF-κB), which regulate the translation of the genes involved in the inflammatory and immune reactions. Polymorphisms (rs2233406, rs3138053, and rs696) of NFKBIA have been implicated in susceptibility to many cancer types. Material/Methods To evaluate the association between polymorphisms of NFKBIA and cancer susceptibility, a meta-analysis including a total of 7182 cancer cases and 10 057 controls from 28 case-control studies was performed. Data were extracted and pooled odds ratios (ORs) with 95% confidence intervals (CIs) were calculated. Results Combined data demonstrated that rs3138053 polymorphism of NFKBIA was associated with cancer susceptibility in an allelic model (C vs. T: OR=10.754, 95%CI=4.175–27.697, Pheterogeneity=0.000), while the polymorphism of rs696 appeared to play a protective role in tumorigenesis (CC+CT vs. TT: OR=0.879, 95%CI=0.787–0.982, Pheterogeneity=0.107). When stratification analysis was performed by cancer type, an increased association of rs3138053 was recognized in hepatocarcinoma (C vs. T: OR=42.180, 95%CI=27.970–63.612, Pheterogeneity=0.007), while a decreased association of rs696 was identified in Hodgkin lymphoma (C vs. T: OR=0.792, 95%CI=0.656–0.956, Pheterogeneity=0.116; CC vs. TT: OR=0.658, 95%CI=0.448–0.965, Pheterogeneity=0.076; CC vs. CT+TT: OR=0.734, 95%CI=0.562–0.958, Pheterogeneity=0.347). By ethnicity, rs696 appears to be a protective candidate among Caucasians (CT vs. TT: OR=0.809, 95%CI=0.676–0.969, Pheterogeneity=0.459). Conclusions Our data demonstrated that the rs3138053 polymorphism of NFKBIA gene is a candidate for susceptibility to overall cancers, while rs696 plays a protective role. PMID:26488500

  1. Tumor necrosis factor alpha gene -376 polymorphism and susceptibility to multiple sclerosis: an Egyptian study.

    PubMed

    Nada, Mona Abd el Fattah; Labib, Dalia Ahmed

    2011-03-01

    Tumor necrosis factor alpha, a proinflammatory cytokine, plays an important role in the clinical activity of relapsing-remitting multiple sclerosis and the development of progression. Dysregulation in the expression of tumor necrosis factor gene had been suggested in the pathogenesis of multiple sclerosis. Our aim was to investigate the relationship between tumor necrosis factor α-376 polymorphism with disease susceptibility and course of multiple sclerosis in Egyptian patients. Polymerase chain reaction and restriction fragment length polymorphism were carried out on 36 primary progressive multiple sclerosis patients, 36 age- and sex-matched remitting relapsing multiple sclerosis patients (diagnosed according to McDonald's Diagnostic criteria) and 30 age- and sex-matched healthy controls. The GG genotype and the guanine allele (G) were detected significantly more often in the primary progressive (p = 0.02; p = 0.004, respectively) and remitting relapsing (p = 0.015; p = 0.024, respectively) multiple sclerosis groups as compared with the healthy control group. The G allele in the examined position in tumor necrosis factor alpha might have a role as regards susceptibility in both remitting relapsing and primary progressive multiple sclerosis.

  2. Genetic analysis of dilated cardiomyopathy--HLA and immunoglobulin genes may confer susceptibility.

    PubMed

    Nishi, H; Kimura, A; Fukuta, S; Kusukawa, R; Kawamura, K; Nimura, Y; Nagano, M; Yasuda, H; Kawai, C; Sugimoto, T

    1992-10-01

    To identify genetic factors in the immune system which control the susceptibility to dilated cardiomyopathy (DCM), HLA class II DNA typing was performed in 61 Japanese patients, using PCR/SSO probe analyses. The frequencies of HLA-DQB1*0503 (15% vs 5%; RR = 3.06, chi 2 = 7.19) and DQB1*0604 (21% vs 10%; RR = 2.41, chi 2 = 6.20) were significantly increased and that of HLA-DQB1*0502 (RR = 1.74) was slightly increased in the DCM patients. The frequency of DQB1*0303 (16% vs 31%; RR = 0.44, chi 2 = 5.16) was significantly decreased in the patients. The increased HLA-DQB1 alleles have a histidine residue in common at the 30th codon for the HLA-DQ beta chain. Among the genetic markers studied by Southern blot analyses, IGLV (immunoglobulin lambda light chain, pV3.3) showed a strong association with DCM, i.e. A2/A2 genotype was found in 37.7% of patients whereas it was observed in only 18.9% of the control subjects (RR = 2.6, chi 2 = 7.77). The frequency of this genotype was higher in patients under age 45 years at the time of diagnosis (45.5%, RR = 3.6, chi 2 = 10.02). These results suggest that HLA and immunoglobulin genes are closely linked to susceptibility to DCM.

  3. Association Between Leptin (-2548G/A) Genes Polymorphism and Breast Cancer Susceptibility: A Meta-Analysis.

    PubMed

    Yan, Wanjun; Ma, Xingcong; Gao, Xiaoyan; Zhang, Shuqun

    2016-01-01

    Leptin is a confirmed breast cancer susceptibility gene. However, published studies reported mixed results. This meta-analysis was conducted to systematically get a more accurate estimation of the association between the Leptin (-2548G/A) gene polymorphism and breast cancer risk. To assess the effect of Leptin (-2548G/A) gene polymorphism on breast cancer susceptibility, we searched PUBMED, ISI Web of Knowledge, EMBASE, Chinese National Knowledge Infrastructure (CNKI) databases until September 2015 to identify eligible studies, without restriction. Summary odds ratios (ORs) and 95% confidence intervals (CIs) were used to evaluate the susceptibility to breast cancer. Separate analyses were conducted on features of the population such as ethnicity, source of controls, and country. A total of 9 case-control studies on Leptin (-2548G/A) gene polymorphism and breast cancer risk, including 3725 cases and 3093 case-free controls were identified. The results revealed that compared with the G allele, the A allele was associated with modestly increased risk of overall breast cancer (A vs G: OR = 1.12, 95%CI = 1.04-1.20, P = 0.002, Phet P < 0.00001). Following further stratified analyses, in the subgroup analyses by ethnicity, a significantly increased risk was observed among Caucasian (A vs G: OR = 1.11, 95%CI = 1.03-1.20, P = 0.006, Phet = 0.00001). No publication bias was found in the present study. In conclusion, our meta-analysis suggests that the Leptin (-2548G/A) gene polymorphism plays an important role in breast cancer susceptibility, especially in Caucasian. PMID:26825898

  4. Association of gene variants with susceptibility to type 2 diabetes among Omanis

    PubMed Central

    Al-Sinani, Sawsan; Woodhouse, Nicolas; Al-Mamari, Ali; Al-Shafie, Omaima; Al-Shafaee, Mohammed; Al-Yahyaee, Said; Hassan, Mohammed; Jaju, Deepali; Al-Hashmi, Khamis; Al-Abri, Mohammed; Al-Rassadi, Khalid; Rizvi, Syed; Loic, Yengo; Froguel, Philippe; Bayoumi, Riad

    2015-01-01

    AIM: To investigate the association of 10 known common gene variants with susceptibility to type 2 diabetes mellitus (T2D) among Omanis. METHODS: Using case-control design, a total of 992 diabetic patients and 294 normoglycemic Omani Arabs were genotyped, by an allelic discrimination assay-by-design TaqMan method on fast real time polymerase chain reaction system, for the following gene variants: KCNJ11 (rs5219), TCF7L2 (rs7903146), CDKAL1 (rs10946398), CDKN2A/B (rs10811661), FTO (rs9939609 and rs8050136), IGF2BP2 (rs4402960), SLC30A8 (rs13266634) CAPN10 (rs3792267) and HHEX (rs1111875). T2D patients were recruited from the Diabetes Clinic (n = 243) and inpatients (n = 749) at Sultan Qaboos Univesity Hospital (SQUH), Muscat, Oman. Adult control participants (n = 294) were volunteers from the community and from those visiting Family Medicine Clinic at SQU, for regular medical checkup. The difficulty in recruiting Omani participants with no family history of diabetes was the main reason behind the small number of control participants in this study. Almost all volunteers questioned had a relative with diabetes mellitus. Inspite of the small number of normoglycemic controls in this study, this sample was sufficient for detection of genes and loci for common alleles influencing T2D with an odds ratio of ≥ 1.3 reaching at least 80% power. Data was collected from June 2010 to February 2012. RESULTS: Using binary logistic regression analysis, four gene variants showed significant association with T2D risk: KCNJ11 (rs5219, P = 5.8 × 10-6, OR = 1.74), TCF7L2 (rs7903146, P = 0.001, OR = 1.46), CDKAL1 (rs10946398, P = 0.002, OR = 1.44) and CDKN2A/B (rs10811661, P = 0.020, OR = 1.40). The fixation index analysis of these four gene variants indicated significant genetic differentiation between diabetics and controls {[KCNJ11 (rs5219), P < 0.001], [TCF7L2 (rs7903146), P < 0.001], [CDKAL1 (rs10946398), P < 0.05], [CDKN2A/B (rs10811661), P < 0.05]}. The highest genotype

  5. A meta-analysis of xeroderma pigmentosum gene D Ls751Gln polymorphism and susceptibility to hepatocellular carcinoma.

    PubMed

    Wang, Yu; Zhao, Yingren; Zhang, Aiyun; Ma, Juan; Wang, Zhenzhen; Zhang, Xu

    2015-01-01

    Hepatocellular carcinoma (HCC) is one of most common malignant tumors worldwide, but with unclear mechanisms. Xeroderma pigmentosum gene D (XPD) is one important DNA damage repair gene and can be involved in protein mutation. Currently little has been known about XPD polymorphism and HCC susceptibility in Chinese people. This study used a meta-analysis approach to comprehensively investigate the correlation between XPD polymorphism and HCC susceptibility in Chinese population, based on previously published literatures. A computer retrieval system was used to collect all case-control studies about XPD Lys751Gln polymorphism and HCC susceptibility. Data in literatures were extracted for meta-analysis. After the primary screening, four independent studies, which were published in 3 English articles and one Chinese article, were recruited in this study. There were 1,717 samples included in all studies. Using Gln/Gln + Lys/Gln, Lys/Lys + Lys/Gln and Lys allels as the reference, HCC disease alleles including Lys/Lys, Gln/Gln and Gln had OR values (95% CI, I(2)) of 1.007 (0.657~4.672, 91%), 3.516 (0.220~20.661, 48%) and 3.225 (0.278~12.326, 84%), respectively. The polymorphism of XPD751 loci is closely correlated with primary HCC. Lys751Gln polymorphism of XPD gene can be used as one susceptibility factor for HCC. PMID:26722489

  6. An Integrated Genome-Wide Systems Genetics Screen for Breast Cancer Metastasis Susceptibility Genes.

    PubMed

    Bai, Ling; Yang, Howard H; Hu, Ying; Shukla, Anjali; Ha, Ngoc-Han; Doran, Anthony; Faraji, Farhoud; Goldberger, Natalie; Lee, Maxwell P; Keane, Thomas; Hunter, Kent W

    2016-04-01

    Metastasis remains the primary cause of patient morbidity and mortality in solid tumors and is due to the action of a large number of tumor-autonomous and non-autonomous factors. Here we report the results of a genome-wide integrated strategy to identify novel metastasis susceptibility candidate genes and molecular pathways in breast cancer metastasis. This analysis implicates a number of transcriptional regulators and suggests cell-mediated immunity is an important determinant. Moreover, the analysis identified novel or FDA-approved drugs as potentially useful for anti-metastatic therapy. Further explorations implementing this strategy may therefore provide a variety of information for clinical applications in the control and treatment of advanced neoplastic disease. PMID:27074153

  7. TLR9 gene region polymorphisms and susceptibility to tuberculosis in Vietnam.

    PubMed

    Graustein, A D; Horne, D J; Arentz, M; Bang, N D; Chau, T T H; Thwaites, G E; Caws, M; Thuong, N T T; Dunstan, S J; Hawn, T R

    2015-03-01

    Humans exposed to Mycobacterium tuberculosis (Mtb) show variation in susceptibility to infection and differences in tuberculosis (TB) disease outcome. Toll-like receptor 9 (TLR9) is a pattern recognition receptor that mediates recognition of Mtb and modulates Mtb-specific T-cell responses. Using a case-population design, we evaluated whether single nucleotide polymorphisms (SNPs) in the TLR9 gene region are associated with susceptibility to pulmonary or meningeal TB as well as neurologic presentation and mortality in the meningeal TB group. In a discovery cohort (n = 352 cases, 382 controls), three SNPs were associated with TB (all forms, p < 0.05) while three additional SNPs neared significance (0.05 < p < 0.1). When these six SNPs were evaluated in a validation cohort (n = 339 cases, 367 controls), one was significant (rs352142) while another neared significance (rs352143). When the cohorts were combined, rs352142 was most strongly associated with meningeal tuberculosis (dominant model; p = 0.0002, OR 2.36, CI 1.43-3.87) while rs352143 was associated with pulmonary tuberculosis (recessive model; p = 0.006, OR 5.3, CI 1.26-31.13). None of the SNPs were associated with mortality. This is the first demonstration of an association between a TLR9 gene region SNP and tuberculous meningitis. In addition, this extends previous findings that support associations of TLR9 SNPs with pulmonary tuberculosis.

  8. Germline Missense Variants in the BTNL2 Gene Are Associated with Prostate Cancer Susceptibility

    PubMed Central

    FitzGerald, Liesel M.; Kumar, Akash; Boyle, Evan A.; Zhang, Yuzheng; McIntosh, Laura M.; Kolb, Suzanne; Stott-Miller, Marni; Smith, Tiffany; Karyadi, Danielle M.; Ostrander, Elaine A.; Hsu, Li; Shendure, Jay; Stanford, Janet L.

    2013-01-01

    Background Rare, inherited mutations account for 5%–10% of all prostate cancer (PCa) cases. However, to date, few causative mutations have been identified. Methods To identify rare mutations for PCa, we performed whole-exome sequencing (WES) in multiple kindreds (n = 91) from 19 hereditary prostate cancer (HPC) families characterized by aggressive or early onset phenotypes. Candidate variants (n = 130) identified through family- and bioinformatics-based filtering of WES data were then genotyped in an independent set of 270 HPC families (n = 819 PCa cases; n = 496 unaffected relatives) for replication. Two variants with supportive evidence were subsequently genotyped in a population-based case-control study (n = 1,155 incident PCa cases; n = 1,060 age-matched controls) for further confirmation. All participants were men of European ancestry. Results The strongest evidence was for two germline missense variants in the butyrophilin-like 2 (BTNL2) gene (rs41441651, p.Asp336Asn and rs28362675, p.Gly454Cys) that segregated with affection status in two of the WES families. In the independent set of 270 HPC families, 1.5% (rs41441651; P = 0.0032) and 1.2% (rs28362675; P = 0.0070) of affected men, but no unaffected men, carried a variant. Both variants were associated with elevated PCa risk in the population-based study (rs41441651: OR = 2.7; 95% CI, 1.27–5.87; P = 0.010; rs28362675: OR = 2.5; 95% CI, 1.16–5.46; P = 0.019). Conclusions Results indicate that rare BTNL2 variants play a role in susceptibility to both familial and sporadic prostate cancer. Impact Results implicate BTNL2 as a novel PCa susceptibility gene. PMID:23833122

  9. New genes linked to lung cancer susceptibility in Asian women

    Cancer.gov

    An international group of scientists has identified three genes that predispose Asian women who have never smoked to lung cancer. The discovery of specific genetic variations, which have not previously been associated with lung cancer risk in other popul

  10. Natural selection on genes that underlie human disease susceptibility

    PubMed Central

    Blekhman, Ran; Man, Orna; Herrmann, Leslie; Boyko, Adam R.; Indap, Amit; Kosiol, Carolin; Bustamante, Carlos D.; Teshima, Kosuke M.; Przeworski, Molly

    2008-01-01

    What evolutionary forces shape genes that contribute to the risk of human disease? Do similar selective pressures act on alleles that underlie simple vs. complex disorders? [1-3]. Answers to these questions will shed light on the origin of human disorders (e.g., [4]), and help to predict the population frequencies of alleles that contribute to disease risk, with important implications for the efficient design of mapping studies [5-7]. As a first step towards addressing them, we created a hand-curated version of the Mendelian Inheritance in Man database (OMIM). We then examined selective pressures on Mendelian disease genes, genes that contribute to complex disease risk and genes known to be essential in mouse, by analyzing patterns of human polymorphism and of divergence between human and rhesus macaque. We find that Mendelian disease genes appear to be under widespread purifying selection, especially when the disease mutations are dominant (rather than recessive). In contrast, the class of genes that influence complex disease risk shows little signs of evolutionary conservation, possibly because this category includes both targets of purifying and positive selection. PMID:18571414

  11. Search of type 2 diabetes susceptibility gene on chromosome 20q

    SciTech Connect

    Takeuchi, F.; Yanai, K.; Inomata, H.; Kuzuya, N.; Kajio, H.; Honjo, S.; Takeda, N.; Kaburagi, Y.; Yasuda, K.; Shirasawa, S.; Sasazuki, T.; Kato, N. . E-mail: nokato@ri.imcj.go.jp

    2007-06-15

    Significant evidence of linkage to type 2 diabetes (T2D) has been shown in a relatively broad region on chromosome 20q, where the hepatocyte nuclear factor-4{alpha} (HNF4A) has been noted as a positional candidate. To systematically evaluate genetic susceptibility to T2D in the relevant region, we examined the disease association by using 1145 SNPs in two-step screening in the Japanese population. The marker screening enabled us to identify significant disease association in the lipopolysaccharide binding protein (LBP) but not in the HNF4A locus. In a 17.7-Mb interval screened, the strongest association was identified for a SNP, rs2232592, located in the intron of LBP, with an estimated odds ratio of 1.73 (95% CI 1.30-2.31) (P 0.0002) in the whole study panel involving 675 case and 474 control subjects. Our data suggest that the LBP gene may confer genetic susceptibility to T2D and this warrants further replication study.

  12. Arabidopsis enhanced disease susceptibility mutants exhibit enhanced susceptibility to several bacterial pathogens and alterations in PR-1 gene expression.

    PubMed Central

    Rogers, E E; Ausubel, F M

    1997-01-01

    To identify plant defense responses that limit pathogen attack, Arabidopsis eds mutants that exhibit enhanced disease susceptibility to the virulent bacterial pathogen Pseudomonas syringae pv maculicola ES4326 were previously identified. In this study, we show that each of four eds mutants (eds5-1, eds6-1, eds7-1, and eds9-1) has a distinguishable phenotype with respect to the degree of susceptibility to a panel of bacterial phytopathogens and the ability to activate pathogenesis-related PR-1 gene expression after pathogen attack. None of the four eds mutants exhibited observable defects in mounting a hypersensitive response. Although all four eds mutants were also capable of mounting a systemic acquired resistance response, enhanced growth of P. s. maculicola ES4326 was still apparent in the secondarily infected leaves of three of the eds mutants. These data indicate that eds genes define a diverse set of previously unknown defense responses that affect resistance to virulent pathogens. PMID:9090877

  13. Genetic variation in telomere maintenance genes, telomere length, and lung cancer susceptibility.

    PubMed

    Hosgood, H Dean; Cawthon, Richard; He, Xingzhou; Chanock, Stephen; Lan, Qing

    2009-11-01

    Telomeres are responsible for the protection of the chromosome ends and shortened telomere length has been associated with risk of multiple cancers. Genetic variation in telomere-related genes may alter cancer risk associated with telomere length. Using lung cancer cases (n=120) and population-based controls (n=110) from Xuanwei, China, we analyzed telomere length separately and in conjunction with single nucleotide polymorphisms in the telomere maintenance genes POT1, TERT, and TERF2, which we have previously reported were associated with risk of lung cancer in this study. POT1 rs10244817, TERT rs2075786, and TERF2 rs251796 were significantly associated with lung cancer (p(trend)< or =0.05). The shortest tertile of telomere length was not significantly associated with risk of lung cancer (OR=1.58; 95% CI=0.79-3.18) when compared to the longest tertile of telomere length. When stratified by genotype, there was a suggestion of a dose-response relationship between tertiles of telomere length and risk of lung cancer among the POT1 rs10244817 common variant carriers (OR (95% CI)=1.33 (0.47-3.75), 3.30 (1.14-9.56), respectively) but not among variant genotype carriers (p(interaction)=0.05). Our findings provide evidence that telomere length and genetic variation in telomere maintenance genes may be associated with risk of lung cancer susceptibility and warrant replication in larger studies.

  14. Resequencing and Association Analysis of Six PSD-95-Related Genes as Possible Susceptibility Genes for Schizophrenia and Autism Spectrum Disorders

    PubMed Central

    Xing, Jingrui; Kimura, Hiroki; Wang, Chenyao; Ishizuka, Kanako; Kushima, Itaru; Arioka, Yuko; Yoshimi, Akira; Nakamura, Yukako; Shiino, Tomoko; Oya-Ito, Tomoko; Takasaki, Yuto; Uno, Yota; Okada, Takashi; Iidaka, Tetsuya; Aleksic, Branko; Mori, Daisuke; Ozaki, Norio

    2016-01-01

    PSD-95 associated PSD proteins play a critical role in regulating the density and activity of glutamate receptors. Numerous previous studies have shown an association between the genes that encode these proteins and schizophrenia (SZ) and autism spectrum disorders (ASD), which share a substantial portion of genetic risks. We sequenced the protein-encoding regions of DLG1, DLG2, DLG4, DLGAP1, DLGAP2, and SynGAP in 562 cases (370 SZ and 192 ASD patients) on the Ion PGM platform. We detected 26 rare (minor allele frequency <1%), non-synonymous mutations, and conducted silico functional analysis and pedigree analysis when possible. Three variants, G344R in DLG1, G241S in DLG4, and R604C in DLGAP2, were selected for association analysis in an independent sample set of 1315 SZ patients, 382 ASD patients, and 1793 healthy controls. Neither DLG4-G241S nor DLGAP2-R604C was detected in any samples in case or control sets, whereas one additional SZ patient was found that carried DLG1-G344R. Our results suggest that rare missense mutations in the candidate PSD genes may increase susceptibility to SZ and/or ASD. These findings may strengthen the theory that rare, non-synonymous variants confer substantial genetic risks for these disorders. PMID:27271353

  15. Impact of Maspin Polymorphism rs2289520 G/C and Its Interaction with Gene to Gene, Alcohol Consumption Increase Susceptibility to Oral Cancer Occurrence

    PubMed Central

    Yang, Po-Yu; Miao, Nae-Fang; Lin, Chiao-Wen; Chou, Ying-Erh; Yang, Shun-Fa; Huang, Hui-Chuan; Chang, Hsiu-Ju; Tsai, Hsiu-Ting

    2016-01-01

    Background The purpose of this study was to identify gene polymorphisms of mammary serine protease inhibitor (Maspin) specific to patients with oral cancer susceptibility and clinicopathological status. Methodology/Principal Findings Three single-nucleotide polymorphisms (SNPs) of the Maspin gene from 741 patients with oral cancer and 601 non-cancer controls were analyzed by real-time PCR. The participants with G/G homozygotes or with G/C heterozygotes of Maspin rs2289520 polymorphism had a 2.07-fold (p = 0.01) and a 2.01-fold (p = 0.02) risk of developing oral cancer compared to those with C/C homozygotes. Moreover, gene-gene interaction increased the risk of oral cancer susceptibility among subjects expose to oral cancer related risk factors, including areca, alcohol, and tobacco consumption. Conclusion G allele of Maspin rs2289520 polymorphism may be a factor that increases the susceptibility to oral cancer. The interactions of gene to oral cancer-related environmental risk factors have a synergetic effect that can further enhance oral cancer development. PMID:27525723

  16. RAR-related orphan receptor A (RORA): A new susceptibility gene for multiple sclerosis.

    PubMed

    Eftekharian, Mohammad Mahdi; Noroozi, Rezvan; Sayad, Arezou; Sarrafzadeh, Shaghayegh; Toghi, Mehdi; Azimi, Tahereh; Komaki, Alireza; Mazdeh, Mehrdokht; Inoko, Hidetoshi; Taheri, Mohammad; Mirfakhraie, Reza

    2016-10-15

    Retinoic acid receptor-related orphan receptor alpha (RORA) is proposed to promote Th17 cells differentiation that play a crucial role in many inflammatory diseases, including multiple sclerosis (MS). The gene is also involved in regulation of inflammatory responses and neuronal cell development. The aim of the present study is to determine if any relation exists between RORA rs11639084 and rs4774388 gene polymorphisms on the individual susceptibility of multiple sclerosis. 410 patients with clinically definite MS and 500 ethnically-matched healthy controls participated in this study. Genotyping was performed using tetra primer-amplification refractory mutation system-PCR (4P-ARMS-PCR) method for the mentioned polymorphisms in the RORA gene. Both variants showed significant differences in allele and genotype distributions between the studied groups. Genotypes were risk associated in additive (P-value of 0.0003 and odds ratio equal to 1.7 (95% CI: 1.27-2.26)), dominant (P-value of <0.0001 and odds ratio equal to 0.55 (95% CI: 0.41-0.73)) and recessive (P-value of 0.04 and odds ratio equal to 0.33 (95% CI: (0.12-0.96)) models for rs11639084. However, the rs4774388 genotypes were risk associated in recessive model with a P-value of 0.036 and an odds ratio of 0.62 (95% CI: (0.4-0.97)). To the best of our knowledge this is the first report concerning the association between RORΑ gene polymorphisms and MS. The further study of RORΑ related pathways and gene networks might result in the better understanding of the pathophysiology of MS and related symptoms.

  17. RAR-related orphan receptor A (RORA): A new susceptibility gene for multiple sclerosis.

    PubMed

    Eftekharian, Mohammad Mahdi; Noroozi, Rezvan; Sayad, Arezou; Sarrafzadeh, Shaghayegh; Toghi, Mehdi; Azimi, Tahereh; Komaki, Alireza; Mazdeh, Mehrdokht; Inoko, Hidetoshi; Taheri, Mohammad; Mirfakhraie, Reza

    2016-10-15

    Retinoic acid receptor-related orphan receptor alpha (RORA) is proposed to promote Th17 cells differentiation that play a crucial role in many inflammatory diseases, including multiple sclerosis (MS). The gene is also involved in regulation of inflammatory responses and neuronal cell development. The aim of the present study is to determine if any relation exists between RORA rs11639084 and rs4774388 gene polymorphisms on the individual susceptibility of multiple sclerosis. 410 patients with clinically definite MS and 500 ethnically-matched healthy controls participated in this study. Genotyping was performed using tetra primer-amplification refractory mutation system-PCR (4P-ARMS-PCR) method for the mentioned polymorphisms in the RORA gene. Both variants showed significant differences in allele and genotype distributions between the studied groups. Genotypes were risk associated in additive (P-value of 0.0003 and odds ratio equal to 1.7 (95% CI: 1.27-2.26)), dominant (P-value of <0.0001 and odds ratio equal to 0.55 (95% CI: 0.41-0.73)) and recessive (P-value of 0.04 and odds ratio equal to 0.33 (95% CI: (0.12-0.96)) models for rs11639084. However, the rs4774388 genotypes were risk associated in recessive model with a P-value of 0.036 and an odds ratio of 0.62 (95% CI: (0.4-0.97)). To the best of our knowledge this is the first report concerning the association between RORΑ gene polymorphisms and MS. The further study of RORΑ related pathways and gene networks might result in the better understanding of the pathophysiology of MS and related symptoms. PMID:27653902

  18. Identification of susceptibility genes and genetic modifiers of human diseases

    NASA Astrophysics Data System (ADS)

    Abel, Kenneth; Kammerer, Stefan; Hoyal, Carolyn; Reneland, Rikard; Marnellos, George; Nelson, Matthew R.; Braun, Andreas

    2005-03-01

    The completion of the human genome sequence enables the discovery of genes involved in common human disorders. The successful identification of these genes is dependent on the availability of informative sample sets, validated marker panels, a high-throughput scoring technology, and a strategy for combining these resources. We have developed a universal platform technology based on mass spectrometry (MassARRAY) for analyzing nucleic acids with high precision and accuracy. To fuel this technology, we generated more than 100,000 validated assays for single nucleotide polymorphisms (SNPs) covering virtually all known and predicted human genes. We also established a large DNA sample bank comprised of more than 50,000 consented healthy and diseased individuals. This combination of reagents and technology allows the execution of large-scale genome-wide association studies. Taking advantage of MassARRAY"s capability for quantitative analysis of nucleic acids, allele frequencies are estimated in sample pools containing large numbers of individual DNAs. To compare pools as a first-pass "filtering" step is a tremendous advantage in throughput and cost over individual genotyping. We employed this approach in numerous genome-wide, hypothesis-free searches to identify genes associated with common complex diseases, such as breast cancer, osteoporosis, and osteoarthritis, and genes involved in quantitative traits like high density lipoproteins cholesterol (HDL-c) levels and central fat. Access to additional well-characterized patient samples through collaborations allows us to conduct replication studies that validate true disease genes. These discoveries will expand our understanding of genetic disease predisposition, and our ability for early diagnosis and determination of specific disease subtype or progression stage.

  19. Association of XPC Gene Polymorphisms with Susceptibility to Prostate Cancer: Evidence from 3,936 Subjects

    PubMed Central

    Zou, Yan-Feng; Tao, Jin-Hui; Ye, Qian-Ling; Pan, Hai-Feng; Pan, Fa-Ming; Su, Hong

    2013-01-01

    Aim: Polymorphisms of xeroderma pigmentosum complementation group C (XPC) are thought to have significant effects on prostate cancer (PCa) risk. The aim of our study was to evaluate the impact of XPC gene polymorphisms on PCa risk by using a meta-analysis. Methods: Data were collected from the following electronic databases: PubMed, EMBASE, Elsevier Science Direct, Cochrane Library, and CNKI, with the last report up to April 30, 2013. Odds ratios with 95% confidence intervals were used to assess the strength of the association. Results: A total of five separate case–control studies (1966 cases and 1970 controls) were included in this meta-analysis. Meta-analysis was performed for the rs2228001 and PAT+/−polymorphisms. We did not detect a significant association between rs2228001 polymorphism and PCa (p>0.05). Similar results were found in stratification analyses by ethnicity and tumor stage. We detected a significant association of PAT+/−polymorphism with PCa (p<0.05). In stratification analysis, we did not detect a significant association of PAT+/−polymorphism with risk of bone metastasis in PCa patients (p>0.05). Conclusion: These analyses suggest that XPC gene PAT+/−polymorphism, but not rs2228001, likely contributes to susceptibility to PCa. PMID:24093803

  20. Genetic evaluation of BRCA1-A complex genes with triple-negative breast cancer susceptibility in Chinese women

    PubMed Central

    Zheng, Yi-Zi; Qiao, Feng; Yao, Ling; Cao, Zhi-Gang; Ye, Fu-Gui; Wu, Jiong; Hu, Xin; Wang, Bin; Shao, Zhi-Ming

    2016-01-01

    Background The tumor suppressor BRCA1 plays a pivotal role in maintaining genomic stability and tumor suppression. The BRCA1-A complex is required for recruitment of BRCA1 to DNA damage sites, DNA repair and cell cycle checkpoint control. Since germline mutations of BRCA1 often lead to breast tumors that are triple-negative breast cancer (TNBC) type, we aimed to investigate whether genetic deficiency in genes of the BRCA1-A complex is associated with risk to TNBC development. Results We found that rs7250266 in the promoter region of NBA1 confers a decreased risk to TNBC development, but not to non-TNBC susceptibility. In addition, the haplotypes containing two polymorphisms rs7250266 and rs2278256 are associated with a lower chance of TNBC development specifically. Our studies also showed that the protective alleles of rs7250266 (C > G) and rs2278256 (T > C) down-regulate promoter activity of NBA1 in mammary epithelial cells. Methods We investigated associations between the BRCA1-A complex genes and TNBC developing risk in first case-control study of Chinese Han Women population including 414 patients with TNBC and 354 cancer-free controls. We detected 37 common variants in ABRAXAS, RAP80, BRE, BRCC36 and NBA1/MERIT40 genes encoding the BRCA1-A complex and evaluated their genetic susceptibility to the risk of TNBC. An additional cohort with 652 other types of breast cancer (non-TNBC) cases and 890 controls was used to investigate the associations between TNBC-specific SNPs genotype and non-TNBCs susceptibility. Conclusions Genetic variants in NBA1 may be an important genetic determinant of TNBC susceptibility. Further investigation and validation of these SNPs in larger cohorts may facilitate in predication and prevention of TNBC and in counseling individuals for risk of TNBC development. PMID:26848770

  1. Murine candidate bleomycin induced pulmonary fibrosis susceptibility genes identified by gene expression and sequence analysis of linkage regions

    PubMed Central

    Haston, C; Tomko, T; Godin, N; Kerckhoff, L; Hallett, M

    2005-01-01

    Background: Pulmonary fibrosis is a complex disease for which the predisposing genetic variants remain unknown. In a prior study, susceptibility to bleomycin induced pulmonary fibrosis was mapped to loci Blmpf1 and Blmpf2 on chromosomes 17 and 11, respectively, in a C57BL/6J (B6, susceptible) and C3Hf/KAM (C3H, resistant) mouse cross. Methods: Herein, the genetic basis of bleomycin induced pulmonary fibrosis was investigated in an approach combining gene expression and sequencing data with previously mapped linkage intervals. Results: In this study, gene expression analysis with microarrays revealed 1892 genes or ESTs (expressed sequence tags) to be differentially expressed between bleomycin treated B6 and C3H mice and 67 of these genetic elements map to Blmpf1 or Blmpf2. This group included genes involved in an oxidative stress response, in apoptosis, and in immune regulation. A comparison of the B6 and C3H sequence, for Blmpf1 and Blmpf2, made using the NCBI database and available C3H sequence, revealed approximately 35% of the genes in these regions contain non-synonymous coding sequence changes. An assessment of genotype/phenotype correlation among other inbred strains revealed 36% of these B6/C3H sequence variations predict for the known bleomycin induced fibrosis susceptibility of the DBA (susceptible) and A/J (resistant) mouse strains. Conclusions: Combining genomics approaches of differential gene expression and sequence variation potentially identifies approximately 5% the linked genes as fibrosis susceptibility candidate genes in this mouse cross. PMID:15937080

  2. Susceptibility to ozone-induced inflammation. I. Genetic control of the response to subacute exposure

    SciTech Connect

    Kleeberger, S.R.; Levitt, R.C.; Zhang, L.Y. )

    1993-01-01

    We demonstrated previously that C57BL/6J (B6) inbred mice are susceptible and C3H/HeJ (C3) mice are resistant to airway inflammation that is induced by acute (3 h) exposure to 2 parts per million (ppm) ozone (O3). In the present study we tested the hypothesis that B6 and C3 mice are also differentially susceptible to the airway inflammatory responses to subacute (72 h) exposure to environmentally relevant concentrations of O3 (0.12 and 0.30 ppm). Male mice (20-25 g, 5-7 wk) were exposed continuously to 0.12 ppm O3, 0.30 ppm O3, or filtered air (control). Pulmonary inflammation was assessed after 24, 48, and 72 h by differential cell count and total protein in bronchoalveolar lavage (BAL) returns. Exposure to 0.12 ppm O3 caused significant influx of alveolar macrophages, polymorphonuclear leukocytes (PMNs), lymphocytes, and total BAL protein in both strains, but no differences in the magnitude of the responses were found between B6 and C3 mice. In contrast to the effect of 0.12 ppm O3, exposure to 0.30 ppm O3 elicited significantly greater numbers of inflammatory cells and BAL protein concentration in B6 mice relative to C3 mice. The phenotypes of the B6 and C3 mice were termed susceptible and resistant, respectively. To further evaluate the potential genetic contribution to the inflammatory response to 0.30 ppm O3, the F1, F2, and backcross progeny from B6 and C3 progenitors were examined. The ratios of susceptible and resistant phenotypes of these progeny support the hypothesis that a single autosomal recessive gene confers susceptibility to subacute O3-induced inflammation.

  3. Analysis of LRRK2, SNCA, and ITGA8 Gene Variants with Sporadic Parkinson's Disease Susceptibility in Chinese Han Population

    PubMed Central

    Fang, Jie

    2016-01-01

    Background. Parkinson's disease (PD) is an age-related neurodegenerative disease affected by multiple genetic and environmental factors. We performed a case-control study on candidate gene to scrutinize whether genetic variants in LRRK2, SNCA, and ITGA8 genes could be associated with sporadic PD in Chinese Han population. Methods. Five single-nucleotide polymorphisms (SNPs) of LRRK2 (rs1491942), SNCA (rs2301134, rs2301135, and rs356221), and ITGA8 (rs7077361) were selected and genotyped among 583 unrelated PD patients and 558 healthy controls. Results. Rs1491942 of LRRK2 gene had a significantly higher genotype frequency (P = 3.543E − 09) and allelic G/C frequencies (P = 2.601E − 10) in PD patients than controls. Rs2301135 of SNCA gene also showed an obvious difference in genotype frequency (P = 4.394E − 07) and allelic G/C frequencies (P = 9.116E − 13) between PD patients and controls. SNPs rs2301134 and rs356221 of SNCA gene and rs7077361 of ITGA8 gene lacked the significant association with the susceptibility of PD in Chinese Han population. Conclusions. Our study firstly expresses that rs1491942 of LRRK2 and rs2301135 of SNCA gene are substantially associated with sporadic Parkinson's disease in Chinese Han population.

  4. Analysis of LRRK2, SNCA, and ITGA8 Gene Variants with Sporadic Parkinson's Disease Susceptibility in Chinese Han Population

    PubMed Central

    Fang, Jie

    2016-01-01

    Background. Parkinson's disease (PD) is an age-related neurodegenerative disease affected by multiple genetic and environmental factors. We performed a case-control study on candidate gene to scrutinize whether genetic variants in LRRK2, SNCA, and ITGA8 genes could be associated with sporadic PD in Chinese Han population. Methods. Five single-nucleotide polymorphisms (SNPs) of LRRK2 (rs1491942), SNCA (rs2301134, rs2301135, and rs356221), and ITGA8 (rs7077361) were selected and genotyped among 583 unrelated PD patients and 558 healthy controls. Results. Rs1491942 of LRRK2 gene had a significantly higher genotype frequency (P = 3.543E − 09) and allelic G/C frequencies (P = 2.601E − 10) in PD patients than controls. Rs2301135 of SNCA gene also showed an obvious difference in genotype frequency (P = 4.394E − 07) and allelic G/C frequencies (P = 9.116E − 13) between PD patients and controls. SNPs rs2301134 and rs356221 of SNCA gene and rs7077361 of ITGA8 gene lacked the significant association with the susceptibility of PD in Chinese Han population. Conclusions. Our study firstly expresses that rs1491942 of LRRK2 and rs2301135 of SNCA gene are substantially associated with sporadic Parkinson's disease in Chinese Han population. PMID:27668119

  5. Analysis of LRRK2, SNCA, and ITGA8 Gene Variants with Sporadic Parkinson's Disease Susceptibility in Chinese Han Population.

    PubMed

    Fang, Jie; Yi, Kehui; Guo, Mingwei; An, Xingkai; Qu, Hongli; Lin, Qing; Bi, Min; Ma, Qilin

    2016-01-01

    Background. Parkinson's disease (PD) is an age-related neurodegenerative disease affected by multiple genetic and environmental factors. We performed a case-control study on candidate gene to scrutinize whether genetic variants in LRRK2, SNCA, and ITGA8 genes could be associated with sporadic PD in Chinese Han population. Methods. Five single-nucleotide polymorphisms (SNPs) of LRRK2 (rs1491942), SNCA (rs2301134, rs2301135, and rs356221), and ITGA8 (rs7077361) were selected and genotyped among 583 unrelated PD patients and 558 healthy controls. Results. Rs1491942 of LRRK2 gene had a significantly higher genotype frequency (P = 3.543E - 09) and allelic G/C frequencies (P = 2.601E - 10) in PD patients than controls. Rs2301135 of SNCA gene also showed an obvious difference in genotype frequency (P = 4.394E - 07) and allelic G/C frequencies (P = 9.116E - 13) between PD patients and controls. SNPs rs2301134 and rs356221 of SNCA gene and rs7077361 of ITGA8 gene lacked the significant association with the susceptibility of PD in Chinese Han population. Conclusions. Our study firstly expresses that rs1491942 of LRRK2 and rs2301135 of SNCA gene are substantially associated with sporadic Parkinson's disease in Chinese Han population.

  6. Analysis of LRRK2, SNCA, and ITGA8 Gene Variants with Sporadic Parkinson's Disease Susceptibility in Chinese Han Population.

    PubMed

    Fang, Jie; Yi, Kehui; Guo, Mingwei; An, Xingkai; Qu, Hongli; Lin, Qing; Bi, Min; Ma, Qilin

    2016-01-01

    Background. Parkinson's disease (PD) is an age-related neurodegenerative disease affected by multiple genetic and environmental factors. We performed a case-control study on candidate gene to scrutinize whether genetic variants in LRRK2, SNCA, and ITGA8 genes could be associated with sporadic PD in Chinese Han population. Methods. Five single-nucleotide polymorphisms (SNPs) of LRRK2 (rs1491942), SNCA (rs2301134, rs2301135, and rs356221), and ITGA8 (rs7077361) were selected and genotyped among 583 unrelated PD patients and 558 healthy controls. Results. Rs1491942 of LRRK2 gene had a significantly higher genotype frequency (P = 3.543E - 09) and allelic G/C frequencies (P = 2.601E - 10) in PD patients than controls. Rs2301135 of SNCA gene also showed an obvious difference in genotype frequency (P = 4.394E - 07) and allelic G/C frequencies (P = 9.116E - 13) between PD patients and controls. SNPs rs2301134 and rs356221 of SNCA gene and rs7077361 of ITGA8 gene lacked the significant association with the susceptibility of PD in Chinese Han population. Conclusions. Our study firstly expresses that rs1491942 of LRRK2 and rs2301135 of SNCA gene are substantially associated with sporadic Parkinson's disease in Chinese Han population. PMID:27668119

  7. Combination of hearing screening and genetic screening for deafness-susceptibility genes in newborns

    PubMed Central

    YAO, GEN-DONG; LI, SHOU-XIA; CHEN, DING-LI; FENG, HAI-QIN; ZHAO, SU-BIN; LIU, YONG-JIE; GUO, LI-LI; YANG, ZHI-MING; ZHANG, XIAO-FANG; SUN, CAI-XIA; WANG, ZE-HUI; ZHANG, WEI-YONG

    2014-01-01

    The aim of this study was to determine the clinical significance of the results of screening of newborn hearing and the incidence of deafness-susceptibility genes. One thousand newborn babies in the Handan Center Hospital (Handan, China) underwent screening of hearing and deafness-susceptibility genes. The first screening test was carried out using otoacoustic emissions (OAEs). Babies with hearing loss who failed to pass the initial screening were scheduled for rescreening at 42 days after birth. Cord blood was used for the screening of deafness-susceptibility genes, namely the GJB2, SLC26A4 and mitochondrial 12S rRNA (MTRNR1) genes. Among the 1,000 neonates that underwent the first hearing screening, 25 exhibited left-sided hearing loss, 21 exhibited right-sided hearing loss and 15 cases had binaural hearing loss. After rescreening 42 days later, only one of the initial 61 cases exhibited hearing loss under OAE testing. The neonatal deafness gene tests showed two cases with 1555A>G mutation and two cases with 1494C>T mutation of the MTRNR1 gene. In the SLC26A4 gene screening, four cases exhibited the heterozygous IVS7-2A>G mutation and one case exhibited heterozygous 1226G>A mutation. In the GJB2 gene screening, two cases exhibited the homozygous 427C>T mutation and 10 exhibited the heterozygous 235delC mutation. The genetic screening revealed 21 newborns with mutations in the three deafness-susceptibility genes. The overall carrier rate was 2.1% (21/1,000). The association of hearing and gene screening may be the promising screening strategy for the diagnosis of hearing loss. PMID:24348793

  8. Combination of hearing screening and genetic screening for deafness-susceptibility genes in newborns.

    PubMed

    Yao, Gen-Dong; Li, Shou-Xia; Chen, Ding-Li; Feng, Hai-Qin; Zhao, Su-Bin; Liu, Yong-Jie; Guo, Li-Li; Yang, Zhi-Ming; Zhang, Xiao-Fang; Sun, Cai-Xia; Wang, Ze-Hui; Zhang, Wei-Yong

    2014-01-01

    The aim of this study was to determine the clinical significance of the results of screening of newborn hearing and the incidence of deafness-susceptibility genes. One thousand newborn babies in the Handan Center Hospital (Handan, China) underwent screening of hearing and deafness-susceptibility genes. The first screening test was carried out using otoacoustic emissions (OAEs). Babies with hearing loss who failed to pass the initial screening were scheduled for rescreening at 42 days after birth. Cord blood was used for the screening of deafness-susceptibility genes, namely the GJB2, SLC26A4 and mitochondrial 12S rRNA (MTRNR1) genes. Among the 1,000 neonates that underwent the first hearing screening, 25 exhibited left-sided hearing loss, 21 exhibited right-sided hearing loss and 15 cases had binaural hearing loss. After rescreening 42 days later, only one of the initial 61 cases exhibited hearing loss under OAE testing. The neonatal deafness gene tests showed two cases with 1555A>G mutation and two cases with 1494C>T mutation of the MTRNR1 gene. In the SLC26A4 gene screening, four cases exhibited the heterozygous IVS7-2A>G mutation and one case exhibited heterozygous 1226G>A mutation. In the GJB2 gene screening, two cases exhibited the homozygous 427C>T mutation and 10 exhibited the heterozygous 235delC mutation. The genetic screening revealed 21 newborns with mutations in the three deafness-susceptibility genes. The overall carrier rate was 2.1% (21/1,000). The association of hearing and gene screening may be the promising screening strategy for the diagnosis of hearing loss.

  9. Protein-protein interaction and pathway analyses of top schizophrenia genes reveal schizophrenia susceptibility genes converge on common molecular networks and enrichment of nucleosome (chromatin) assembly genes in schizophrenia susceptibility loci.

    PubMed

    Luo, Xiongjian; Huang, Liang; Jia, Peilin; Li, Ming; Su, Bing; Zhao, Zhongming; Gan, Lin

    2014-01-01

    Recent genome-wide association studies have identified many promising schizophrenia candidate genes and demonstrated that common polygenic variation contributes to schizophrenia risk. However, whether these genes represent perturbations to a common but limited set of underlying molecular processes (pathways) that modulate risk to schizophrenia remains elusive, and it is not known whether these genes converge on common biological pathways (networks) or represent different pathways. In addition, the theoretical and genetic mechanisms underlying the strong genetic heterogeneity of schizophrenia remain largely unknown. Using 4 well-defined data sets that contain top schizophrenia susceptibility genes and applying protein-protein interaction (PPI) network analysis, we investigated the interactions among proteins encoded by top schizophrenia susceptibility genes. We found proteins encoded by top schizophrenia susceptibility genes formed a highly significant interconnected network, and, compared with random networks, these PPI networks are statistically highly significant for both direct connectivity and indirect connectivity. We further validated these results using empirical functional data (transcriptome data from a clinical sample). These highly significant findings indicate that top schizophrenia susceptibility genes encode proteins that significantly directly interacted and formed a densely interconnected network, suggesting perturbations of common underlying molecular processes or pathways that modulate risk to schizophrenia. Our findings that schizophrenia susceptibility genes encode a highly interconnected protein network may also provide a novel explanation for the observed genetic heterogeneity of schizophrenia, ie, mutation in any member of this molecular network will lead to same functional consequences that eventually contribute to risk of schizophrenia.

  10. Polymorphisms in exon 2 of CD1 genes are associated with susceptibility to Guillain-Barré syndrome.

    PubMed

    Liu, Hongbo; Xing, Yanmeng; Guo, Yake; Liu, Peidong; Zhang, Hui; Xue, Bing; Shou, Jifei; Qian, Juanfeng; Peng, Jing; Wang, Rui; Gao, YiWei; Fang, Shuyou

    2016-10-15

    Guillain-Barré syndrome (GBS) is a post-infectious autoimmune peripheral neuropathy. Studies have shown that a T cell-mediated immune response to peripheral nerve is associated with the pathogenesis of GBS. CD1 molecules are MCH-like glycoproteins specialized to capture and present glycolipids to T cells. Polymorphisms of CD1 genes may affect susceptibility to GBS. We investigated the polymorphisms of CD1 genes in GBS patients in a Chinese Han population. In 126 patients and in 138 controls we genotyped exon 2 of the CD1A and CD1E genes. The results indicated that polymorphisms of CD1A genes are associated with GBS. Furthermore, subjects with CD1A*01/02 had a 2.9 times lower risk of developing GBS, and those with CD1A*02/02 had a 2.5 times higher risk to developing GBS than the controls, while there was no association between polymorphisms of CD1E genes and the susceptibilities to GBS.

  11. Immune complex type disease induced by HgCl2 in Brown-Norway rats: genetic control of susceptibility.

    PubMed

    Sapin, C; Mandet, C; Druet, E; Gunther, E; Druet, P

    1982-06-01

    Mercuric chloride induces a biphasic autoimmune glomerulonephritis in Brown-Norway (BN) rats but not in Lewis (LEW) rats. The genetic control of susceptibility to both phases was investigated by testing the response of segregants between BN and LEW rats and of congenic LEW.1N rats. It was confirmed that susceptibility to the first phase, characterized by the appearance of anti-glomerular basement membrane antibodies, depends on several genes one of which is RT1 linked. Susceptibility to the second phase, which is an immune complex type glomerulonephritis, was found to depend on one major RT1 linked gene or cluster of genes with a role for other(s) non-RT1 linked gene(s) controlling the magnitude of the response. However, congenic LEW.1N rats were found to be resistant. This suggests that the disease gene has been lost during the strain derivation. The question of whether both phases are two different diseases or expression of the same process cannot be definitely answered; data however indicate a dissociation of both disease processes.

  12. The role of ERBB2 gene polymorphisms in leprosy susceptibility.

    PubMed

    Rêgo, Jamile Leão; Oliveira, Joyce Moura; Santana, Nadja de Lima; Machado, Paulo Roberto Lima; Castellucci, Léa Cristina

    2015-01-01

    Mycobacterium leprae infects skin and peripheral nerves causing deformities and disability. The M. leprae bacterium binds to ErbB2 on the Schwann cell surface causing demyelination and favoring spread of the bacilli and causing nerve injury. Polymorphisms at the ERBB2 gene were previously investigated as genetic risk factors for leprosy in two Brazilian populations but with inconsistent results. Herein we extend the analysis of ERBB2 variants to a third geographically distinct population in Brazil. Our results show that there is no association between the genotyped SNPs and the disease (p>0.05) in this population. A gene set or pathway analysis under the genomic region of ERBB2 will be necessary to clarify its regulation under M. leprae stimulus.

  13. Hsp70-2 gene polymorphism: susceptibility implication in Tunisian patients with coronary artery disease

    PubMed Central

    2012-01-01

    Abstract Coronary artery disease (CAD) is a multifactorial disease where genetic and environmental factors interact in complex ways to cause the disease. Heat shock protein genes are involved in the progress of CAD. This implies that genetic variants of Hsp70–2 genes might contribute to the development of the CAD. Aim of study The aim of this study was to characterize statistical correlation of linkage between lipid profiles, polymorphism PstI site of Hsp70–2 gene and CAD. Patients and methods This study was carried out on Tunisian patients with CAD recruited from Hospital of Fattouma Bourguiba of Monastir-Tunisia. Polymerase chain reaction and restriction enzymes were used to determine the genotypic distributions in 252 unrelated patients and 151 healthy control subjects. Further, ApoA-I and ApoB as well as the serum total of cholesterol, HDL, triglyceride, and hs-CRP levels were measured. Results We showed a decreased level of ApoA-I, whereas the levels of each of ApoB and hs-CRP were increased in patients with CAD compared with control group. In addition our studies of a polymorphic PstI site of Hsp70-2 gene at position 1267 of the Hsp70–2 gene have revealed that the allelic frequency of P2 was significantly more frequent in CAD patients than controls group (p=0.007, OR=1.495). The genotypic distribution showed a high incidence of P2/P2 genotype in CAD patients (0.190) compared to healthy control (0.009) with reach significant difference (p=0.006). The P2 carriers showed a significantly increased of Total-Cholesterol (CT) and C-reactive protein (hs-CRP) levels in CAD patients (p=0.008 and p=0.018, respectively). Conclusion The high incidence of P2-Hsp70-2 genotype in CAD patients and the significantly association of P2/P2 genotype with elevated Total Cholesterol and hs-CRP levels, supported that P2–Hsp70–2 genotype has susceptibility implication in CAD and could increased the risk of CAD in Tunisian population. Virtual slides The virtual slide(s) for

  14. Vitamin D receptor gene FokI polymorphisms and tuberculosis susceptibility: a meta-analysis

    PubMed Central

    Cao, Yan; Cao, Zhihong; Cheng, Xiaoxing

    2016-01-01

    Introduction The association between FokI polymorphism of vitamin D receptor (VDR) and tuberculosis (TB) susceptibility has been investigated previously; however, the results were inconsistent and conflicting. In the present study, a meta-analysis was performed to assess the relationship between VDR FokI gene polymorphism and the risk of TB. Material and methods Databases including PubMed and Embase were searched for genetic association studies of FokI polymorphism of vitamin D receptor (VDR) and TB. Data were extracted by two independent authors and the pooled odds ratio (OR) with 95% confidence interval (CI) was calculated to assess the strength of the association between VDR FokI gene polymorphism and TB risk. Meta-regression and subgroup analyses were performed to identify the source of heterogeneity. Results Thirty-four studies with a total of 5669 cases and 6525 controls were reviewed in the present meta-analysis. A statistically significant correlation was found between VDR FokI gene polymorphism and increased TB risk in two comparison models: the homozygote model (ff vs. FF: OR = 1.37, 95% CI: 1.17–1.60; Pheterogeneity = 0.001) and the recessive model (ff vs. Ff + FF: OR = 1.32, 95% CI: 1.14–1.52; Pheterogeneity = 0.006). Meta-regression found no source contributing to heterogeneity. However, sub-group analyses revealed that there was a statistically increased TB risk in the East and Southeast Asian population. Conclusions Synthesis of the available studies suggests that homozygosity for the FokI polymorphism of the VDR gene might be associated with an increased TB risk, especially in the East and Southeast Asian population. Additional well-designed, larger-scale epidemiological studies among different ethnicities are needed. PMID:27695504

  15. No Significant Effect of ASAP1 Gene Variants on the Susceptibility to Tuberculosis in Chinese Population

    PubMed Central

    Hu, Xuejiao; Peng, Wu; Chen, Xuerong; Zhao, Zhenzhen; Zhang, Jingya; Zhou, Juan; Cai, Bei; Chen, Jie; Zhou, Yanhong; Lu, Xiaojun; Ying, Binwu

    2016-01-01

    Abstract Recent studies have proposed that the ASAP1 gene participates in regulating the adaptive immune response to Mycobacterium tuberculosis infection. A GWAS study has reported that ASAP1 polymorphisms (rs4733781 and rs10956514) were associated with the risk of tuberculosis (TB) in Russians. But due to population heterogeneity, different races would have different causative polymorphisms, and the aim of this study was to investigate the association between single nucleotide polymorphisms (SNPs) of the ASAP1 gene and TB risk in Chinese population. A total of 7 SNPs in the ASAP1 gene were genotyped in 1115 Western Chinese Han and 914 Tibetan population using an improved multiplex ligation detection reaction (iMLDR) method. The associations of SNPs with TB risk and clinical phenotypes were determined based on the distributions of allelic frequencies and different genetic models. A meta-analysis was carried out to further assess the relationship between ASAP1 polymorphism and TB risk. Statistical comparisons of cases and controls after correction for multiple testing did not yield any significant associations with the risk of TB via analyses of a single locus, haplotype, and subgroup differences. Meta-analysis showed no evidence supporting association between rs10956514 and overall risk for TB. Subsequent analysis referring to the genotypes of SNPs in relationship to clinical phenotypes identified that rs4236749 was associated with different serum C-reactive protein levels, suggesting a role of this locus in influencing the inflammatory state of Western Chinese Han patients with TB. Our present data revealed that ASAP1 polymorphisms are unlikely to confer susceptibility to TB in the Western Chinese Han and Tibetan populations, which challenges the promising roles of the ASAP1 gene in the development of TB and highlights the importance of validating the association findings across ethnicities. PMID:27227929

  16. Vitamin D receptor gene FokI polymorphisms and tuberculosis susceptibility: a meta-analysis

    PubMed Central

    Cao, Yan; Cao, Zhihong; Cheng, Xiaoxing

    2016-01-01

    Introduction The association between FokI polymorphism of vitamin D receptor (VDR) and tuberculosis (TB) susceptibility has been investigated previously; however, the results were inconsistent and conflicting. In the present study, a meta-analysis was performed to assess the relationship between VDR FokI gene polymorphism and the risk of TB. Material and methods Databases including PubMed and Embase were searched for genetic association studies of FokI polymorphism of vitamin D receptor (VDR) and TB. Data were extracted by two independent authors and the pooled odds ratio (OR) with 95% confidence interval (CI) was calculated to assess the strength of the association between VDR FokI gene polymorphism and TB risk. Meta-regression and subgroup analyses were performed to identify the source of heterogeneity. Results Thirty-four studies with a total of 5669 cases and 6525 controls were reviewed in the present meta-analysis. A statistically significant correlation was found between VDR FokI gene polymorphism and increased TB risk in two comparison models: the homozygote model (ff vs. FF: OR = 1.37, 95% CI: 1.17–1.60; Pheterogeneity = 0.001) and the recessive model (ff vs. Ff + FF: OR = 1.32, 95% CI: 1.14–1.52; Pheterogeneity = 0.006). Meta-regression found no source contributing to heterogeneity. However, sub-group analyses revealed that there was a statistically increased TB risk in the East and Southeast Asian population. Conclusions Synthesis of the available studies suggests that homozygosity for the FokI polymorphism of the VDR gene might be associated with an increased TB risk, especially in the East and Southeast Asian population. Additional well-designed, larger-scale epidemiological studies among different ethnicities are needed.

  17. Whole-exome sequencing identifies MST1R as a genetic susceptibility gene in nasopharyngeal carcinoma

    PubMed Central

    Dai, Wei; Zheng, Hong; Cheung, Arthur Kwok Leung; Tang, Clara Sze-man; Ko, Josephine Mun Yee; Wong, Bonnie Wing Yan; Leong, Merrin Man Long; Sham, Pak Chung; Cheung, Florence; Kwong, Dora Lai-Wan; Ngan, Roger Kai Cheong; Ng, Wai Tong; Yau, Chun Chung; Pan, Jianji; Peng, Xun; Tung, Stewart; Zhang, Zengfeng; Ji, Mingfang; Chiang, Alan Kwok-Shing; Lee, Anne Wing-Mui; Lee, Victor Ho-fun; Lam, Ka-On; Au, Kwok Hung; Cheng, Hoi Ching; Yiu, Harry Ho-Yin; Lung, Maria Li

    2016-01-01

    Multiple factors, including host genetics, environmental factors, and Epstein–Barr virus (EBV) infection, contribute to nasopharyngeal carcinoma (NPC) development. To identify genetic susceptibility genes for NPC, a whole-exome sequencing (WES) study was performed in 161 NPC cases and 895 controls of Southern Chinese descent. The gene-based burden test discovered an association between macrophage-stimulating 1 receptor (MST1R) and NPC. We identified 13 independent cases carrying the MST1R pathogenic heterozygous germ-line variants, and 53.8% of these cases were diagnosed with NPC aged at or even younger than 20 y, indicating that MST1R germ-line variants are relevant to disease early-age onset (EAO) (age of ≤20 y). In total, five MST1R missense variants were found in EAO cases but were rare in controls (EAO vs. control, 17.9% vs. 1.2%, P = 7.94 × 10−12). The validation study, including 2,160 cases and 2,433 controls, showed that the MST1R variant c.G917A:p.R306H is highly associated with NPC (odds ratio of 9.0). MST1R is predominantly expressed in the tissue-resident macrophages and is critical for innate immunity that protects organs from tissue damage and inflammation. Importantly, MST1R expression is detected in the ciliated epithelial cells in normal nasopharyngeal mucosa and plays a role in the cilia motility important for host defense. Although no somatic mutation of MST1R was identified in the sporadic NPC tumors, copy number alterations and promoter hypermethylation at MST1R were often observed. Our findings provide new insights into the pathogenesis of NPC by highlighting the involvement of the MST1R-mediated signaling pathways. PMID:26951679

  18. DNA repair gene XPD and susceptibility to arsenic-induced hyperkeratosis.

    PubMed

    Ahsan, Habibul; Chen, Yu; Wang, Qiao; Slavkovich, Vesna; Graziano, Joseph H; Santella, Regina M

    2003-07-20

    Chronic exposure to inorganic arsenic is known to cause non-melanocytic skin and internal cancers in humans. An estimated 50-70 million people in Bangladesh have been chronically exposed to arsenic from drinking water and are at risk of skin and other cancers. We undertook the first study to examine whether genetic susceptibility, as determined by the codon 751 SNP (A-->C) of the DNA repair gene XPD, influences the risk of arsenic-induced hyperkeratotic skin lesions, precursors of skin cancer, in a case-control study of 29 hyperkeratosis cases and 105 healthy controls from the same community in an area of Bangladesh. As expected, there was a monotonic increase in risk of hyperkeratosis in relation to urinary arsenic measures but the XPD genotype was not independently associated with the risk. However, the increase in hyperkeratosis risk in relation to urinary arsenic measures genotype was borderline significant for urinary total arsenic (P for trend=0.06) and statistically significant for urinary creatinine adjusted arsenic (P for trend=0.01) among subjects with the XPD A allele (AA) but not among subjects with the other XPD genotypes. Among AA carriers, the risk for the highest arsenic exposed group compared with the lowest was more than 7-fold for urinary total arsenic and about 11-fold for urinary creatinine adjusted arsenic. In conclusion, our findings suggest that the DNA repair gene XPD may influence the risk of arsenic-induced premalignant hyperkeratotic skin lesions. Future larger studies are needed to confirm this novel finding and investigate how combinations of different candidate genes and/or other host and environmental factors may influence the risk of arsenic induced skin and other cancers.

  19. Convergent lines of evidence support CAMKK2 as a schizophrenia susceptibility gene.

    PubMed

    Luo, X-J; Li, M; Huang, L; Steinberg, S; Mattheisen, M; Liang, G; Donohoe, G; Shi, Y; Chen, C; Yue, W; Alkelai, A; Lerer, B; Li, Z; Yi, Q; Rietschel, M; Cichon, S; Collier, D A; Tosato, S; Suvisaari, J; Rujescu, Dan; Golimbet, V; Silagadze, T; Durmishi, N; Milovancevic, M P; Stefansson, H; Schulze, T G; Nöthen, M M; Chen, C; Lyne, R; Morris, D W; Gill, M; Corvin, A; Zhang, D; Dong, Q; Moyzis, R K; Stefansson, K; Sigurdsson, E; Hu, F; Su, B; Gan, L

    2014-07-01

    Genes that are differentially expressed between schizophrenia patients and healthy controls may have key roles in the pathogenesis of schizophrenia. We analyzed two large-scale genome-wide expression studies, which examined changes in gene expression in schizophrenia patients and their matched controls. We found calcium/calmodulin (CAM)-dependent protein kinase kinase 2 (CAMKK2) is significantly downregulated in individuals with schizophrenia in both studies. To seek the potential genetic variants that may regulate the expression of CAMKK2, we investigated the association between single-nucleotide polymorphisms (SNPs) within CAMKK2 and the expression level of CAMKK2. We found one SNP, rs1063843, which is located in intron 17 of CAMKK2, is strongly associated with the expression level of CAMKK2 in human brains (P=1.1 × 10(-6)) and lymphoblastoid cell lines (the lowest P=8.4 × 10(-6)). We further investigated the association between rs1063843 and schizophrenia in multiple independent populations (a total of 130 623 subjects) and found rs1063843 is significantly associated with schizophrenia (P=5.17 × 10(-5)). Interestingly, we found the T allele of rs1063843, which is associated with lower expression level of CAMKK2, has a higher frequency in individuals with schizophrenia in all of the tested samples, suggesting rs1063843 may be a causal variant. We also found that rs1063843 is associated with cognitive function and personality in humans. In addition, protein-protein interaction (PPI) analysis revealed that CAMKK2 participates in a highly interconnected PPI network formed by top schizophrenia genes, which further supports the potential role of CAMKK2 in the pathogenesis of schizophrenia. Taken together, these converging lines of evidence strongly suggest that CAMKK2 may have pivotal roles in schizophrenia susceptibility. PMID:23958956

  20. Dopaminergic genes predict individual differences in susceptibility to confirmation bias

    PubMed Central

    Doll, Bradley B.; Hutchison, Kent E.; Frank, Michael J.

    2011-01-01

    The striatum is critical for the incremental learning of values associated with behavioral actions. The pre-frontal cortex (PFC) represents abstract rules and explicit contingencies to support rapid behavioral adaptation in the absence of cumulative experience. Here we test two alternative models of the interaction between these systems, and individual differences thereof, when human subjects are instructed with prior information about reward contingencies that may or may not be accurate. Behaviorally, subjects are overly influenced by prior instructions, at the expense of learning true reinforcement statistics. Computational analysis found that this pattern of data is best accounted for by a confirmation bias mechanism in which prior beliefs - putatively represented in PFC - influence the learning that occurs in the striatum such that reinforcement statistics are distorted. We assessed genetic variants affecting prefrontal and striatal dopaminergic neurotransmission. A polymorphism in the COMT gene (rs4680), associated with prefrontal dopaminergic function, was predictive of the degree to which participants persisted in responding in accordance with prior instructions even as evidence against their veracity accumulated. Polymorphisms in genes associated with striatal dopamine function (DARPP-32, rs907094, and DRD2, rs6277), were predictive of learning from positive and negative outcomes. Notably, these same variants were predictive of the degree to which such learning was overly inflated or neglected when outcomes are consistent or inconsistent with prior instructions. These findings indicate dissociable neurocomputational and genetic mechanisms by which initial biases are strengthened by experience. PMID:21508242

  1. Evidence that variation in the peripheral benzodiazepine receptor (PBR) gene influences susceptibility to panic disorder.

    PubMed

    Nakamura, Kazuhiko; Yamada, Kazuo; Iwayama, Yoshimi; Toyota, Tomoko; Furukawa, Aizou; Takimoto, Takahiro; Terayama, Hayato; Iwahashi, Kazuhiko; Takei, Nori; Minabe, Yoshio; Sekine, Yoshimoto; Suzuki, Katsuaki; Iwata, Yasuhide; Pillai, Anitha; Nakamoto, Yurie; Ikeda, Kazutaka; Yoshii, Mitsunobu; Fukunishi, Isao; Yoshikawa, Takeo; Mori, Norio

    2006-04-01

    Panic disorder (PD) is the repeated sudden occurrence of panic attacks, episodes characterized by psychological symptoms. Peripheral benzodiazepine receptor (PBR) is closely associated with personality traits for anxiety tolerance, and that it holds promise as a biological marker of stressful conditions. We have performed association analyses using the polymorphism to determine the PBR in PD. We screened the subjects for sequence variations within the 5' region, the coding region (exons 2-4), and the 3' noncoding region. One novel missense variant in exon 4, derived from the nucleotide transition in codon 162 (CGT --> CAT:485G > A) resulting in an arginine-to-histidine (Arg --> His) change, was detected in these subjects. The 485G > polymorphism of the PBR gene was analyzed in 91 PD patients and 178 controls. The genotypic and allelic analyses of the 485G > A revealed significant differences between the panic patients and the comparison subjects (P = 0.021 and 0.014, respectively). The present study provides new and important evidence that variation in the PBR gene influences susceptibility to PD.

  2. Combined analysis of DNA methylome and transcriptome reveal novel candidate genes with susceptibility to bovine Staphylococcus aureus subclinical mastitis

    PubMed Central

    Song, Minyan; He, Yanghua; Zhou, Huangkai; Zhang, Yi; Li, Xizhi; Yu, Ying

    2016-01-01

    Subclinical mastitis is a widely spread disease of lactating cows. Its major pathogen is Staphylococcus aureus (S. aureus). In this study, we performed genome-wide integrative analysis of DNA methylation and transcriptional expression to identify candidate genes and pathways relevant to bovine S. aureus subclinical mastitis. The genome-scale DNA methylation profiles of peripheral blood lymphocytes in cows with S. aureus subclinical mastitis (SA group) and healthy controls (CK) were generated by methylated DNA immunoprecipitation combined with microarrays. We identified 1078 differentially methylated genes in SA cows compared with the controls. By integrating DNA methylation and transcriptome data, 58 differentially methylated genes were shared with differently expressed genes, in which 20.7% distinctly hypermethylated genes showed down-regulated expression in SA versus CK, whereas 14.3% dramatically hypomethylated genes showed up-regulated expression. Integrated pathway analysis suggested that these genes were related to inflammation, ErbB signalling pathway and mismatch repair. Further functional analysis revealed that three genes, NRG1, MST1 and NAT9, were strongly correlated with the progression of S. aureus subclinical mastitis and could be used as powerful biomarkers for the improvement of bovine mastitis resistance. Our studies lay the groundwork for epigenetic modification and mechanistic studies on susceptibility of bovine mastitis. PMID:27411928

  3. Combined analysis of DNA methylome and transcriptome reveal novel candidate genes with susceptibility to bovine Staphylococcus aureus subclinical mastitis.

    PubMed

    Song, Minyan; He, Yanghua; Zhou, Huangkai; Zhang, Yi; Li, Xizhi; Yu, Ying

    2016-01-01

    Subclinical mastitis is a widely spread disease of lactating cows. Its major pathogen is Staphylococcus aureus (S. aureus). In this study, we performed genome-wide integrative analysis of DNA methylation and transcriptional expression to identify candidate genes and pathways relevant to bovine S. aureus subclinical mastitis. The genome-scale DNA methylation profiles of peripheral blood lymphocytes in cows with S. aureus subclinical mastitis (SA group) and healthy controls (CK) were generated by methylated DNA immunoprecipitation combined with microarrays. We identified 1078 differentially methylated genes in SA cows compared with the controls. By integrating DNA methylation and transcriptome data, 58 differentially methylated genes were shared with differently expressed genes, in which 20.7% distinctly hypermethylated genes showed down-regulated expression in SA versus CK, whereas 14.3% dramatically hypomethylated genes showed up-regulated expression. Integrated pathway analysis suggested that these genes were related to inflammation, ErbB signalling pathway and mismatch repair. Further functional analysis revealed that three genes, NRG1, MST1 and NAT9, were strongly correlated with the progression of S. aureus subclinical mastitis and could be used as powerful biomarkers for the improvement of bovine mastitis resistance. Our studies lay the groundwork for epigenetic modification and mechanistic studies on susceptibility of bovine mastitis.

  4. Germline melanoma susceptibility and prognostic genes: a review of the literature.

    PubMed

    Ward, Katherine A; Lazovich, DeAnn; Hordinsky, Maria K

    2012-11-01

    In recent years, there have been increasing efforts to identify germline genetic variants that may alter melanoma susceptibility and prognosis. The findings of these studies have indicated the presence of rare, high-penetrance alleles with large effects, such as CDKN2A and CDK4, more common, moderately penetrant genes like MC1R, and very common, low-penetrance polymorphisms with small effects that are related to pigmentation, nevus count, immune responses, DNA repair, metabolism, and the vitamin D receptor. The study of these low-penetrance single nucleotide polymorphisms is relatively new; thus many of them are termed 'candidate melanoma susceptibility or prognostic genes.' This review summarizes the research on germline polymorphisms that have been implicated in melanoma susceptibility and prognosis in order to provide a framework for additional studies to meet the ultimate goal of predicting a patient's risk of, and prognosis in, cutaneous malignant melanoma. PMID:22583682

  5. A strong candidate for the breast and ovarian cancer susceptibility gene BRCA1

    SciTech Connect

    Miki, Y.; Swenson, J.; Yakumo, K.; Lewis, C.; Neuhausen, S.; Goldgar, D.; Shattuck-Eidens, D.; Harshman, K.; Tavtigian, S.; Liu, Q.

    1994-10-07

    A strong candidate for the 17q-linked BRCA1 gene, which influences susceptibility to breast and ovarian cancer, has been identified by positional cloning methods. Probable predisposing mutations have been detected in five of eight kindreds presumed to segregate BRCA1 susceptibility alleles. The mutations include an 11-base pair deletion, a 1-base pair insertion, a stop codon, a missense substitution, and an inferred regulatory mutation. The BRCA1 gene is expressed in numerous tissues, including breast and ovary, and encodes a predicted protein of 1863 amino acids. This protein contains a zinc finger domain in its amino-terminal region, but is otherwise unrelated to previously described proteins. Identification of BRCA1 should facilitate early diagnosis of breast and ovarian cancer susceptibility in some individuals as well as a better understanding of breast cancer biology.

  6. fosI Is a New Integron-Associated Gene Cassette Encoding Reduced Susceptibility to Fosfomycin

    PubMed Central

    Pelegrino, Karla de Oliveira; Campos, Juliana Coutinho; Sampaio, Suely Carlos Ferreira; Lezirovitz, Karina; Seco, Bruna Mara; Pereira, Mayne de Oliveira; Rocha, Darlan Augusto da Costa; Jové, Thomas; Nicodemo, Antonio Carlos

    2015-01-01

    In this work, we demonstrate that the fosI gene encodes a predicted small protein with 134 amino acids and determines reduced susceptibility to fosfomycin. It raised the MIC from 0.125 to 6 μg/ml when the pBRA100 plasmid was introduced into Escherichia coli TOP10 and to 16 μg/ml when the gene was cloned into the pBC_SK(−) vector and expressed in E. coli TOP10. PMID:26552984

  7. fosI Is a New Integron-Associated Gene Cassette Encoding Reduced Susceptibility to Fosfomycin.

    PubMed

    Pelegrino, Karla de Oliveira; Campos, Juliana Coutinho; Sampaio, Suely Carlos Ferreira; Lezirovitz, Karina; Seco, Bruna Mara; Pereira, Mayne de Oliveira; Rocha, Darlan Augusto da Costa; Jové, Thomas; Nicodemo, Antonio Carlos; Sampaio, Jorge Luiz Mello

    2015-11-09

    In this work, we demonstrate that the fosI gene encodes a predicted small protein with 134 amino acids and determines reduced susceptibility to fosfomycin. It raised the MIC from 0.125 to 6 μg/ml when the pBRA100 plasmid was introduced into Escherichia coli TOP10 and to 16 μg/ml when the gene was cloned into the pBC_SK(-) vector and expressed in E. coli TOP10.

  8. ALTERED HEPATIC GENE EXPRESSION IN MORBIDLY OBESE WOMEN AND ITS IMPLICATIONS FOR SUSCEPTIBILITY TO OTHER DISEASES

    EPA Science Inventory

    The objective of this study was to determine the molecular bases of disordered hepatic function and disease susceptibility in obesity. We compared global gene expression in liver biopsies from morbidly obese (MO) women undergoing gastric bypass (GBP) surgery with that of women un...

  9. Major Histocompatibility Complex and Background Genes in Chickens Influence Susceptibility to High Pathogenicity Avian Influenza Virus

    Technology Transfer Automated Retrieval System (TEKTRAN)

    The chicken’s major histocompatibility complex (MHC) haplotype has profound influence on the resistance or susceptibility to certain pathogens such as B21 MHC haplotype confers resistance to Marek’s disease (MD). However, non-MHC genes are also important in disease resistance. For example, both line...

  10. Association Between Polymorphisms of DRD2, COMT, DBH, and MAO-A Genes and Migraine Susceptibility: A Meta-Analysis.

    PubMed

    Chen, Hu; Ji, Chun-Xue; Zhao, Lian-Li; Kong, Xiang-Jun; Zeng, Xian-Tao

    2015-11-01

    Some epidemiological studies have investigated the relationship between genetic polymorphisms of DRD2, COMT, DBH, and MAO-A and migraine susceptibility, but the results are still inconsistent. Thus, our aim was to further assess the association through a meta-analysis.We examined 5 single nucleotide polymorphisms (SNPs) in 4 genes, including DRD2 rs1799732 and rs6275, DBH rs7239728, MAI-A-VNTR, and COMT rs4680, and performed a meta-analysis of 11 published case-control studies including 3138 cases and 4126 controls. Odd ratios (ORs) with 95% confidence intervals (95% CIs) were used to evaluate the association between the 5 genetic polymorphisms and migraine susceptibility.There was no significant relationship between migraine susceptibility and 4 genetic polymorphisms of DRD2 rs1799732 and rs6275, DBH rs7239728, and MAO-A-VNTR. Nevertheless, decreased risk of migraine was observed to be in association with COMT rs4680 polymorphism in overall analysis (AA vs. GG + GA: OR = 0.76, 95% CI = 0.60-0.97, PHet > 0.642, I = 0), and in Caucasian group after subgroup analysis (AA vs. GG + GA: OR = 0.75, 95% CI = 0.58-0.96, PHet > 0.433, I = 0).Studied polymorphisms of DRD2, DBH, and MAO-A genes may not be associated with migraine susceptibility. However, COMT rs4680 polymorphism may decrease the risk of migraine, especially in Caucasians. The failure to evaluate environmental influence and provide adjusted effect size estimates highlights the need for additional studies in a large number to take these factors into consideration, thus better elucidating the role of the genes tested in migraine. PMID:26632697

  11. Prion-like Doppel gene polymorphisms and scrapie susceptibility in Portuguese sheep breeds.

    PubMed

    Mesquita, P; Batista, M; Marques, M R; Santos, I C; Pimenta, J; Silva Pereira, M; Carolino, I; Santos Silva, F; Oliveira Sousa, M C; Gama, L T; Fontes, C M; Horta, A E M; Prates, J A M; Pereira, R M

    2010-06-01

    The establishment of an association between prion protein gene (PRNP) polymorphisms and scrapie susceptibility in sheep has enabled the development of breeding programmes to increase scrapie resistance in the European Union. Intense selection for PRNP genotype may lead to correlated selection for genes linked to PRNP. We intended to investigate if any association exists between genetic variation in prion-like protein Doppel gene (PRND) and scrapie susceptibility, determined through PRNP genotyping. Sampling included 460 sheep from eight Portuguese breeds and the PRND gene coding region was analysed by multiple restriction fragment-single strand conformation polymorphism (MRF-SSCP), whereas PRNP genotyping was carried out by primer extension. A synonymous substitution (c.78G>A) was detected in codon 26 of the PRND gene, in all breeds except Churra Mondegueira. Linkage disequilibrium was found between the PRND and PRNP loci (P = 0.000). Specifically, PRND was monomorphic in the 45 animals with the more resistant ARR/ARR PRNP genotype (P = 0.003), whereas a higher frequency of PRND heterozygotes (GA) was associated with ARQ/AHQ (P = 0.029). These results constitute preliminary evidence of an association between a polymorphism in the PRND gene and scrapie susceptibility, and indicate that the possibility of undesirable consequences from widespread selection for PRNP genotype on genetic diversity and reproduction traits needs to be further investigated.

  12. Differential gene expression of two extreme honey bee (Apis mellifera) colonies showing varroa tolerance and susceptibility.

    PubMed

    Jiang, S; Robertson, T; Mostajeran, M; Robertson, A J; Qiu, X

    2016-06-01

    Varroa destructor, an ectoparasitic mite of honey bees (Apis mellifera), is the most serious pest threatening the apiculture industry. In our honey bee breeding programme, two honey bee colonies showing extreme phenotypes for varroa tolerance/resistance (S88) and susceptibility (G4) were identified by natural selection from a large gene pool over a 6-year period. To investigate potential defence mechanisms for honey bee tolerance to varroa infestation, we employed DNA microarray and real time quantitative (PCR) analyses to identify differentially expressed genes in the tolerant and susceptible colonies at pupa and adult stages. Our results showed that more differentially expressed genes were identified in the tolerant bees than in bees from the susceptible colony, indicating that the tolerant colony showed an increased genetic capacity to respond to varroa mite infestation. In both colonies, there were more differentially expressed genes identified at the pupa stage than at the adult stage, indicating that pupa bees are more responsive to varroa infestation than adult bees. Genes showing differential expression in the colony phenotypes were categorized into several groups based on their molecular functions, such as olfactory signalling, detoxification processes, exoskeleton formation, protein degradation and long-chain fatty acid metabolism, suggesting that these biological processes play roles in conferring varroa tolerance to naturally selected colonies. Identification of differentially expressed genes between the two colony phenotypes provides potential molecular markers for selecting and breeding varroa-tolerant honey bees. PMID:26919127

  13. The genetic basis of aminoglycoside ototoxicity: The search for susceptibility genes

    SciTech Connect

    Prezant, T.R.; Fischel-Ghodsian, F.

    1994-09-01

    The susceptibility to aminoglycoside ototoxicity appears to be genetically determined. Recently we identified a mutation in the small ribosomal RNA gene of the mitochondrial DNA that can cause deafness after aminoglycoside treatment in families with maternally-inherited susceptibility to the ototoxic effect of these antibiotics. The mutation produces a structural change in the 12S rRNA, which allows increased binding of aminoglycosides, mistranslation of mitochondrial proteins, decreased energy production, and cell death. Because only a minority of sporadic patients have mutations in the 12S rRNA gene, we anticipate the involvement of other genes in ototoxic deafness. We have developed a model system in the yeast Saccharomyces cerevisiae to functionally identify genes whose products interact with aminoglycosides. Besides its small genome size and well-developed genetic tools, a unique advantage of using this haploid organism is that recessive drug-responsive mutations will not be missed. An additional advantage is that yeast can be grown in either fermentative or respiratory media, allowing the functional categorization of mutants. Over 100 antibiotic-resistant mutants have now been isolated. The majority of these mutations (69%) are dominant and are being sorted by segregation tests. The 31% of mutations that are recessive have been sorted into two major complementation groups, indicating that two genes appear to be responsible for most of the recessive cases. Our strategy is to isolate the yeast genes that most commonly acquire mutations, clone the human homologs, and screen patients for susceptibility mutations.

  14. Detection of vanC1 gene transcription in vancomycin-susceptible Enterococcus faecalis.

    PubMed

    Moura, Tiane Martin de; Cassenego, Ana Paula Vaz; Campos, Fabrício Souza; Ribeiro, Andrea Machado Leal; Franco, Ana Cláudia; d'Azevedo, Pedro Alves; Frazzon, Jeverson; Frazzon, Ana Paula Guedes

    2013-06-01

    Here we report the presence and expression levels of the vanC1 and vanC(2/3) genes in vancomycin-susceptible strains of Enterococcus faecalis. The vanC1 and vanC(2/3) genes were located in the plasmid DNA and on the chromosome, respectively. Specific mRNA of the vanC1 gene was detected in one of these strains. Additionally, analysis of the vanC gene sequences showed that these genes are related to the vanC genes of Enterococcus gallinarum and Enterococcus casseliflavus. The presence of vanC genes is useful for the identification of E. gallinarum and E. casseliflavus. Moreover, this is the first report of vanC mRNA in E. faecalis.

  15. Common variants of the PINK1 and PARL genes do not confer genetic susceptibility to schizophrenia in Han Chinese.

    PubMed

    Li, Xiao; Zhang, Wen; Zhang, Chen; Yi, Zhenghui; Zhang, Deng-Feng; Gong, Wei; Tang, Jinsong; Wang, Dong; Lu, Weihong; Chen, Xiaogang; Fang, Yiru; Yao, Yong-Gang

    2015-04-01

    Schizophrenia is a prevalent psychiatric disorder with a complex etiology. Mitochondrial dysfunction has been frequently reported in schizophrenia. Phosphatase and tension homologue-induced kinase 1 (PINK1) and presenilin-associated rhomboid-like protease (PARL) are mitochondrial proteins, and genetic variants of these two genes may confer genetic susceptibility to schizophrenia by influencing mitochondrial function. In this study, we conducted a two-stage genetic association study to test this hypothesis. We genotyped 4 PINK1 and 5 PARL genetic variants and evaluated the potential association of the 9 SNPs with schizophrenia in two independent case-control cohorts of 2510 Han Chinese individuals. No positive association of common genetic variants of the PINK1 and PARL genes with schizophrenia was identified in our samples after Bonferroni correction. Re-analysis of the newly updated Psychiatric Genetics Consortium (PGC) data sets confirmed our negative result. Intriguingly, one PINK1 SNP (rs10916832), which showed a marginally significant association in only Hunan samples (P = 0.032), is associated with the expression of a schizophrenia susceptible gene KIF17 according to the expression quantitative trait locus (eQTL) analysis. Our study indicated that common genetic variants of the PINK1 and PARL genes are unlikely to be involved in schizophrenia. Further studies are essential to characterize the role of the PINK1 and PARL genes in schizophrenia.

  16. Neuropsychological deficits in mice depleted of the schizophrenia susceptibility gene CSMD1.

    PubMed

    Steen, Vidar M; Nepal, Chirag; Ersland, Kari M; Holdhus, Rita; Nævdal, Marianne; Ratvik, Siri M; Skrede, Silje; Håvik, Bjarte

    2013-01-01

    Recent meta-analyses of schizophrenia genome-wide association studies (GWASs) have identified the CUB and SUSHI multiple domains 1 (CSMD1) gene as a statistically strong risk factor. CSMD1 is a complement control-related protein suggested to inhibit the classical complement pathway, being expressed in developing neurons. However, expression of CSMD1 is largely uncharacterized and relevance for behavioral phenotypes is not previously demonstrated. Here, we assess neuropsychological behaviors of a Csmd1 knockout (KO) mouse in a selection of standard behavioral tests. Deregulation of neuropsychological responses were observed in both the open field and the elevated plus maze tests, in which KO mice spent 55% and 33% less time than WT littermate mice in open areas, respectively. Altered behaviors were also observed in tail suspension and to higher acoustic stimuli, for which Csmd1 KO mice showed helplessness and moderate increase in startle amplitude, respectively. Furthermore, Csmd1 KO mice also displayed increased weight-gain and glucose tolerance, similar to a major phenotype of the metabolic syndrome that also has been associated to the human CSMD1 locus. Consistent with a role in the control of behaviors, Csmd1 was found highly expressed in the central nervous system (CNS), and with some expression in visceral fat and ovary, under tissue-specific control by a novel promoter-associated lncRNA. In summary, disruption of Csmd1 induces behaviors reminiscent of blunted emotional responses, anxiety and depression. These observations suggest an influence of the CSMD1 schizophrenia susceptibility gene on psychopathology and endophenotypes of the negative symptom spectra. PMID:24244513

  17. Gene Expression Analysis of Plum pox virus (Sharka) Susceptibility/Resistance in Apricot (Prunus armeniaca L.).

    PubMed

    Rubio, Manuel; Ballester, Ana Rosa; Olivares, Pedro Manuel; Castro de Moura, Manuel; Dicenta, Federico; Martínez-Gómez, Pedro

    2015-01-01

    RNA-Seq has proven to be a very powerful tool in the analysis of the Plum pox virus (PPV, sharka disease)/Prunus interaction. This technique is an important complementary tool to other means of studying genomics. In this work an analysis of gene expression of resistance/susceptibility to PPV in apricot is performed. RNA-Seq has been applied to analyse the gene expression changes induced by PPV infection in leaves from two full-sib apricot genotypes, "Rojo Pasión" and "Z506-7", resistant and susceptible to PPV, respectively. Transcriptomic analyses revealed the existence of more than 2,000 genes related to the pathogen response and resistance to PPV in apricot. These results showed that the response to infection by the virus in the susceptible genotype is associated with an induction of genes involved in pathogen resistance such as the allene oxide synthase, S-adenosylmethionine synthetase 2 and the major MLP-like protein 423. Over-expression of the Dicer protein 2a may indicate the suppression of a gene silencing mechanism of the plant by PPV HCPro and P1 PPV proteins. On the other hand, there were 164 genes involved in resistance mechanisms that have been identified in apricot, 49 of which are located in the PPVres region (scaffold 1 positions from 8,050,804 to 8,244,925), which is responsible for PPV resistance in apricot. Among these genes in apricot there are several MATH domain-containing genes, although other genes inside (Pleiotropic drug resistance 9 gene) or outside (CAP, Cysteine-rich secretory proteins, Antigen 5 and Pathogenesis-related 1 protein; and LEA, Late embryogenesis abundant protein) PPVres region could also be involved in the resistance.

  18. Gene Expression Analysis of Plum pox virus (Sharka) Susceptibility/Resistance in Apricot (Prunus armeniaca L.)

    PubMed Central

    Rubio, Manuel; Ballester, Ana Rosa; Olivares, Pedro Manuel; Castro de Moura, Manuel; Dicenta, Federico; Martínez-Gómez, Pedro

    2015-01-01

    RNA-Seq has proven to be a very powerful tool in the analysis of the Plum pox virus (PPV, sharka disease)/Prunus interaction. This technique is an important complementary tool to other means of studying genomics. In this work an analysis of gene expression of resistance/susceptibility to PPV in apricot is performed. RNA-Seq has been applied to analyse the gene expression changes induced by PPV infection in leaves from two full-sib apricot genotypes, “Rojo Pasión” and “Z506-7”, resistant and susceptible to PPV, respectively. Transcriptomic analyses revealed the existence of more than 2,000 genes related to the pathogen response and resistance to PPV in apricot. These results showed that the response to infection by the virus in the susceptible genotype is associated with an induction of genes involved in pathogen resistance such as the allene oxide synthase, S-adenosylmethionine synthetase 2 and the major MLP-like protein 423. Over-expression of the Dicer protein 2a may indicate the suppression of a gene silencing mechanism of the plant by PPV HCPro and P1 PPV proteins. On the other hand, there were 164 genes involved in resistance mechanisms that have been identified in apricot, 49 of which are located in the PPVres region (scaffold 1 positions from 8,050,804 to 8,244,925), which is responsible for PPV resistance in apricot. Among these genes in apricot there are several MATH domain-containing genes, although other genes inside (Pleiotropic drug resistance 9 gene) or outside (CAP, Cysteine-rich secretory proteins, Antigen 5 and Pathogenesis-related 1 protein; and LEA, Late embryogenesis abundant protein) PPVres region could also be involved in the resistance. PMID:26658051

  19. Gene Expression Analysis of Plum pox virus (Sharka) Susceptibility/Resistance in Apricot (Prunus armeniaca L.).

    PubMed

    Rubio, Manuel; Ballester, Ana Rosa; Olivares, Pedro Manuel; Castro de Moura, Manuel; Dicenta, Federico; Martínez-Gómez, Pedro

    2015-01-01

    RNA-Seq has proven to be a very powerful tool in the analysis of the Plum pox virus (PPV, sharka disease)/Prunus interaction. This technique is an important complementary tool to other means of studying genomics. In this work an analysis of gene expression of resistance/susceptibility to PPV in apricot is performed. RNA-Seq has been applied to analyse the gene expression changes induced by PPV infection in leaves from two full-sib apricot genotypes, "Rojo Pasión" and "Z506-7", resistant and susceptible to PPV, respectively. Transcriptomic analyses revealed the existence of more than 2,000 genes related to the pathogen response and resistance to PPV in apricot. These results showed that the response to infection by the virus in the susceptible genotype is associated with an induction of genes involved in pathogen resistance such as the allene oxide synthase, S-adenosylmethionine synthetase 2 and the major MLP-like protein 423. Over-expression of the Dicer protein 2a may indicate the suppression of a gene silencing mechanism of the plant by PPV HCPro and P1 PPV proteins. On the other hand, there were 164 genes involved in resistance mechanisms that have been identified in apricot, 49 of which are located in the PPVres region (scaffold 1 positions from 8,050,804 to 8,244,925), which is responsible for PPV resistance in apricot. Among these genes in apricot there are several MATH domain-containing genes, although other genes inside (Pleiotropic drug resistance 9 gene) or outside (CAP, Cysteine-rich secretory proteins, Antigen 5 and Pathogenesis-related 1 protein; and LEA, Late embryogenesis abundant protein) PPVres region could also be involved in the resistance. PMID:26658051

  20. Genetics of canine diabetes mellitus: are the diabetes susceptibility genes identified in humans involved in breed susceptibility to diabetes mellitus in dogs?

    PubMed

    Catchpole, Brian; Adams, Jamie P; Holder, Angela L; Short, Andrea D; Ollier, William E R; Kennedy, Lorna J

    2013-02-01

    Diabetes mellitus is a common endocrinopathy in companion animals, characterised by hyperglycaemia, glycosuria and weight loss, resulting from an absolute or relative deficiency in the pancreatic hormone insulin. There are breed differences in susceptibility to diabetes mellitus in dogs, with the Samoyed breed being overrepresented, while Boxers are relatively absent in the UK population of diabetic dogs, suggesting that genetic factors play an important role in determining susceptibility to the disease. A number of genes, linked with susceptibility to diabetes mellitus in humans, are associated with an increased risk of diabetes mellitus in dogs, some of which appear to be relatively breed-specific. Diabetes mellitus in dogs has been associated with major histocompatibility complex (MHC) class II genes (dog leucocyte antigen; DLA), with similar haplotypes and genotypes being identified in the most susceptible breeds. A region containing a variable number of tandem repeats (VNTR) and several polymorphisms have been identified in the canine insulin gene, with some alleles associated with susceptibility or resistance to diabetes mellitus in a breed-specific manner. Polymorphisms in the canine CTLA4 promoter and in other immune response genes are associated with susceptibility to diabetes mellitus in a number of pedigree breeds. Genome wide association studies are currently underway that should shed further light on the genetic factors responsible for the breed profile seen in the diabetic dog population.

  1. Colonic microbiota alters host susceptibility to infectious colitis by modulating inflammation, redox status, and ion transporter gene expression.

    PubMed

    Ghosh, S; Dai, C; Brown, K; Rajendiran, E; Makarenko, S; Baker, J; Ma, C; Halder, S; Montero, M; Ionescu, V A; Klegeris, A; Vallance, B A; Gibson, D L

    2011-07-01

    Individuals vary in their resistance to enteric infections. The role of the intestinal microbiota in altering susceptibility to enteric infection is relatively unknown. Previous studies have identified that C3H/HeOuJ mice suffer 100% mortality during Citrobacter rodentium-induced colitis, whereas C57BL/6 mice recover from infection. The basis for their differences in susceptibility is unclear and has been mainly attributed to differences in host genetics. This study investigated the role of the intestinal microbiota in altering susceptibility to C. rodentium-induced colitis. When the feces of C57BL/6 mice were gavaged into antibiotic treated C3H/HeOuJ mice, the C57BL/6 microflora led to a complete reversal in mortality patterns where 100% of the C3H/HeOuJ mice survived infection. This protection corresponded with reduced colonic pathology and less systemic pathogen load and was associated with increased inflammatory and redox responses with reduced epithelial cell death. C3H/HeOuJ mice are normally susceptible to infection-induced dehydration due to defective expression of colonic ion transporters such as Dra, CA IV, and CA I; expression of these genes was normalized when C3H/HeOuJ mice were colonized with the C57BL/6 microflora. Together, these data reveal that the colonic microbiota play a critical role in protecting against intestinal infection by inducing proinflammatory and prooxidant responses that control pathogen load as well as ion transporter gene expression previously shown to prevent fatal dehydration. Protection of mice from lethal colitis was associated with higher levels of bacteria from Bacteroidetes. This study reveals that the microbiota is sufficient to overcome inherent genetic susceptibility patterns in C3H/HeOuJ mice that cause mortality during C. rodentium infection.

  2. The Association between GWAS-identified BARD1 Gene SNPs and Neuroblastoma Susceptibility in a Southern Chinese Population

    PubMed Central

    Zhang, Ruizhong; Zou, Yan; Zhu, Jinhong; Zeng, Xinhao; Yang, Tianyou; Wang, Fenghua; He, Jing; Xia, Huimin

    2016-01-01

    A previous genome-wide association study (GWAS) has found that some common variations in the BARD1 gene were associated with neuroblastoma susceptibility especially for high-risk subjects, and the associations have been validated in Caucasians and African-Americans. However, the associations between BARD1 gene polymorphisms and neuroblastoma susceptibility have not been studied among Asians, not to mention Chinese subjects. In the present study, we investigated the association of three BARD1 polymorphisms (rs7585356 G>A, rs6435862 T>G and rs3768716 A>G) with neuroblastoma susceptibility in 201 neuroblastoma patients and 531 controls using TaqMan methodology. Overall, none of these polymorphisms was significantly associated with neuroblastoma susceptibility. However, stratified analysis showed a more profound association between neuroblastoma risk and rs6435862 TG/GG variant genotypes among older children (adjusted OR=1.55, 95% CI=1.04-2.31), and children with adrenal gland-originated disease (adjusted OR=2.94, 95% CI=1.40-6.18), or with ISSN clinical stages III+IV disease (adjusted OR=1.75, 95% CI=1.09-2.84). Similar results were observed for the variant genotypes of rs3768716 A>G polymorphism among these three subgroups. Our results suggest that the BARD1 rs6435862 T>G and rs3768716 A>G polymorphisms may contribute to increased susceptibility to neuroblastoma, especially for the subjects at age ≥12 months, with adrenal gland-originated or with late clinical stage neuroblastoma. These findings need further validation by prospective studies with larger sample size with subjects enrolled from multicenter, involving different ethnicities. PMID:26941572

  3. The Association between GWAS-identified BARD1 Gene SNPs and Neuroblastoma Susceptibility in a Southern Chinese Population.

    PubMed

    Zhang, Ruizhong; Zou, Yan; Zhu, Jinhong; Zeng, Xinhao; Yang, Tianyou; Wang, Fenghua; He, Jing; Xia, Huimin

    2016-01-01

    A previous genome-wide association study (GWAS) has found that some common variations in the BARD1 gene were associated with neuroblastoma susceptibility especially for high-risk subjects, and the associations have been validated in Caucasians and African-Americans. However, the associations between BARD1 gene polymorphisms and neuroblastoma susceptibility have not been studied among Asians, not to mention Chinese subjects. In the present study, we investigated the association of three BARD1 polymorphisms (rs7585356 G>A, rs6435862 T>G and rs3768716 A>G) with neuroblastoma susceptibility in 201 neuroblastoma patients and 531 controls using TaqMan methodology. Overall, none of these polymorphisms was significantly associated with neuroblastoma susceptibility. However, stratified analysis showed a more profound association between neuroblastoma risk and rs6435862 TG/GG variant genotypes among older children (adjusted OR=1.55, 95% CI=1.04-2.31), and children with adrenal gland-originated disease (adjusted OR=2.94, 95% CI=1.40-6.18), or with ISSN clinical stages III+IV disease (adjusted OR=1.75, 95% CI=1.09-2.84). Similar results were observed for the variant genotypes of rs3768716 A>G polymorphism among these three subgroups. Our results suggest that the BARD1 rs6435862 T>G and rs3768716 A>G polymorphisms may contribute to increased susceptibility to neuroblastoma, especially for the subjects at age ≥12 months, with adrenal gland-originated or with late clinical stage neuroblastoma. These findings need further validation by prospective studies with larger sample size with subjects enrolled from multicenter, involving different ethnicities. PMID:26941572

  4. Association of Environmental Arsenic Exposure, Genetic Polymorphisms of Susceptible Genes, and Skin Cancers in Taiwan

    PubMed Central

    Hsu, Ling-I; Wu, Meei-Maan; Wang, Yuan-Hung; Lee, Cheng-Yeh; Yang, Tse-Yen; Hsiao, Bo-Yu; Chen, Chien-Jen

    2015-01-01

    Deficiency in the capability of xenobiotic detoxification and arsenic methylation may be correlated with individual susceptibility to arsenic-related skin cancers. We hypothesized that glutathione S-transferase (GST M1, T1, and P1), reactive oxygen species (ROS) related metabolic genes (NQO1, EPHX1, and HO-1), and DNA repair genes (XRCC1, XPD, hOGG1, and ATM) together may play a role in arsenic-induced skin carcinogenesis. We conducted a case-control study consisting of 70 pathologically confirmed skin cancer patients and 210 age and gender matched participants with genotyping of 12 selected polymorphisms. The skin cancer risks were estimated by odds ratio (OR) and 95% confidence interval (CI) using logistic regression. EPHX1 Tyr113His, XPD C156A, and GSTT1 null genotypes were associated with skin cancer risk (OR = 2.99, 95% CI = 1.01–8.83; OR = 2.04, 95% CI = 0.99–4.27; OR = 1.74, 95% CI = 1.00–3.02, resp.). However, none of these polymorphisms showed significant association after considering arsenic exposure status. Individuals carrying three risk polymorphisms of EPHX1 Tyr113His, XPD C156A, and GSTs presented a 400% increased skin cancer risk when compared to those with less than or equal to one polymorphism. In conclusion, GSTs, EPHX1, and XPD are potential genetic factors for arsenic-induced skin cancers. The roles of these genes for arsenic-induced skin carcinogenesis need to be further evaluated. PMID:26295053

  5. LMO1 gene polymorphisms contribute to decreased neuroblastoma susceptibility in a Southern Chinese population

    PubMed Central

    Zhu, Jinhong; Zhang, Ruizhong; Wang, Fenghua; Yang, Tianyou; Zou, Yan; Xia, Huimin

    2016-01-01

    Neuroblastoma is one of the most commonly diagnosed extracranial solid tumors in infancy; however, the etiology of neuroblastoma remains largely unknown. Previous genome-wide association study (GWAS) indicated that several common genetic variations (rs110419 A > G, rs4758051 G > A, rs10840002 A > G and rs204938 A > G) in the LIM domain only 1 (LMO1) gene were associated with neuroblastoma susceptibility. The aim of this study was to evaluate the correlation between the four GWAS-identified LMO1 gene polymorphisms and neuroblastoma risk in a Southern Chinese population. We genotyped the four polymorphisms in 256 neuroblastoma cases and 531 controls. Odds ratios (ORs) and 95% confidence intervals (CIs) were used to evaluate the strength of the associations. False-positive report probability was calculated for all significant findings. We found that the rs110419 A > G polymorphism was associated with a significantly decreased neuroblastoma risk (AG vs. AA: adjusted OR = 0.65, 95% CI = 0.47–0.91; GG vs. AA: adjusted OR = 0.58, 95% CI = 0.36–0.91; AG/GG vs. AA: adjusted OR = 0.63, 95% CI = 0.46–0.86), and the protective effect was more predominant in children of age > 18 months, males, subgroups with tumor in adrenal gland and mediastinum, and patients in clinical stages III/IV. These results suggested that LMO1 gene rs110419 A > G polymorphism may contribute to protection against neuroblastoma. Our findings call for further validation studies with larger sample size. PMID:27009839

  6. Systematic prioritization and integrative analysis of copy number variations in schizophrenia reveal key schizophrenia susceptibility genes.

    PubMed

    Luo, Xiongjian; Huang, Liang; Han, Leng; Luo, Zhenwu; Hu, Fang; Tieu, Roger; Gan, Lin

    2014-11-01

    Schizophrenia is a common mental disorder with high heritability and strong genetic heterogeneity. Common disease-common variants hypothesis predicts that schizophrenia is attributable in part to common genetic variants. However, recent studies have clearly demonstrated that copy number variations (CNVs) also play pivotal roles in schizophrenia susceptibility and explain a proportion of missing heritability. Though numerous CNVs have been identified, many of the regions affected by CNVs show poor overlapping among different studies, and it is not known whether the genes disrupted by CNVs contribute to the risk of schizophrenia. By using cumulative scoring, we systematically prioritized the genes affected by CNVs in schizophrenia. We identified 8 top genes that are frequently disrupted by CNVs, including NRXN1, CHRNA7, BCL9, CYFIP1, GJA8, NDE1, SNAP29, and GJA5. Integration of genes affected by CNVs with known schizophrenia susceptibility genes (from previous genetic linkage and association studies) reveals that many genes disrupted by CNVs are also associated with schizophrenia. Further protein-protein interaction (PPI) analysis indicates that protein products of genes affected by CNVs frequently interact with known schizophrenia-associated proteins. Finally, systematic integration of CNVs prioritization data with genetic association and PPI data identifies key schizophrenia candidate genes. Our results provide a global overview of genes impacted by CNVs in schizophrenia and reveal a densely interconnected molecular network of de novo CNVs in schizophrenia. Though the prioritized top genes represent promising schizophrenia risk genes, further work with different prioritization methods and independent samples is needed to confirm these findings. Nevertheless, the identified key candidate genes may have important roles in the pathogenesis of schizophrenia, and further functional characterization of these genes may provide pivotal targets for future therapeutics and

  7. Polymorphic Regions in the Interleukin-1 Gene and Susceptibility to Chronic Periodontitis: A Genetic Association Study

    PubMed Central

    Lavu, Vamsi; Venkatesan, Vettriselvi; Lakkakula, Bhaskar Venkata Kameswara Subrahmanya; Venugopal, Priyanka; Paul, Solomon Franklin Durairaj

    2015-01-01

    Objective: The objectives of this study were to determine the association between single nucleotide polymorphisms (SNPs) in IL1B (−511, +3954), IL1A (−889, +4845), and the variable number of tandem repeats (VNTRs) polymorphism in the IL-1RN gene with chronic periodontitis susceptibility and to analyze gene–gene interactions in a hospital-based sample population from South India. Subjects and Methods: A total of 400 individuals were recruited for this study; 200 individuals with healthy gingiva and 200 chronic periodontitis patients. Genomic DNA was isolated from peripheral blood samples and genotyping was performed for the above-mentioned single nucleotide and VNTR polymorphisms by polymerase chain reaction, DNA sequencing, and agarose gel electrophoresis. Results: A higher proportion of the variant alleles were observed in the chronic periodontitis group for all the SNPs examined. The SNP at +3954 (C>T) in the IL1B gene was found to be significantly associated with chronic periodontitis (p=0.007). VNTR genotypes (χ2 value: 5.163, df=1, p=0.023) and alleles (χ2 value: 6.818, df=1, p=0.009) were found to have a significant association with chronic periodontitis susceptibility. Conclusion: In the study population examined, the SNP in the IL1B gene (+3954) and VNTR polymorphisms in the IL1RN gene were found to have a significant association with chronic periodontitis susceptibility. PMID:25710474

  8. Social Environmental Variation, Plasticity Genes, and Aggression: Evidence for the Differential Susceptibility Hypothesis

    PubMed Central

    Simons, Ronald L.; Lei, Man Kit; Beach, Steven R.H.; Brody, Gene H.; Philibert, Robert A.; Gibbons, Frederick X.

    2011-01-01

    Although G×E studies are typically based on the assumption that some individuals possess genetic variants that enhance their vulnerability to environmental adversity, the differential susceptibility perspective posits that these individuals are simply more susceptible to environmental influence than others. An important implication of this model is that those persons most vulnerable to adverse social environments are the same ones who reap the most benefit from environmental support. The present study tested several implications of this proposition. Using longitudinal data from a sample of several hundred African Americans, we found that relatively common variants of the dopamine receptor gene and the serotonin transporter gene interact with social environmental conditions to predict aggression in a manner consonant with differential susceptibility. When the social environment was adverse, individuals with these genetic variants manifested more aggression than other genotypes, whereas when the environment was supportive they demonstrated less aggression than other genotypes. Further, we found that these genetic variants interact with environmental conditions to foster various cognitive schemas and emotions in a manner consistent with differential susceptibility and that a latent construct formed by these schemas and emotions mediated the effect of gene by environment interaction on aggression. PMID:22199399

  9. Localization of a breast cancer susceptibility gene, BRCA2, to chromosome 13q12-13

    SciTech Connect

    Wooster, R.; Mangion, J.; Quirk, Y.; Collins, N.; Seal, S.; Ford, D.; Averill, D. ); Neuhausen, S.L.; Nguyen, K.; Tran, T. )

    1994-09-30

    A small proportion of breast cancer, in particular those cases arising at a young age, is due to the inheritance of dominant susceptibility genes conferring a high risk of the disease. A genomic linkage search was performed with 15 high-risk breast cancer families that were unlinked to the BRCA1 locus on chromosome 17q21. This analysis localized a second breast cancer susceptibility locus, BRCA2, to a 6-centimorgan interval on chromosome 13q12-13. Preliminary, evidence suggests that BRCA2 confers a high risk of breast cancer but, unlike BRCA1, does not confer a substantially elevated risk of ovarian cancer.

  10. The BTNL2 Gene and Sarcoidosis Susceptibility in African Americans and Whites

    PubMed Central

    Rybicki, Benjamin A.; Walewski, José L.; Maliarik, Mary J.; Kian, Hamed; Iannuzzi, Michael C.

    2005-01-01

    The BTNL2 gene is a member of the B7 receptor family that probably functions as a T-cell costimulatory molecule. It resides in the class II major histocompatibility complex (MHC) region of chromosome 6p and has recently been associated with sarcoidosis susceptibility in a white German population. We sought to replicate the BTNL2 association in an African American family-based study population (n=219 nuclear families) and two case-control populations—one African American (n=295 pairs) and one white (n=366 pairs). Ten SNPs were detected within a 490-bp region spanning exon/intron 5 of BTNL2. Haplotype variation within this region was significantly associated with sarcoidosis in all three study populations but more so in whites (P=.0006) than in the African American case-control (P=.02) or family-based (P=.03) samples. The previously reported BTNL2 SNP with the strongest sarcoidosis association, rs2076530, was also the SNP with the strongest association in our white population (P<.0001). The A allele of rs2076530 results in a premature exon-splice site and increases risk for sarcoidosis (odds ratio=2.03; 95% confidence interval 1.32–3.12). Although rs2076530 was not associated with sarcoidosis in either African American sample, a three-locus haplotype that included rs2076530 was associated with sarcoidosis across all three study samples. Multivariable logistic regression analyses showed that BTNL2 effects are independent of human leukocyte antigen class II genes in whites but may interact antagonistically in African Americans. Our results underscore the complexity of genetic risk for sarcoidosis emanating from the MHC region. PMID:16080124

  11. Autophagy gene polymorphism is associated with susceptibility to leprosy by affecting inflammatory cytokines.

    PubMed

    Yang, Degang; Chen, Jia; Shi, Chao; Jing, Zhichun; Song, Ningjing

    2014-04-01

    Autophagy and inflammation closely interact with each other, and together, they play critical roles in bacterial infection. Leprosy is caused by the infection of Mycobacterium leprae (M. leprae). The objective of the study was to investigate the association between polymorphisms in IRGM, an autophagy gene, and susceptibility to leprosy, and identify possible functions of the polymorphism in the infection of M. leprae. Two polymorphisms in IRGM, rs4958842 and rs13361189, were tested in 412 leprosy cases and 432 healthy controls. Levels of inflammatory cytokines including interleukin 1 beta, IL-4, IL-6, and interferon gamma (INF-γ) were measured after the infection of M. leprae in the peripheral blood mononuclear cell (PBMC) of subjects with different genotypes of rs13361189. Data showed that prevalence of rs13361189TC and CC genotypes were significantly higher in leprosy patients than in healthy controls (odds ratio (OR) = 1.49, 95 % confidence interval (CI) 1.09-2.04, P = 0.012; OR = 2.58, 95 % CI 1.65-4.05, P < 0.001; respectively). Furthermore, the frequency of rs13361189CC genotype was increased in patients with complications than those without complications (P = 0.011). When analyzing the effect of rs13361189 polymorphism on M. leprae infection, we identified that M. leprae-infected PBMC with rs13361189CC genotype expressed significantly elevated levels of INF-γ and IL-4 than those with TT genotype. Our results suggested autophagy gene polymorphism was associated with the increased risk of leprosy by affecting inflammatory cytokines.

  12. Class I (H-2Kb) gene transfection reduces susceptibility of YAC-1 lymphoma targets to natural killer cells.

    PubMed

    Carlow, D A; Payne, U; Hozumi, N; Roder, J C; Czitrom, A A

    1990-04-01

    A "hybrid gene" (MTKb) comprised of the human metallothionein IIA promoter ligated to the genomic sequence of the major histocompatibility complex class I (H-2Kb) gene was subcloned into the expression vector pSV2neo and transfected into the natural killer (NK) cell-sensitive YAC-1 lymphoma. The Kb gene product was readily detectable on the cell surface of G418-resistant transfectants using both Kb-specific monoclonal antibodies and H-2b-specific cytolytic T cells. Unlike control pSV2neo transfectants, MTKb-pSV2neo transfectants were relatively resistant to lysis by NK cells from H-2a, H-2b, H-2k or H-2 (a x b)F1 haplotype mice. These data strongly suggest that the effects of MHC expression on susceptibility to NK cells can be mediated by a single and well-defined class I molecule, Kb.

  13. Retroviral expression of the hepatitis B virus x gene promotes liver cell susceptibility to carcinogen-induced site specific mutagenesis.

    PubMed

    Sohn, S; Jaitovitch-Groisman, I; Benlimame, N; Galipeau, J; Batist, G; Alaoui-Jamali, M A

    2000-06-30

    Mutational inactivation of the tumor suppressor gene p53 is common in hepatocellular carcinomas (HCC). AGG to AGT transversion in codon 249 of exon 7 of the p53 gene occurs in over 50% of HCC from endemic regions, where both chronic infection with the hepatitis B virus (HBV) and exposure to carcinogens such as aflatoxin B1 (AFB1) prevail. In this study, we report the effect of the HBV x protein (HBx) on carcinogen-induced cytotoxicity and AGG to AGT mutation in codon 249 of the p53 gene in the human liver cell line CCL13. Expression of HBx, as revealed by its transactivation function, results in enhanced cell susceptibility to cytotoxicity induced by the AFB1 active metabolite, AFB1-8,9-epoxide, and benzo(a)pyrene diol-epoxide. Under similar conditions, expression of HBx promotes apoptosis in a subset of cell population. Exposure to AFB1-8, 9-epoxide alone induces a low frequency of AGG to AGT mutation in codon 249 of the p53 gene, as determined by an allele-specific polymerase chain reaction (AS-PCR) assay. However, expression of HBx enhances the frequency of AFB1-epoxide-induced AGG to AGT mutation compared to control cells. In summary, this study demonstrates that expression of HBx enhances liver cell susceptibility to carcinogen-induced mutagenesis, possibly through alteration of the balance between DNA repair and apoptosis, two cellular defense mechanisms against genotoxic stress. PMID:10856831

  14. Association between SLC2A9 (GLUT9) gene polymorphisms and gout susceptibility: an updated meta-analysis.

    PubMed

    Zhang, Xu; Yang, Xiao; Wang, Mengmeng; Li, Xiaona; Xia, Qing; Xu, Shengqian; Xu, Jianhua; Cai, Guoqi; Wang, Li; Xin, Lihong; Zou, Yanfeng; Pan, Faming

    2016-08-01

    The relationship between the SLC2A9 (solute carrier family 2, member 9) gene polymorphisms and gout was still inconsistent among the individual genetic association studies. Therefore, this present research was aimed to systematically evaluate the association between SLC2A9 gene polymorphisms and gout susceptibility. Relevant studies were enrolled by searching databases systematically. The pooled odds ratios (ORs) with 95 % confidence intervals (CIs) were used to assess the associations. The heterogeneity between each of the studies was calculated by using the Q statistic methods, and Begg's funnel plot and Egger's tests were performed to evaluate publication bias. A total of 13 studies investigated four single nucleotide polymorphisms (SNPs) in SLC2A9 were included. In this study, we found that the allele C of rs3733591 was higher in patients than in controls in both all-pooled population [C vs. T: OR (95 % CI) = 1.432 (1.213-1.691)] and Asians-pooled population [C vs. T: OR (95 % CI) = 1.583 (1.365-1.835)]. The allele frequency C of s6449213 was lower in the gout patients than in controls in both all-pooled population and Caucasians-pooled population. Additionally, the allele frequency T of rs16890979 and the allele frequency C of rs1014290 were lower in gout patients than in controls. This study demonstrated that the genetic susceptibility for gout is associated with the SLC2A9 gene polymorphisms. Four of them except for the rs3733591 are protective SNPs in Caucasians, and rs16890979 and rs1014290 are protective SNPs in both Caucasians and Asians, while rs3733591 may be susceptibility SNP in Asians. PMID:27255295

  15. Association between two interleukin-2 gene polymorphisms and cancer susceptibility: a meta-analysis

    PubMed Central

    Zhang, Meng; Tan, Xiuxiu; Huang, Junjie; Xie, Lijuan; Wang, Hao; Shi, Jizhou; Lu, Wei; Lv, Zhaojie; Mei, Hongbing; Liang, Chaozhao

    2016-01-01

    Background Several epidemiological studies have illustrated that polymorphisms in interleukin-2 (IL-2) were associated with diverse cancer types. However, recently published statistics were inconsistent and inconclusive. Therefore, the current meta-analysis was performed to elaborate the effects of IL-2 polymorphisms (rs2069762 and rs2069763) on cancer susceptibility. Material and methods A total of 5,601 cancer cases and 7,809 controls from 21 published case–control studies were enrolled in our meta-analysis. Odds ratios (ORs) with 95% confidence intervals (CIs) were estimated to assess the association between IL-2 polymorphisms and cancer susceptibility. Results Our study demonstrated an increased susceptibility to cancer in rs2069762 (G vs T: OR =1.268, 95% CI =1.113–1.445; GG vs TT: OR =1.801, 95% CI =1.289–2.516; GT vs TT: OR =1.250, 95% CI =1.061–1.473; GG + GT vs TT: OR =1.329, 95% CI =1.118–1.579; GG vs GT + TT: OR =1.536, 95% CI =1.162–2.030). In the subgroup analysis, increased susceptibility to cancer was identified in the hospital-based group and PHWE<0.05 (P-value of the Hardy–Weinberg equilibrium [HWE]) group. In addition, a positive association with cancer susceptibility was observed among both Chinese and non-Chinese. However, no relationship was detected between the rs2069763 polymorphism of IL-2 and cancer susceptibility. Conclusion To conclude, rs2069762 polymorphism of IL-2 contributed to an increased susceptibility to cancer, whereas no association was identified between rs2069763 polymorphism and cancer susceptibility. Further detailed studies are warranted to confirm our findings. PMID:27143914

  16. Evaluation of a Susceptibility Gene for Schizophrenia: Genotype Based Meta-Analysis of RGS4 Polymorphisms from Thirteen Independent Samples

    PubMed Central

    Talkowski, Michael E.; Seltman, Howard; Bassett, Anne S.; Brzustowicz, Linda M.; Chen, Xiangning; Chowdari, Kodavali V.; Collier, David A.; Cordeiro, Quirino; Corvin, Aiden P.; Deshpande, Smita N.; Egan, Michael F.; Gill, Michael; Kendler, Kenneth S.; Kirov, George; Heston, Leonard L.; Levitt, Pat; Lewis, David A.; Li, Tao; Mirnics, Karoly; Morris, Derek W.; Norton, Nadine; O’Donovan, Michael C.; Owen, Michael J.; Richard, Christian; Semwal, Prachi; Sobell, Janet L.; Clair, David St; Straub, Richard E.; Thelma, B.K.; Vallada, Homero; Weinberger, Daniel R.; Williams, Nigel M.; Wood, Joel; Zhang, Feng; Devlin, Bernie; Nimgaonkar, Vishwajit L.

    2011-01-01

    Background Associations between schizophrenia (SCZ) and polymorphisms at the regulator of G-protein signaling 4 (RGS4) gene have been reported (single nucleotide polymorphisms [SNPs] 1, 4, 7, and 18). Yet, similar to other SCZ candidate genes, studies have been inconsistent with respect to the associated alleles. Methods In an effort to resolve the role for RGS4 in SCZ susceptibility, we undertook a genotype-based meta-analysis using both published and unpublished family-based and case-control samples (total n = 13,807). Results The family-based dataset consisted of 10 samples (2160 families). Significant associations with individual SNPs/haplotypes were not observed. In contrast, global analysis revealed significant transmission distortion (p = .0009). Specifically, analyses suggested overtransmission of two common haplotypes that account for the vast majority of all haplotypes. Separate analyses of 3486 cases and 3755 control samples (eight samples) detected a significant association with SNP 4 (p = .01). Individual haplotype analyses were not significant, but evaluation of test statistics from individual samples suggested significant associations. Conclusions Our collaborative meta-analysis represents one of the largest SCZ association studies to date. No individual risk factor arose from our analyses, but interpretation of these results is not straightforward. Our analyses suggest risk due to at least two common haplotypes in the presence of heterogeneity. Similar analysis for other putative susceptibility genes is warranted. PMID:16631129

  17. A candidate gene approach for the genetic analysis of susceptibility to tuberculosis

    SciTech Connect

    Morgan, K.; Liu, J.; Boothroyd, L.

    1994-09-01

    Tuberculosis is the most frequent and severe human disease caused by mycobacteria. In the mouse a candidate gene for innate resistance to mycobacteria (Bcg) was recently isolated and termed Nramp. We used SSCA and DNA sequencing to identify mutations in the human homologue, NRAMP, in chromosome region 2q35 in order to test if NRAMP contributes to susceptibility to tuberculosis. We have identified 16 sequence variants in or near NRAMP and defined haplotypes segregating in multiplex tuberculosis families from Canada, Columbia and Hong Kong. We defined a recessive susceptibility model for linkage analysis with four liability classes which take into account clinical status, age, exposure, and BCG vaccination. Our preliminary results support a role of NRAMP in tuberculosis susceptibility in an epidemic situation. This research was supported by grants from the Medical Research Council of Canada and the Canadian Genetic Diseases Network.

  18. Gene for familial psoriasis susceptibility mapped to the distal end of human chromosome 17q

    SciTech Connect

    Tomfohrde, J.; Barnes, R.; Bowcock, A.; Fernandez-Vina, M.A.; Stastny, P.; Silverman, A.; Young, M.; Lory, D.; Morris, L.; Menter, A.

    1994-05-20

    A gene involved in psoriasis susceptibility was localized to the distal region of human chromosomes 17q as a result of a genome-wide linkage analysis with polymorphic microsatellites and eight multiply affected psoriasis kindreds. In the family which showed the strongest evidence for linkage, the recombination fraction between a psoriasis susceptibility locus and D17S784 was 0.04 with a maximum two-point lod score of 5.33. There was also evidence for genetic heterogeneity and although none of the linked families showed any association with HLA-Cw6, two unlinked families showed weak levels of association. This study demonstrates that is some families, psoriasis susceptibility is due to variation at a single major genetic locus other than the human lymphocyte antigen locus. 28 refs., 2 figs., 1 tab.

  19. Variation of the genes encoding the human glutamate EAAT2, serotonin and dopamine transporters and Susceptibility to idiopathic generalized epilepsy.

    PubMed

    Sander, T; Berlin, W; Ostapowicz, A; Samochowiec, J; Gscheidel, N; Hoehe, M R

    2000-08-01

    Several interacting genetic factors are likely to be involved in the epileptogenesis of idiopathic generalized epilepsies (IGE). Neurotransmitter transporters play a central role in the fine tuning of neurotransmission by removal of released neurotransmitters from the synaptic cleft. The present association study tested the hypotheses that variation of the genes encoding neurotransmitter transporters confers susceptibility to IGE. The genotypes of 133 German IGE subjects and 223 ethnically matched controls were assessed for DNA polymorphisms of genes encoding the glutamate (EAAT2), the serotonin (SERT), and dopamine (DAT) transporters. To increase genetic homogeneity, a subgroup of 76 patients with idiopathic absence epilepsy (IAE) was analyzed separately. We found no evidence for an allelic association of either the silent G603A substitution polymorphism in exon 5 of the EAAT2 gene or the regulatory promoter polymorphism of the SERT gene with either IGE or IAE. The frequency of the nine-copy allele of the 40 base pair repeat polymorphism in the 3' un pop popd region of the DAT gene was significantly increased in the IGE patients (chi2 = 4.11, degrees of freedom (d.f.) = 1, P = 0.043) and, in particular, in the IAE patients (chi2 = 7.81, d.f. = 1, P = 0.005) compared with the controls. The present findings strengthen previous evidence that genetic variation of the DAT gene modulates neuronal network excitability and contributes to the epileptogenesis of IAE.

  20. Association of the solute carrier family 11 member 1 gene polymorphisms with susceptibility to leprosy in a Brazilian sample

    PubMed Central

    Brochado, Maria José Franco; Gatti, Maria Fernanda Chociay; Zago, Marco Antônio; Roselino, Ana Maria

    2016-01-01

    Natural resistance-associated macrophage protein 1/solute carrier family 11 member 1 gene (Nramp1/Slc11a1) is a gene that controls the susceptibility of inbred mice to intracellular pathogens. Polymorphisms in the human Slc11a1/Nramp1 gene have been associated with host susceptibility to leprosy. This study has evaluated nine polymorphisms of the Slc11a1/Nramp1 gene [(GT)n, 274C/T, 469+14G/C, 577-18G/A, 823C/T, 1029 C/T, 1465-85G/A, 1703G/A, and 1729+55del4] in 86 leprosy patients (67 and 19 patients had the multibacillary and the paucibacillary clinical forms of the disease, respectively), and 239 healthy controls matched by age, gender, and ethnicity. The frequency of allele 2 of the (GT)n polymorphism was higher in leprosy patients [p = 0.04, odds ratio (OR) = 1.49], whereas the frequency of allele 3 was higher in the control group (p = 0.03; OR = 0.66). Patients carrying the 274T allele (p = 0.04; OR = 1.49) and TT homozygosis (p = 0.02; OR = 2.46), such as the 469+14C allele (p = 0.03; OR = 1.53) of the 274C/T and 469+14G/C polymorphisms, respectively, were more frequent in the leprosy group. The leprosy and control groups had similar frequency of the 577-18G/A, 823C/T, 1029C/T, 1465-85G/A, 1703G/A, and 1729+55del4 polymorphisms. The 274C/T polymorphism in exon 3 and the 469+14G/C polymorphism in intron 4 were associated with susceptibility to leprosy, while the allele 2 and 3 of the (GT)n polymorphism in the promoter region were associated with susceptibility and protection to leprosy, respectively. PMID:26814595

  1. Association of KCNJ11 (E23K) gene polymorphism with susceptibility to type 2 diabetes in Iranian patients

    PubMed Central

    Rastegari, Ali; Rabbani, Mohammad; Sadeghi, Hamid Mirmohammad; Imani, Elham Faghih; Hasanzadeh, Akbar; Moazen, Fatemeh

    2015-01-01

    Background: Type 2 diabetes (T2D) is a multifactorial disease with susceptibility of several genes that are related to T2D. Insulin secretion pathway starts with potassium channels in pancreatic beta cells. KCNJ11 gene encodes ATP-sensitive potassium channel subunits. Some studies suggested that KCNJ11 (E23K) mutation increases the risk of T2D. Therefore, present study was designed to investigate the association between E23K polymorphism of KCNJ11 gene and type 2 diabetes mellitus (T2DM) in the Iranian population. Materials and Methods: The type of study was case-control and 40 unrelated subjects, including 20 healthy controls and 20 diabetic patients were recruited (diagnosed based on American Diabetes Association criteria). Blood samples were used for isolation of genomic deoxyribonucleic acid (DNA). Having extracted the genomic DNA from human blood leukocytes by means of High Pure PCR Template Preparation Kit, PCR-restriction fragment length polymorphism method was used to detect KCNJ11 E23K gene polymorphism. BanII restriction enzyme was used for digestion. Data were analyzed using Chi-square or Fisher exact test or independent t-test, as appropriate. P < 0.05 was considered. Results: We found that the carrier homozygous for KK genotype are susceptible to T2D (0.049) and in patients the frequency of K allele was higher than control subjects (0.048). Conclusion: The present study suggests that KCNJ11 (E23K) gene polymorphism is associated with T2DM. PMID:25625107

  2. Antioxidant defense enzyme genes and asthma susceptibility: gender-specific effects and heterogeneity in gene-gene interactions between pathogenetic variants of the disease.

    PubMed

    Polonikov, Alexey V; Ivanov, Vladimir P; Bogomazov, Alexey D; Freidin, Maxim B; Illig, Thomas; Solodilova, Maria A

    2014-01-01

    Oxidative stress resulting from an increased amount of reactive oxygen species and an imbalance between oxidants and antioxidants plays an important role in the pathogenesis of asthma. The present study tested the hypothesis that genetic susceptibility to allergic and nonallergic variants of asthma is determined by complex interactions between genes encoding antioxidant defense enzymes (ADE). We carried out a comprehensive analysis of the associations between adult asthma and 46 single nucleotide polymorphisms of 34 ADE genes and 12 other candidate genes of asthma in Russian population using set association analysis and multifactor dimensionality reduction approaches. We found for the first time epistatic interactions between ADE genes underlying asthma susceptibility and the genetic heterogeneity between allergic and nonallergic variants of the disease. We identified GSR (glutathione reductase) and PON2 (paraoxonase 2) as novel candidate genes for asthma susceptibility. We observed gender-specific effects of ADE genes on the risk of asthma. The results of the study demonstrate complexity and diversity of interactions between genes involved in oxidative stress underlying susceptibility to allergic and nonallergic asthma. PMID:24895604

  3. Antioxidant Defense Enzyme Genes and Asthma Susceptibility: Gender-Specific Effects and Heterogeneity in Gene-Gene Interactions between Pathogenetic Variants of the Disease

    PubMed Central

    Polonikov, Alexey V.; Ivanov, Vladimir P.; Bogomazov, Alexey D.; Freidin, Maxim B.; Illig, Thomas; Solodilova, Maria A.

    2014-01-01

    Oxidative stress resulting from an increased amount of reactive oxygen species and an imbalance between oxidants and antioxidants plays an important role in the pathogenesis of asthma. The present study tested the hypothesis that genetic susceptibility to allergic and nonallergic variants of asthma is determined by complex interactions between genes encoding antioxidant defense enzymes (ADE). We carried out a comprehensive analysis of the associations between adult asthma and 46 single nucleotide polymorphisms of 34 ADE genes and 12 other candidate genes of asthma in Russian population using set association analysis and multifactor dimensionality reduction approaches. We found for the first time epistatic interactions between ADE genes underlying asthma susceptibility and the genetic heterogeneity between allergic and nonallergic variants of the disease. We identified GSR (glutathione reductase) and PON2 (paraoxonase 2) as novel candidate genes for asthma susceptibility. We observed gender-specific effects of ADE genes on the risk of asthma. The results of the study demonstrate complexity and diversity of interactions between genes involved in oxidative stress underlying susceptibility to allergic and nonallergic asthma. PMID:24895604

  4. Genetic differential susceptibility in literacy-delayed children: a randomized controlled trial on emergent literacy in kindergarten.

    PubMed

    Plak, Rachel D; Kegel, Cornelia A T; Bus, Adriana G

    2015-02-01

    In this randomized controlled trial, 508 5-year-old kindergarten children participated, of whom 257 were delayed in literacy skills because they belonged to the lowest quartile of a national standard literacy test. We tested the hypothesis that some children are more susceptible to school-entry educational interventions than their peers due to their genetic makeup, and thus whether the dopamine receptor D4 gene moderated intervention effects. Children were randomly assigned to a control condition or one of two interventions involving computer programs tailored to the literacy needs of delayed pupils: Living Letters for alphabetic knowledge and Living Books for text comprehension. Effects of Living Books met the criteria of differential susceptibility. For carriers of the dopamine receptor D4 gene seven-repeat allele (about one-third of the delayed group), the Living Books program was an important addition to the common core curriculum in kindergarten (effect size d = 0.56), whereas the program did not affect the other children (d = -0.09). The same seven-repeat carriers benefited more from Living Letters than did the noncarriers, as reflected in effect sizes of 0.63 and 0.34, respectively, although such differences did not fulfill the statistical criteria for differential susceptibility. The implications of differential susceptibility for education and regarding the crucial question "what works for whom?" are discussed.

  5. Bipolar disorder: idioms of susceptibility and disease and the role of 'genes' in illness explanations.

    PubMed

    Baart, Ingrid; Widdershoven, Guy

    2013-11-01

    This qualitative study explores (1) how members of the Dutch Association for People with Bipolar Disorder explain the affliction of bipolar disorder; (2) the relationship between genetic, environmental and personal factors in these explanations and (3) the relationship between illness explanations, self-management and identity. A total of 40 participants took part in seven different focus group discussions. The results demonstrate that there are two different explanatory idioms, each one centred around an opposing concept, that is, susceptibility and disease. Individuals who construct explanations around the concept of 'disease' attach more importance to 'genes and chemicals' than to environmental components in the onset of the disorder, whereas individuals adhering to the central concept of 'susceptibility' tend to do this much less. Compared with individuals using the 'susceptibility' idiom, those who use a 'disease' idiom tend to observe fewer possibilities for self-management and are less inclined to construct normalcy through a quest for personal growth. Stories of suffering seem more integral to the 'disease' idiom than to the 'susceptibility' idiom. The 'disease' idiom seems less integrated in a contemporary surveillance psychiatric discourse than the 'susceptibility' idiom; however, both vocabularies can offer normative constraints.

  6. From mouse to humans: discovery of the CACNG2 pain susceptibility gene.

    PubMed

    Nissenbaum, J

    2012-10-01

    Chronic pain is a major healthcare problem affecting the daily lives of millions with enormous financial costs. The notorious variability and lack of efficient pain relief pharmaceuticals provide both genetic and therapeutic challenge. There are several genetic approaches that aim to uncover the molecular nature of pain phenotypes into their genetic components. Gene mapping using model organisms for various pain phenotypes has led to the identification of novel genes affecting susceptibility and response to pain stimuli. Translational studies have succeeded to tie those genes to human pain syndromes, thus suggesting new targets for drug discovery. In this short review, a perspective on pain genetics and the trajectory from pain phenotype to pain gene involving fine-mapping strategies, bioinformatic analysis and microarray profiling alongside human association analysis will be introduced. This integrated approach has led to identification of CACNG2 as a novel neuropathic pain gene affecting pain susceptibility both in mice and humans. It also serves as a prototype for efficient and economic discovery of pain genes. Comparisons to other methods as well as future directions of pain genetics will be discussed as well. PMID:22775325

  7. From mouse to humans: discovery of the CACNG2 pain susceptibility gene.

    PubMed

    Nissenbaum, J

    2012-10-01

    Chronic pain is a major healthcare problem affecting the daily lives of millions with enormous financial costs. The notorious variability and lack of efficient pain relief pharmaceuticals provide both genetic and therapeutic challenge. There are several genetic approaches that aim to uncover the molecular nature of pain phenotypes into their genetic components. Gene mapping using model organisms for various pain phenotypes has led to the identification of novel genes affecting susceptibility and response to pain stimuli. Translational studies have succeeded to tie those genes to human pain syndromes, thus suggesting new targets for drug discovery. In this short review, a perspective on pain genetics and the trajectory from pain phenotype to pain gene involving fine-mapping strategies, bioinformatic analysis and microarray profiling alongside human association analysis will be introduced. This integrated approach has led to identification of CACNG2 as a novel neuropathic pain gene affecting pain susceptibility both in mice and humans. It also serves as a prototype for efficient and economic discovery of pain genes. Comparisons to other methods as well as future directions of pain genetics will be discussed as well.

  8. Identification of New Genetic Susceptibility Loci for Breast Cancer Through Consideration of Gene-Environment Interactions

    PubMed Central

    Schoeps, Anja; Rudolph, Anja; Seibold, Petra; Dunning, Alison M.; Milne, Roger L.; Bojesen, Stig E.; Swerdlow, Anthony; Andrulis, Irene; Brenner, Hermann; Behrens, Sabine; Orr, Nicholas; Jones, Michael; Ashworth, Alan; Li, Jingmei; Cramp, Helen; Connley, Dan; Czene, Kamila; Darabi, Hatef; Chanock, Stephen J.; Lissowska, Jolanta; Figueroa, Jonine D.; Knight, Julia; Glendon, Gord; Mulligan, Anna M.; Dumont, Martine; Severi, Gianluca; Baglietto, Laura; Olson, Janet; Vachon, Celine; Purrington, Kristen; Moisse, Matthieu; Neven, Patrick; Wildiers, Hans; Spurdle, Amanda; Kosma, Veli-Matti; Kataja, Vesa; Hartikainen, Jaana M.; Hamann, Ute; Ko, Yon-Dschun; Dieffenbach, Aida K.; Arndt, Volker; Stegmaier, Christa; Malats, Núria; Arias Perez, JoséI.; Benítez, Javier; Flyger, Henrik; Nordestgaard, Børge G.; Truong, Théresè; Cordina-Duverger, Emilie; Menegaux, Florence; Silva, Isabel dos Santos; Fletcher, Olivia; Johnson, Nichola; Häberle, Lothar; Beckmann, Matthias W.; Ekici, Arif B.; Braaf, Linde; Atsma, Femke; van den Broek, Alexandra J.; Makalic, Enes; Schmidt, Daniel F.; Southey, Melissa C.; Cox, Angela; Simard, Jacques; Giles, Graham G.; Lambrechts, Diether; Mannermaa, Arto; Brauch, Hiltrud; Guénel, Pascal; Peto, Julian; Fasching, Peter A.; Hopper, John; Flesch-Janys, Dieter; Couch, Fergus; Chenevix-Trench, Georgia; Pharoah, Paul D. P.; Garcia-Closas, Montserrat; Schmidt, Marjanka K.; Hall, Per; Easton, Douglas F.; Chang-Claude, Jenny

    2014-01-01

    Genes that alter disease risk only in combination with certain environmental exposures may not be detected in genetic association analysis. By using methods accounting for gene-environment (G × E) interaction, we aimed to identify novel genetic loci associated with breast cancer risk. Up to 34,475 cases and 34,786 controls of European ancestry from up to 23 studies in the Breast Cancer Association Consortium were included. Overall, 71,527 single nucleotide polymorphisms (SNPs), enriched for association with breast cancer, were tested for interaction with 10 environmental risk factors using three recently proposed hybrid methods and a joint test of association and interaction. Analyses were adjusted for age, study, population stratification, and confounding factors as applicable. Three SNPs in two independent loci showed statistically significant association: SNPs rs10483028 and rs2242714 in perfect linkage disequilibrium on chromosome 21 and rs12197388 in ARID1B on chromosome 6. While rs12197388 was identified using the joint test with parity and with age at menarche (P-values = 3 × 10−07), the variants on chromosome 21 q22.12, which showed interaction with adult body mass index (BMI) in 8,891 postmenopausal women, were identified by all methods applied. SNP rs10483028 was associated with breast cancer in women with a BMI below 25 kg/m2 (OR = 1.26, 95% CI 1.15–1.38) but not in women with a BMI of 30 kg/m2 or higher (OR = 0.89, 95% CI 0.72–1.11, P for interaction = 3.2 × 10−05). Our findings confirm comparable power of the recent methods for detecting G × E interaction and the utility of using G × E interaction analyses to identify new susceptibility loci. PMID:24248812

  9. The LEP G-2548A gene polymorphism is associated with age at menarche and breast cancer susceptibility.

    PubMed

    Rostami, Sara; Kohan, Leila; Mohammadianpanah, Mohammad

    2015-02-25

    Leptin is an adipocytokine made by fat cells and plays a key role in proliferation, cell survival, migration and immune response. It has a powerful effect on the initiation of puberty and in determining age at menarche. The current study is the first investigation to examine the effect of G-2548A leptin gene polymorphism on the age at menarche and breast cancer susceptibility. This case-control study was performed on 203 patients with breast cancer and 171 healthy women. The leptin genotypes were determined using the PCR-RFLP method and age at menarche was obtained by questionnaires. There was a significant difference between the leptin G-2548A genotypes between case and control groups (P<0.05). AA genotype is significantly higher in patients compared to the controls. Furthermore, women carrying the AA genotype had a significantly younger age at menarche (12.47 years) than women with the AG (12.94 years) and GG (13.47 years) genotypes. Also, we found that the AA genotype frequency in women with age at menarche <13 years was higher than in women with age at menarche ≥13 years (OR: 3.4, 95% CI: 1.7-6.7, P: 0.001). In conclusion, the G-2548A leptin gene polymorphism has an important role in the onset of menarche and breast cancer susceptibility.

  10. TGFβ receptor 1: an immune susceptibility gene in HPV-associated cancer.

    PubMed

    Levovitz, Chaya; Chen, Dan; Ivansson, Emma; Gyllensten, Ulf; Finnigan, John P; Alshawish, Sara; Zhang, Weijia; Schadt, Eric E; Posner, Marshal R; Genden, Eric M; Boffetta, Paolo; Sikora, Andrew G

    2014-12-01

    Only a minority of those exposed to human papillomavirus (HPV) develop HPV-related cervical and oropharyngeal cancer. Because host immunity affects infection and progression to cancer, we tested the hypothesis that genetic variation in immune-related genes is a determinant of susceptibility to oropharyngeal cancer and other HPV-associated cancers by performing a multitier integrative computational analysis with oropharyngeal cancer data from a head and neck cancer genome-wide association study (GWAS). Independent analyses, including single-gene, gene-interconnectivity, protein-protein interaction, gene expression, and pathway analysis, identified immune genes and pathways significantly associated with oropharyngeal cancer. TGFβR1, which intersected all tiers of analysis and thus selected for validation, replicated significantly in the head and neck cancer GWAS limited to HPV-seropositive cases and an independent cervical cancer GWAS. The TGFβR1 containing p38-MAPK pathway was significantly associated with oropharyngeal cancer and cervical cancer, and TGFβR1 was overexpressed in oropharyngeal cancer, cervical cancer, and HPV(+) head and neck cancer tumors. These concordant analyses implicate TGFβR1 signaling as a process dysregulated across HPV-related cancers. This study demonstrates that genetic variation in immune-related genes is associated with susceptibility to oropharyngeal cancer and implicates TGFβR1/TGFβ signaling in the development of both oropharyngeal cancer and cervical cancer. Better understanding of the immunogenetic basis of susceptibility to HPV-associated cancers may provide insight into host/virus interactions and immune processes dysregulated in the minority of HPV-exposed individuals who progress to cancer. PMID:25273091

  11. TGFβ Receptor 1: An Immune Susceptibility Gene in HPV-Associated Cancer

    PubMed Central

    Levovitz, Chaya; Chen, Dan; Ivansson, Emma; Gyllensten, Ulf; Finnigan, John P.; Alshawish, Sara; Zhang, Weijia; Schadt, Eric E.; Posner, Marshal R.; Genden, Eric M.; Boffetta, Paolo; Sikora, Andrew G.

    2015-01-01

    Only a minority of those exposed to human papillomavirus (HPV) develop HPV-related cervical and oropharyngeal cancer. Because host immunity affects infection and progression to cancer, we tested the hypothesis that genetic variation in immune-related genes is a determinant of susceptibility to oropharyngeal cancer and other HPV-associated cancers by performing a multitier integrative computational analysis with oropharyngeal cancer data from a head and neck cancer genome-wide association study (GWAS). Independent analyses, including single-gene, gene-interconnectivity, protein–protein interaction, gene expression, and pathway analysis, identified immune genes and pathways significantly associated with oropharyngeal cancer. TGFβR1, which intersected all tiers of analysis and thus selected for validation, replicated significantly in the head and neck cancer GWAS limited to HPV-seropositive cases and an independent cervical cancer GWAS. The TGFβR1 containing p38–MAPK pathway was significantly associated with oropharyngeal cancer and cervical cancer, and TGFβR1 was overexpressed in oropharyngeal cancer, cervical cancer, and HPV+ head and neck cancer tumors. These concordant analyses implicate TGFβR1 signaling as a process dysregulated across HPV-related cancers. This study demonstrates that genetic variation in immune-related genes is associated with susceptibility to oropharyngeal cancer and implicates TGFβR1/TGFβ signaling in the development of both oropharyngeal cancer and cervical cancer. Better understanding of the immunogenetic basis of susceptibility to HPV-associated cancers may provide insight into host/virus interactions and immune processes dysregulated in the minority of HPV-exposed individuals who progress to cancer. PMID:25273091

  12. Implications of critical PPARγ2, ADIPOQ and FTO gene polymorphisms in type 2 diabetes and obesity-mediated susceptibility to type 2 diabetes in an Indian population.

    PubMed

    Phani, Nagaraja M; Vohra, Manik; Rajesh, Somyasree; Adhikari, Prabha; Nagri, Shivashankara K; D'Souza, Sydney C; Satyamoorthy, Kapaettu; Rai, Padmalatha S

    2016-02-01

    Peroxisome proliferator-activated receptors (PPARγ), adiponectin (ADIPOQ) and fat mass and obesity-associated gene (FTO) have been reported as a key candidate genes for obesity, type 2 diabetes (T2D) susceptibility and insulin resistance, and we hypothesize that in the background of obesity, the effect of PPARγ2 (rs1801282), ADIPOQ (rs16861194) and FTO (rs9939609) variant could potentially influence T2D susceptibility. To decipher a more accurate estimation toward its population-specific impact of these variants toward susceptibility to T2D, a case-control study, systematic review and a meta-analysis was performed in a South Asian population. A case-control analysis of 518 T2D cases and 518 controls of Karnataka origin were performed to analyze the association of PPARγ2 (rs1801282), ADIPOQ (rs16861194) and FTO (rs9939609) on the risk of T2D. In addition, a systematic review and meta-analysis for PPARγ2 (rs1801282) and FTO (rs9939609) was elucidated from Asian population. Our investigation showed that PPARγ2 (rs1801282) and FTO (rs9939609) are associated with T2D susceptibility. When T2D cohort was further stratified according to the obesity status, PPARγ2 (rs1801282) and FTO (rs9939609) showed association with T2D only in the obese diabetic group and ADIPOQ (rs16861194) showed no difference in risk of susceptibility to the disease. The meta-analysis of PPARγ2 (rs1801282) showed population-specific association for T2D susceptibility as opposed to FTO (rs9939609) which showed no difference in population effect toward T2D susceptibility. In conclusion, our study showed that PPARγ2 (rs1801282) and FTO (rs9939609) variants are associated with T2D susceptibility when associated with adiposity in Indian population.

  13. Genetic polymorphisms of interleukin-6 gene and susceptibility to coronary artery disease in Chinese population: Evidence based on 4582 subjects.

    PubMed

    Liu, Shun-Lin; Yin, Yan-Wei; Sun, Qian-Qian; Hu, Ai-Min; Zhang, Shi-Jie

    2015-07-01

    The aim of this study was to explore whether interleukin-6 (IL-6) gene (-174 G/C and -572 C/G) polymorphisms are associated with susceptibility to coronary artery disease (CAD) risk in Chinese population. All the statistical tests were performed using Stata version 11.0. Twelve articles involving 16 studies were included in this meta-analysis, covering a total of 2309 CAD cases and 2273 controls. For IL-6 gene -572 C/G polymorphism, the results showed evidence for significant association between IL-6 gene -572 C/G polymorphism and CAD risk (for G allele vs. C allele: OR=1.48, 95% CI=1.26-1.74, p<0.001; for G/G vs. C/C: OR=2.60, 95% CI=1.54-4.39, p<0.001; for G/G vs. G/C+C/C: OR=2.15, 95% CI=1.35-3.42, p=0.001; for G/G+G/C vs. C/C: OR=1.55, 95% CI=1.29-1.85, p<0.001). However, for IL-6 gene -174 G/C polymorphism, no significant association was found between this variation and CAD risk. In summary, our meta-analysis showed evidence that IL-6 gene -572 C/G polymorphism may be a risk factor for CAD susceptibility. For IL-6 gene -174 G/C polymorphism, no significant association was found between this variation and CAD risk.

  14. Tumor necrosis factor-α and interleukin-6 gene polymorphism association with susceptibility to celiac disease in Italian patients.

    PubMed

    de Albuquerque Maranhão, R M; Martins Esteves, F A; Crovella, S; Segat, L; Eleutério Souza, P R

    2015-12-09

    The aim of this research was to study polymorphisms in the genes encoding cytokines interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNF-α) in patients with celiac disease (CD) antigens DQ2 (DQ2-positive) or DQ8 (DQ8-positive). We compared the results with healthy controls to determine whether any of the polymorphisms have a role in susceptibility to CD. A case-control of 192 patients with CD (96 DQ2-positive and 96 DQ8-positive) and 96 healthy controls from northeast Italy were included in the study. Analysis of single nucleotide polymorphisms (SNPs) was carried out using the polymerase chain reaction-restriction fragment length polymorphism method. Significant differences for the TNF-α(-308 G>A) polymorphism were observed when we compared the flowing groups: DQ2-positive with controls [odds ratio (OR) = 0.45, P = 0.0002]; DQ8-positive with controls (OR = 3.55, P < 0.0001); and DQ2-positive with DQ8-positive (OR = 0.12, P < 0.0001). We did not observe a statistically significant association between IL-6 (-174 G>C) polymorphism and CD (P > 0.05). Our results suggest that TNF-α(-308 G>A) polymorphism may play a role in susceptibility to CD in Italian patients.

  15. Genes Expressed Differentially in Hessian Fly Larvae Feeding in Resistant and Susceptible Plants

    Technology Transfer Automated Retrieval System (TEKTRAN)

    The Hessian fly, Mayetiola destructor, is a destructive pest of wheat worldwide and mainly controlled by deploying resistant cultivars. Hessian fly larvae manipulate susceptible plants extensively, but are unable to manipulate resistant plants and thus die in them. The mechanisms for Hessian fly l...

  16. The Correlation Between Interferon Lambda 3 Gene Polymorphisms and Susceptibility to Hepatitis B Virus Infection

    PubMed Central

    Heidari, Zahra; Moudi, Bita; Mahmoudzadeh-Sagheb, Hamidreza; Hashemi, Mohammad

    2016-01-01

    Background Cytokines are proteins that mediate innate and adaptive immunity responses. It is hypothesized that interferon lambda 3 (IFNL3) levels can influence the outcome of chronic hepatitis B virus (HBV) infection. Polymorphisms in IFN genes have been associated with response to infection. Objectives This study was carried-out to investigate the association of IFNL3 gene polymorphisms (rs12979860 and rs8099917) with HBV susceptibility, in chronic HBV-infected patients. Patients and Methods In this case-control study, we determined IFNL3 single nucleotide polymorphisms (SNPs) (rs12979860 and rs8099917) in 221 individuals, with chronic HBV infection, and 200 healthy individuals, who were voluntary blood donors, with negative test for HBV. Alleles and genotypes analyses were performed by amplification refractory mutation system-polymerase chain reaction (ARMS-PCR) and polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) methods. Results The frequencies of the rs12979860 and rs8099917 genotypes were not significantly different between the HBV-infected and the control groups (CC:CT:TT of 30.3%:48.0%:21.7% vs. 33.0%:49.0%:18.0%, P > 0.05, and GG:GT:TT of 5.8%:39.4%:54.8% vs. 5.0%:41.0%:54.0%, P > 0.05, respectively). Also, the frequencies of the alleles were not significantly different between both groups (C:T of 54.3%:45.7% vs. 57.5%:42.5%, P > 0.05, and G:T of 25.6%:74.4% vs. 25.5%:74.5%, P > 0.05, respectively) and the chronic HBV infection. There were no significant differences between patients, with at least one rs12979860C and or rs8099917T alleles compared to the healthy controls (rs12979860: CT + CC:TT, OR = 1.26, 95%CI = 0.78 - 2.04, P = 0.341 and rs8099917: GT + TT:GG, OR = 1.03, 95%CI = 0.70 - 1.51, P = 0.877, respectively). Conclusions Our study showed no correlation between rs12979860 and rs8099917 SNPs and chronic HBV infection. Further studies, with larger sample sizes and different ethnicities, are necessary to validate our

  17. A gene for familial psoriasis susceptibility maps to the distal end of human chromosome 17q

    SciTech Connect

    Bowcock, A.; Tomfohrde, J.; Barnes, R.

    1994-09-01

    Psoriasis is a chronic inflammatory dermatosis that affects approximately 2% of the population. A gene for psoriasis susceptibility was localized to the distal region of human chromosome 17q as a result of a genome wide linkage-analysis with polymorphic microsatellites and eight multiply affected psoriasis kindreds. With one large kindred a maximum two-point lod score with D17S784 was 5.70 at 15% recombination. Heterogeneity testing indicated that psoriasis susceptibility in 50% of the families was linked to distal 17q. Susceptibility to psoriasis has repeatedly been found to be associated with HLA-Cw6 and associated HLA alleles. We therefore genotyped the families for loci within and flanking HLA; these included PCR assays for susceptibility alleles. By lod score analysis no evidence of linkage of psoriasis susceptibility to HLA was detected. The distribution of HLA-Cw6 and HLA-Class II alleles showed that HLA-Cw6 was frequent among patients, particularly in 4 of the 5 unlinked families. All affected members of two of these unlinked families carried HLA-Cw6 (empirical P values of 0.027 and 0.004). In 2 other families 4 of 6 and 6 of 7 had HLA-Cw6. In some of these families, an inability to detect linkage to HLA may have been due to the occurrence of multiple haplotypes carrying the psoriasis associated allele, HLA-Cw6. Contrasting with these findings, we observed a lack of association between HLA-Cw6 and psoriasis in the 3 families in which 17q markers were linked to susceptibility. The ability to detect linkage to 17q confirms that some forms of familial psoriasis are due to molecular defects at a single major genetic locus other than HLA.

  18. Genetic association of cyclooxygenase-2 gene polymorphisms with Parkinson’s disease susceptibility in Chinese Han population

    PubMed Central

    Dai, Yi; Wu, Yuquan; Li, Yansheng

    2015-01-01

    Objective: The aim of this study was to explore the genetic association of cyclooxygenase-2 (COX2) gene promoter region polymorphisms with Parkinson’s disease (PD) susceptibility in Chinese Han population. Methods: The genotyping of COX2 gene polymorphisms was conducted by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) in 122 patients with PD and 120 healthy persons. The association strength of gene polymorphism with disease was measured by odds ratio (OR) and 95% confidence interval (95% CI) calculated using χ2 test which also evaluated the Hardy-Weinberg equilibrium (HWE) of gene polymorphism in controls. The linkage disequilibrium and haplotype were also analyzed as evidence in the analysis of association. Results: On condition that the genotypes distributions of COX2 -1290A>G, -1195G>A, -765G>C in the control group all conformed to HWE, however, only the homozygous genotype AA of -1195G>A polymorphism showed an association with PD (OR=0.432, 95% CI=0.196-0.950). In addition, in haplotype analysis, G-A-C haplotype frequency in cases was significantly lower than the controls, compared with the common haplotype A-G-G (P=0.031, OR=0.375, 95% CI=0.149-0.940). Conclusions: COX2 -1195G>A polymorphism might play a protective role in the onset of PD and G-A-C haplotype in this three promoter region polymorphisms also showed a negative association. PMID:26722563

  19. Beta-lactamase genes of the penicillin-susceptible Bacillus anthracis Sterne strain.

    PubMed

    Chen, Yahua; Succi, Janice; Tenover, Fred C; Koehler, Theresa M

    2003-02-01

    Susceptibility to penicillin and other beta-lactam-containing compounds is a common trait of Bacillus anthracis. Beta-lactam agents, particularly penicillin, have been used worldwide to treat anthrax in humans. Nonetheless, surveys of clinical and soil-derived strains reveal penicillin G resistance in 2 to 16% of isolates tested. Bacterial resistance to beta-lactam agents is often mediated by production of one or more types of beta-lactamases that hydrolyze the beta-lactam ring, inactivating the antimicrobial agent. Here, we report the presence of two beta-lactamase (bla) genes in the penicillin-susceptible Sterne strain of B. anthracis. We identified bla1 by functional cloning with Escherichia coli. bla1 is a 927-nucleotide (nt) gene predicted to encode a protein with 93.8% identity to the type I beta-lactamase gene of Bacillus cereus. A second gene, bla2, was identified by searching the unfinished B. anthracis chromosome sequence database of The Institute for Genome Research for open reading frames (ORFs) predicted to encode beta-lactamases. We found a partial ORF predicted to encode a protein with significant similarity to the carboxy-terminal end of the type II beta-lactamase of B. cereus. DNA adjacent to the 5' end of the partial ORF was cloned using inverse PCR. bla2 is a 768-nt gene predicted to encode a protein with 92% identity to the B. cereus type II enzyme. The bla1 and bla2 genes confer ampicillin resistance to E. coli and Bacillus subtilis when cloned individually in these species. The MICs of various antimicrobial agents for the E. coli clones indicate that the two beta-lactamase genes confer different susceptibility profiles to E. coli; bla1 is a penicillinase, while bla2 appears to be a cephalosporinase. The beta-galactosidase activities of B. cereus group species harboring bla promoter-lacZ transcriptional fusions indicate that bla1 is poorly transcribed in B. anthracis, B. cereus, and B. thuringiensis. The bla2 gene is strongly expressed in B

  20. Antimicrobial Susceptibility of Bordetella bronchiseptica Isolates from Swine and Companion Animals and Detection of Resistance Genes.

    PubMed

    Prüller, Sandra; Rensch, Ulrike; Meemken, Diana; Kaspar, Heike; Kopp, Peter A; Klein, Günter; Kehrenberg, Corinna

    2015-01-01

    Bordetella bronchiseptica causes infections of the respiratory tract in swine and other mammals and is a precursor for secondary infections with Pasteurella multocida. Treatment of B. bronchiseptica infections is conducted primarily with antimicrobial agents. Therefore it is essential to get an overview of the susceptibility status of these bacteria. The aim of this study was to comparatively analyse broth microdilution susceptibility testing according to CLSI recommendations with an incubation time of 16 to 20 hours and a longer incubation time of 24 hours, as recently proposed to obtain more homogenous MICs. Susceptibility testing against a panel of 22 antimicrobial agents and two fixed combinations was performed with 107 porcine isolates from different farms and regions in Germany and 43 isolates obtained from companion animals in Germany and other European countries. Isolates with increased MICs were investigated by PCR assays for the presence of resistance genes. For ampicillin, all 107 porcine isolates were classified as resistant, whereas only a single isolate was resistant to florfenicol. All isolates obtained from companion animals showed elevated MICs for β-lactam antibiotics and demonstrated an overall low susceptibility to cephalosporines. Extension of the incubation time resulted in 1-2 dilution steps higher MIC50 values of porcine isolates for seven antimicrobial agents tested, while isolates from companion animals exhibited twofold higher MIC50/90 values only for tetracycline and cefotaxime. For three antimicrobial agents, lower MIC50 and MIC90 values were detected for both, porcine and companion animal isolates. Among the 150 isolates tested, the resistance genes blaBOR-1 (n = 147), blaOXA-2, (n = 4), strA and strB (n = 17), sul1 (n = 10), sul2 (n = 73), dfrA7 (n = 3) and tet(A) (n = 8) were detected and a plasmid localisation was identified for several of the resistance genes.

  1. Antimicrobial Susceptibility of Bordetella bronchiseptica Isolates from Swine and Companion Animals and Detection of Resistance Genes.

    PubMed

    Prüller, Sandra; Rensch, Ulrike; Meemken, Diana; Kaspar, Heike; Kopp, Peter A; Klein, Günter; Kehrenberg, Corinna

    2015-01-01

    Bordetella bronchiseptica causes infections of the respiratory tract in swine and other mammals and is a precursor for secondary infections with Pasteurella multocida. Treatment of B. bronchiseptica infections is conducted primarily with antimicrobial agents. Therefore it is essential to get an overview of the susceptibility status of these bacteria. The aim of this study was to comparatively analyse broth microdilution susceptibility testing according to CLSI recommendations with an incubation time of 16 to 20 hours and a longer incubation time of 24 hours, as recently proposed to obtain more homogenous MICs. Susceptibility testing against a panel of 22 antimicrobial agents and two fixed combinations was performed with 107 porcine isolates from different farms and regions in Germany and 43 isolates obtained from companion animals in Germany and other European countries. Isolates with increased MICs were investigated by PCR assays for the presence of resistance genes. For ampicillin, all 107 porcine isolates were classified as resistant, whereas only a single isolate was resistant to florfenicol. All isolates obtained from companion animals showed elevated MICs for β-lactam antibiotics and demonstrated an overall low susceptibility to cephalosporines. Extension of the incubation time resulted in 1-2 dilution steps higher MIC50 values of porcine isolates for seven antimicrobial agents tested, while isolates from companion animals exhibited twofold higher MIC50/90 values only for tetracycline and cefotaxime. For three antimicrobial agents, lower MIC50 and MIC90 values were detected for both, porcine and companion animal isolates. Among the 150 isolates tested, the resistance genes blaBOR-1 (n = 147), blaOXA-2, (n = 4), strA and strB (n = 17), sul1 (n = 10), sul2 (n = 73), dfrA7 (n = 3) and tet(A) (n = 8) were detected and a plasmid localisation was identified for several of the resistance genes. PMID:26275219

  2. Antimicrobial Susceptibility of Bordetella bronchiseptica Isolates from Swine and Companion Animals and Detection of Resistance Genes

    PubMed Central

    Prüller, Sandra; Rensch, Ulrike; Meemken, Diana; Kaspar, Heike; Kopp, Peter A.; Klein, Günter; Kehrenberg, Corinna

    2015-01-01

    Bordetella bronchiseptica causes infections of the respiratory tract in swine and other mammals and is a precursor for secondary infections with Pasteurella multocida. Treatment of B. bronchiseptica infections is conducted primarily with antimicrobial agents. Therefore it is essential to get an overview of the susceptibility status of these bacteria. The aim of this study was to comparatively analyse broth microdilution susceptibility testing according to CLSI recommendations with an incubation time of 16 to 20 hours and a longer incubation time of 24 hours, as recently proposed to obtain more homogenous MICs. Susceptibility testing against a panel of 22 antimicrobial agents and two fixed combinations was performed with 107 porcine isolates from different farms and regions in Germany and 43 isolates obtained from companion animals in Germany and other European countries. Isolates with increased MICs were investigated by PCR assays for the presence of resistance genes. For ampicillin, all 107 porcine isolates were classified as resistant, whereas only a single isolate was resistant to florfenicol. All isolates obtained from companion animals showed elevated MICs for β-lactam antibiotics and demonstrated an overall low susceptibility to cephalosporines. Extension of the incubation time resulted in 1–2 dilution steps higher MIC50 values of porcine isolates for seven antimicrobial agents tested, while isolates from companion animals exhibited twofold higher MIC50/90 values only for tetracycline and cefotaxime. For three antimicrobial agents, lower MIC50 and MIC90 values were detected for both, porcine and companion animal isolates. Among the 150 isolates tested, the resistance genes blaBOR-1 (n = 147), blaOXA-2, (n = 4), strA and strB (n = 17), sul1 (n = 10), sul2 (n = 73), dfrA7 (n = 3) and tet(A) (n = 8) were detected and a plasmid localisation was identified for several of the resistance genes. PMID:26275219

  3. 13. CONTROL ROOM OF GENE PUMPING STATION. CONTROL CUBICLES ARRAYED ...

    Library of Congress Historic Buildings Survey, Historic Engineering Record, Historic Landscapes Survey

    13. CONTROL ROOM OF GENE PUMPING STATION. CONTROL CUBICLES ARRAYED BEHIND MANAGER'S ART DECO-STYLE CONTROL DESK, WITH CONTROL CUBICLE 1 AT FAR RIGHT AND CONTROL CUBICLE 9 AT FAR LEFT. - Gene Pump Plant, South of Gene Wash Reservoir, 2 miles west of Whitsett Pump Plant, Parker Dam, San Bernardino County, CA

  4. PON1 as a model for integration of genetic, epigenetic, and expression data on candidate susceptibility genes

    PubMed Central

    Huen, Karen; Yousefi, Paul; Street, Kelly; Eskenazi, Brenda; Holland, Nina

    2016-01-01

    Recent genome- and epigenome-wide studies demonstrate that the DNA methylation is controlled in part by genetics, highlighting the importance of integrating genetic and epigenetic data. To better understand molecular mechanisms affecting gene expression, we used the candidate susceptibility gene paraoxonase 1 (PON1) as a model to assess associations of PON1 genetic polymorphisms with DNA methylation and arylesterase activity, a marker of PON1 expression. PON1 has been associated with susceptibility to obesity, cardiovascular disease, and pesticide exposure. In this study, we assessed DNA methylation in 18 CpG sites located along PON1 shores, shelves, and its CpG island in blood specimens collected from newborns and 9-year-old children participating (n = 449) in the CHAMACOS birth cohort study. The promoter polymorphism, PON1−108, was strongly associated with methylation, particularly for CpG sites located near the CpG island (P << 0.0005). Among newborns, these relationships were even more pronounced after adjusting for blood cell composition. We also observed significant decreases in arylesterase activity with increased methylation at the same nine CpG sites at both ages. Using causal mediation analysis, we found statistically significant indirect effects of methylation (β(95% confidence interval): 6.9(1.5, 12.4)) providing evidence that DNA methylation mediates the relationship between PON1−108 genotype and PON1 expression. Our findings show that integration of genetic, epigenetic, and expression data can shed light on the functional mechanisms involving genetic and epigenetic regulation of candidate susceptibility genes like PON1. PMID:26913202

  5. A Novel Differential Susceptibility Gene: "CHRNA4" and Moderation of the Effect of Maltreatment on Child Personality

    ERIC Educational Resources Information Center

    Grazioplene, Rachael G.; DeYoung, Colin G.; Rogosch, Fred A.; Cicchetti, Dante

    2013-01-01

    Background: The differential susceptibility hypothesis states that some genetic variants that confer risk in adverse environments are beneficial in normal or nurturing environments. The cholinergic system is promising as a source of susceptibility genes because of its involvement in learning and neural plasticity. The cholinergic receptor gene…

  6. Comparison of gene activation by two TAL effectors from Xanthomonas axonopodis pv. manihotis reveals candidate host susceptibility genes in cassava.

    PubMed

    Cohn, Megan; Morbitzer, Robert; Lahaye, Thomas; Staskawicz, Brian J

    2016-08-01

    Xanthomonas axonopodis pv. manihotis (Xam) employs transcription activator-like (TAL) effectors to promote bacterial growth and symptom formation during infection of cassava. TAL effectors are secreted via the bacterial type III secretion system into plant cells, where they are directed to the nucleus, bind DNA in plant promoters and activate the expression of downstream genes. The DNA-binding activity of TAL effectors is carried out by a central domain which contains a series of repeat variable diresidues (RVDs) that dictate the sequence of bound nucleotides. TAL14Xam668 promotes virulence in Xam strain Xam668 and has been shown to activate multiple cassava genes. In this study, we used RNA sequencing to identify the full target repertoire of TAL14Xam668 in cassava, which includes over 50 genes. A subset of highly up-regulated genes was tested for activation by TAL14CIO151 from Xam strain CIO151. Although TAL14CIO151 and TAL14Xam668 differ by only a single RVD, they display differential activation of gene targets. TAL14CIO151 complements the TAL14Xam668 mutant defect, implying that shared target genes are important for TAL14Xam668 -mediated disease susceptibility. Complementation with closely related TAL effectors is a novel approach to the narrowing down of biologically relevant susceptibility genes of TAL effectors with multiple targets. This study provides an example of how TAL effector target activation by two strains within a single species of Xanthomonas can be dramatically affected by a small change in RVD-nucleotide affinity at a single site, and reflects the parameters of RVD-nucleotide interaction determined using designer TAL effectors in transient systems. PMID:26575863

  7. Comparison of gene activation by two TAL effectors from Xanthomonas axonopodis pv. manihotis reveals candidate host susceptibility genes in cassava.

    PubMed

    Cohn, Megan; Morbitzer, Robert; Lahaye, Thomas; Staskawicz, Brian J

    2016-08-01

    Xanthomonas axonopodis pv. manihotis (Xam) employs transcription activator-like (TAL) effectors to promote bacterial growth and symptom formation during infection of cassava. TAL effectors are secreted via the bacterial type III secretion system into plant cells, where they are directed to the nucleus, bind DNA in plant promoters and activate the expression of downstream genes. The DNA-binding activity of TAL effectors is carried out by a central domain which contains a series of repeat variable diresidues (RVDs) that dictate the sequence of bound nucleotides. TAL14Xam668 promotes virulence in Xam strain Xam668 and has been shown to activate multiple cassava genes. In this study, we used RNA sequencing to identify the full target repertoire of TAL14Xam668 in cassava, which includes over 50 genes. A subset of highly up-regulated genes was tested for activation by TAL14CIO151 from Xam strain CIO151. Although TAL14CIO151 and TAL14Xam668 differ by only a single RVD, they display differential activation of gene targets. TAL14CIO151 complements the TAL14Xam668 mutant defect, implying that shared target genes are important for TAL14Xam668 -mediated disease susceptibility. Complementation with closely related TAL effectors is a novel approach to the narrowing down of biologically relevant susceptibility genes of TAL effectors with multiple targets. This study provides an example of how TAL effector target activation by two strains within a single species of Xanthomonas can be dramatically affected by a small change in RVD-nucleotide affinity at a single site, and reflects the parameters of RVD-nucleotide interaction determined using designer TAL effectors in transient systems.

  8. Chimeric EWSR1-FLI1 regulates the Ewing sarcoma susceptibility gene EGR2 via a GGAA microsatellite

    PubMed Central

    Grünewald, Thomas G. P.; Bernard, Virginie; Gilardi-Hebenstreit, Pascale; Raynal, Virginie; Surdez, Didier; Aynaud, Marie-Ming; Mirabeau, Olivier; Cidre-Aranaz, Florencia; Tirode, Franck; Zaidi, Sakina; Perot, Gaëlle; Jonker, Anneliene H.; Lucchesi, Carlo; Le Deley, Marie-Cécile; Oberlin, Odile; Marec-Bérard, Perrine; Véron, Amélie S.; Reynaud, Stephanie; Lapouble, Eve; Boeva, Valentina; Frio, Thomas Rio; Alonso, Javier; Bhatia, Smita; Pierron, Gaëlle; Cancel-Tassin, Geraldine; Cussenot, Olivier; Cox, David G.; Morton, Lindsay M.; Machiela, Mitchell J.; Chanock, Stephen J.; Charnay, Patrick; Delattre, Olivier

    2015-01-01

    Deciphering the ways in which somatic mutations and germline susceptibility variants cooperate to promote cancer is challenging. Ewing sarcoma is characterized by fusions between EWSR1 and members of the ETS gene family, usually EWSR1-FLI1, leading to the generation of oncogenic transcription factors that bind DNA at GGAA motifs1–3. A recent genome-wide association study4 identified susceptibility variants near EGR2. Here we found that EGR2 knockdown inhibited proliferation, clonogenicity and spheroidal growth in vitro and induced regression of Ewing sarcoma xenografts. Targeted germline deep sequencing of the EGR2 locus in affected subjects and controls revealed 291 Ewing-associated SNPs. At rs79965208, the A risk allele connected adjacent GGAA repeats by converting an interspaced GGAT motif into a GGAA motif, thereby increasing the number of consecutive GGAA motifs and thus the EWSR1-FLI1–dependent enhancer activity of this sequence, with epigenetic characteristics of an active regulatory element. EWSR1-FLI1 preferentially bound to the A risk allele, which increased global and allele-specific EGR2 expression. Collectively, our findings establish cooperation between a dominant oncogene and a susceptibility variant that regulates a major driver of Ewing sarcomagenesis. PMID:26214589

  9. Chimeric EWSR1-FLI1 regulates the Ewing sarcoma susceptibility gene EGR2 via a GGAA microsatellite.

    PubMed

    Grünewald, Thomas G P; Bernard, Virginie; Gilardi-Hebenstreit, Pascale; Raynal, Virginie; Surdez, Didier; Aynaud, Marie-Ming; Mirabeau, Olivier; Cidre-Aranaz, Florencia; Tirode, Franck; Zaidi, Sakina; Perot, Gaëlle; Jonker, Anneliene H; Lucchesi, Carlo; Le Deley, Marie-Cécile; Oberlin, Odile; Marec-Bérard, Perrine; Véron, Amélie S; Reynaud, Stephanie; Lapouble, Eve; Boeva, Valentina; Rio Frio, Thomas; Alonso, Javier; Bhatia, Smita; Pierron, Gaëlle; Cancel-Tassin, Geraldine; Cussenot, Olivier; Cox, David G; Morton, Lindsay M; Machiela, Mitchell J; Chanock, Stephen J; Charnay, Patrick; Delattre, Olivier

    2015-09-01

    Deciphering the ways in which somatic mutations and germline susceptibility variants cooperate to promote cancer is challenging. Ewing sarcoma is characterized by fusions between EWSR1 and members of the ETS gene family, usually EWSR1-FLI1, leading to the generation of oncogenic transcription factors that bind DNA at GGAA motifs. A recent genome-wide association study identified susceptibility variants near EGR2. Here we found that EGR2 knockdown inhibited proliferation, clonogenicity and spheroidal growth in vitro and induced regression of Ewing sarcoma xenografts. Targeted germline deep sequencing of the EGR2 locus in affected subjects and controls identified 291 Ewing-associated SNPs. At rs79965208, the A risk allele connected adjacent GGAA repeats by converting an interspaced GGAT motif into a GGAA motif, thereby increasing the number of consecutive GGAA motifs and thus the EWSR1-FLI1-dependent enhancer activity of this sequence, with epigenetic characteristics of an active regulatory element. EWSR1-FLI1 preferentially bound to the A risk allele, which increased global and allele-specific EGR2 expression. Collectively, our findings establish cooperation between a dominant oncogene and a susceptibility variant that regulates a major driver of Ewing sarcomagenesis. PMID:26214589

  10. Variants of the SFTPA1 and SFTPA2 genes and susceptibility to tuberculosis in Ethiopia.

    PubMed

    Malik, S; Greenwood, C M T; Eguale, T; Kifle, A; Beyene, J; Habte, A; Tadesse, A; Gebrexabher, H; Britton, S; Schurr, E

    2006-02-01

    Lungs are the central organ affected and targeted by Mycobacterium tuberculosis and immune processes in the lung are of critical importance in the pathogenesis of tuberculosis. A major lung defense against invading pathogens is provided by surfactant protein A, a multi-chain protein encoded by the SFTPA1 and SFTPA2 genes. Here, we investigated polymorphisms in the SFTPA1 and SFTPA2 genes for association with tuberculosis in 181 Ethiopian families comprising 226 tuberculosis cases. Four polymorphisms, SFTPA1 307A, SFTPA1 776T, SFTPA2 355C, and SFTPA2 751C, were associated with tuberculosis (P=0.00008; P=0.019, P=0.029 and P=0.042, respectively). Additional subgroup analysis in male, female and more severely affected patients provided evidence for SFTPA1/2-covariate interaction. Finally, out of five intragenic haplotypes identified in the SFTPA1 gene and nine identified in the SFTPA2 gene, 1A(3) was most significantly associated with tuberculosis susceptibility (P=0.026). These findings suggest that SFTPA1 and SFTPA2 modify the risk of tuberculosis susceptibility and that this risk is influenced by additional covariates. PMID:16292672

  11. STK39 and WNK1 Are Potential Hypertension Susceptibility Genes in the BELHYPGEN Cohort.

    PubMed

    Persu, Alexandre; Evenepoel, Lucie; Jin, Yu; Mendola, Antonella; Ngueta, Gérard; Yang, Wen-Yi; Gruson, Damien; Horman, Sandrine; Staessen, Jan A; Vikkula, Miikka

    2016-04-01

    The serine/threonine kinase With-No-Lysine (K) Kinase 1 (WNK1) activates the thiazide-sensitive Na(+)/Cl(-) cotransporter through phosphorylation of STE20/SPS1-related proline/alanine-rich kinase, another serine/threonine kinase encoded by STK39. The aim of this study was to look for association between WNK1 and STK39 gene variants, and blood pressure (BP) and hypertension. Seven hundred seventy-nine Caucasian hypertensive patients (HYP) recruited in 6 academic centers from Belgium, and 906 normotensive (NT) controls were genotyped for 5 single nucleotide polymorphisms-rs3754777, rs6749447, rs35929607 (STK39), rs1468326, and rs765250 (WNK1)-using the Snapshot method. The rare TT genotype at the rs3754777 locus (STK39) was overrepresented in HYP versus NT (7.3% vs 3.0%, P = 0.0002). In the whole study population, the multivariable-adjusted odds ratio (OR) for having hypertension associated with the TT genotype was 5.9 (95% confidence interval: 2.2-15.6), and systolic BP was 10 mm Hg higher in TT compared with wild-type subjects (140.1 vs 130.4 mm Hg, P = 0.002). Similarly, the AA genotype at the rs1468326 locus (WNK1) was twice as frequent in HYP versus NT (5.5% vs 2.3%, P < 0.0001), and associated with an increased adjusted OR of hypertension (4.1; 1.5-11.7) and a higher systolic BP (139.8 vs 130.1 mm Hg, P = 0.003). In the whole cohort, a dose-dependent increase in systolic BP was observed according to the number of at-risk genotypes (0: 129.8 mm Hg; 1: 133.0 mm Hg; 2: 149.3 mm Hg, P = 0.02). Single nucleotide polymorphisms rs3754777 (STK39) and rs1468326 (WNK1) were associated with hypertension and BP in our multicenter Belgian case-control study, which supports the role of STK39 and WNK1 as potential hypertension susceptibility genes. Replication in different clinical settings and study of other candidate loci belonging to the same molecular pathway is warranted. PMID:27082544

  12. STK39 and WNK1 Are Potential Hypertension Susceptibility Genes in the BELHYPGEN Cohort

    PubMed Central

    Persu, Alexandre; Evenepoel, Lucie; Jin, Yu; Mendola, Antonella; Ngueta, Gérard; Yang, Wen-Yi; Gruson, Damien; Horman, Sandrine; Staessen, Jan A.; Vikkula, Miikka

    2016-01-01

    Abstract The serine/threonine kinase With-No-Lysine (K) Kinase 1 (WNK1) activates the thiazide-sensitive Na+/Cl− cotransporter through phosphorylation of STE20/SPS1-related proline/alanine-rich kinase, another serine/threonine kinase encoded by STK39. The aim of this study was to look for association between WNK1 and STK39 gene variants, and blood pressure (BP) and hypertension. Seven hundred seventy-nine Caucasian hypertensive patients (HYP) recruited in 6 academic centers from Belgium, and 906 normotensive (NT) controls were genotyped for 5 single nucleotide polymorphisms—rs3754777, rs6749447, rs35929607 (STK39), rs1468326, and rs765250 (WNK1)—using the Snapshot method. The rare TT genotype at the rs3754777 locus (STK39) was overrepresented in HYP versus NT (7.3% vs 3.0%, P = 0.0002). In the whole study population, the multivariable-adjusted odds ratio (OR) for having hypertension associated with the TT genotype was 5.9 (95% confidence interval: 2.2–15.6), and systolic BP was 10 mm Hg higher in TT compared with wild-type subjects (140.1 vs 130.4 mm Hg, P = 0.002). Similarly, the AA genotype at the rs1468326 locus (WNK1) was twice as frequent in HYP versus NT (5.5% vs 2.3%, P < 0.0001), and associated with an increased adjusted OR of hypertension (4.1; 1.5–11.7) and a higher systolic BP (139.8 vs 130.1 mm Hg, P = 0.003). In the whole cohort, a dose-dependent increase in systolic BP was observed according to the number of at-risk genotypes (0: 129.8 mm Hg; 1: 133.0 mm Hg; 2: 149.3 mm Hg, P = 0.02). Single nucleotide polymorphisms rs3754777 (STK39) and rs1468326 (WNK1) were associated with hypertension and BP in our multicenter Belgian case-control study, which supports the role of STK39 and WNK1 as potential hypertension susceptibility genes. Replication in different clinical settings and study of other candidate loci belonging to the same molecular pathway is warranted. PMID:27082544

  13. Impact of host gene polymorphisms on susceptibility to chronic hepatitis B virus infection.

    PubMed

    Moudi, Bita; Heidari, Zahra; Mahmoudzadeh-Sagheb, Hamidreza

    2016-10-01

    Hepatitis B virus (HBV) infection can result in a number of different clinical conditions, including asymptomatic HBV carriers to chronic hepatitis and primary hepatocellular carcinoma. Variations in cytokine genes have been discussed to affect the natural history of HBV infection. These cytokines may involve in the viral binding to the cells, modulating the host immune response to infection and pathological changes in the liver, and affecting the antiviral therapies. Various studies reveal that SNPs play an important role in pathogenesis of HBV. On the other hand, various outcomes of infection cannot be completely shown by genetic factors because these studies have inconsistent results with regard to the possible impacts of host genetic polymorphisms on susceptibility to infection. Therefore, to identify the real effects of host genetic factors in HBV susceptibility and natural history of the disease, studies with large sample size will be needed. In addition, due to the complex interactions of genetic factors it is better to identify synergies of several SNPs. Such studies can provide better insights into the novel methods of diagnosis and treatment. Current review will discuss significant genetic variations in cytokine genes that may affect the susceptibility to the chronic HBV infection. PMID:27346643

  14. Decreased susceptibility to chlorhexidine and prevalence of disinfectant resistance genes among clinical isolates of Staphylococcus epidermidis.

    PubMed

    Prag, Gustaf; Falk-Brynhildsen, Karin; Jacobsson, Susanne; Hellmark, Bengt; Unemo, Magnus; Söderquist, Bo

    2014-10-01

    Staphylococcus epidermidis is a versatile agent, being both a commensal and a nosocomial pathogen usually with an opportunistic role in association with implanted foreign body materials. Pre-operative antiseptic preparation is an important strategy for reducing the risk of complications such as surgical site infection (SSI). Currently, the most widely used antiseptics are alcohols, quaternary ammonium compounds (QACs), and the bisbiguanide chlorhexidine. Occurrence of resistance to the latter agent has drawn increasing attention. The aim of this study was to investigate if decreased susceptibility to chlorhexidine among S. epidermidis was present in our setting, a Swedish university hospital. Staphylococcus epidermidis (n = 143), retrospectively collected, were obtained from prosthetic joint infections (PJI) (n = 61), post-operative infections after cardiac surgery (n = 31), and the skin of the chest after routine disinfection prior to cardiac surgery (n = 27). In addition, 24 commensal isolates were included. Minimum inhibitory concentration (MIC) of chlorhexidine was determined on Mueller Hinton agar plates supplemented with serial dilutions of chlorhexidine. Five QAC resistance genes, qacA/B, smr, qacH, qacJ, and qacG, were detected using PCR. Decreased susceptibility to chlorhexidine was found in 54% of PJI isolates, 68% of cardiac isolates, 21% of commensal isolates, and 7% of skin isolates from cardiac patients, respectively. The qacA/B gene was present in 62/143 isolates (43%), smr in 8/143 (6%), and qacH in one isolate (0.7%). The qacA/B gene was found in 52% of PJI isolates, 61% of cardiac isolates, 25% of commensal isolates, and 19% of the skin isolates. In conclusion, decreased susceptibility to chlorhexidine, as well as QAC resistance genes, were prevalent among S. epidermidis isolates associated with deep SSIs.

  15. Molecular Basis of Acute Cystitis Reveals Susceptibility Genes and Immunotherapeutic Targets

    PubMed Central

    Cafaro, Caterina; Nadeem, Aftab; Butler, Daniel S. C.; Rydström, Gustav; Filenko, Nina A.; Wullt, Björn; Miethke, Thomas; Svanborg, Catharina

    2016-01-01

    Tissue damage is usually regarded as a necessary price to pay for successful elimination of pathogens by the innate immune defense. Yet, it is possible to distinguish protective from destructive effects of innate immune activation and selectively attenuate molecular nodes that create pathology. Here, we identify acute cystitis as an Interleukin-1 beta (IL-1β)-driven, hyper-inflammatory condition of the infected urinary bladder and IL-1 receptor blockade as a novel therapeutic strategy. Disease severity was controlled by the mechanism of IL-1β processing and mice with intact inflammasome function developed a moderate, self-limiting form of cystitis. The most severe form of acute cystitis was detected in mice lacking the inflammasome constituents ASC or NLRP-3. IL-1β processing was hyperactive in these mice, due to a new, non-canonical mechanism involving the matrix metalloproteinase 7- (MMP-7). ASC and NLRP-3 served as transcriptional repressors of MMP7 and as a result, Mmp7 was markedly overexpressed in the bladder epithelium of Asc-/- and Nlrp3-/- mice. The resulting IL-1β hyper-activation loop included a large number of IL-1β-dependent pro-inflammatory genes and the IL-1 receptor antagonist Anakinra inhibited their expression and rescued susceptible Asc-/- mice from bladder pathology. An MMP inhibitor had a similar therapeutic effect. Finally, elevated levels of IL-1β and MMP-7 were detected in patients with acute cystitis, suggesting a potential role as biomarkers and immunotherapeutic targets. The results reproduce important aspects of human acute cystitis in the murine model and provide a comprehensive molecular framework for the pathogenesis and immunotherapy of acute cystitis, one of the most common infections in man. Trial Registration The clinical studies were approved by the Human Ethics Committee at Lund University (approval numbers LU106-02, LU236-99 and Clinical Trial Registration RTP-A2003, International Committee of Medical Journal Editors, www

  16. Antimicrobial susceptibility and macrolide resistance genes in Streptococcus pyogenes collected in Austria and Hungary.

    PubMed

    Gattringer, Rainer; Sauermann, Robert; Lagler, Heimo; Stich, Karin; Buxbaum, Astrid; Graninger, Wolfgang; Georgopoulos, Apostolos

    2004-09-01

    A total of 341 clinical isolates of Streptococcus pyogenes from Vienna, Austria and three Hungarian cities were tested for susceptibility to four macrolides and 12 other antibiotics. All isolates were fully susceptible to penicillin and the other beta-lactams tested. A high level of tetracycline resistance was found in Austria (26.7%) and in Hungary (30.5%). The rate of resistance to erythromycin, clarithromycin and azithromycin was 4.7% in Vienna and 3.7% in the Hungarian communities. In both countries, the MIC(90) values of erythromycin and clarithromycin were 0.12 mg/L and the MIC(90) of josamycin was 0.5mg/L. The M phenotype of resistance conferred by the mefA genes was predominant (n = 9) among the macrolide-resistant isolates (n = 14).

  17. Association of IL-6 and MMP-3 gene polymorphisms with susceptibility to adolescent idiopathic scoliosis: a meta-analysis.

    PubMed

    Zhao, Jian; Yang, Mingyuan; Li, Ming

    2016-09-01

    Recently, several institutions have investigated the associations of MMP-3-1171 5A/6A and IL-6-174-G/C gene polymorphisms with adolescent idiopathic scoliosis (AIS), while reports from different institutions are not consistent. Therefore, we, comprehensively and systematically performed this meta-analysis to detect whether the two gene polymorphisms are correlated with AIS. From January 1994 to October 2015, all case-control studies focussed on the relationship between the two aforementioned gene polymorphisms and the susceptibility to AIS were retrieved from bibliographic databases. A total of 16 articles were found, of which five consisted of 944 cases and 1177 controls, were finally included after being assessed by two reviewers. We calculated the pooled odds ratio (OR) with 95% confidence interval (95% CI) to assess the associations. The pooled data analyses were based on allele contrast, homozygote, heterozygote, dominant and recessive models. Overall, there was no significant association of IL-6-174-G/C gene polymorphism with AIS risk. Significant association was observed in homozygote model of MMP-3-1171-5A/6A gene polymorphism (5A5A versus 6A6A: OR = 1.69, 95% CI = 1.11-2.58, P = 0.02). When stratified into Caucasian and Asian populations, positive association was found in Caucasian population (5A versus 6A: OR = 1.43, 95% CI = 1.11-1.84, P = 0.006; 5A5A versus 6A6A: OR = 1.90, 95% CI = 1.13-3.19, P = 0.015); however, there was no significant association in Asian population. The present study concluded that 5A5A genotype of MMP-3-1171 5A/6A gene polymorphism was associated with AIS, especially in Caucasian population. However, no significant association was detected between IL-6-174-G/C gene polymorphism and AIS. PMID:27659327

  18. Prion protein gene sequence and chronic wasting disease susceptibility in white-tailed deer (Odocoileus virginianus)

    PubMed Central

    Brandt, Adam L; Kelly, Amy C; Green, Michelle L; Shelton, Paul; Novakofski, Jan; Mateus-Pinilla, Nohra E

    2015-01-01

    ABSTRACT The sequence of the prion protein gene (PRNP) affects susceptibility to spongiform encephalopathies, or prion diseases in many species. In white-tailed deer, both coding and non-coding single nucleotide polymorphisms have been identified in this gene that correlate to chronic wasting disease (CWD) susceptibility. Previous studies examined individual nucleotide or amino acid mutations; here we examine all nucleotide polymorphisms and their combined effects on CWD. A 626 bp region of PRNP was examined from 703 free-ranging white-tailed deer. Deer were sampled between 2002 and 2010 by hunter harvest or government culling in Illinois and Wisconsin. Fourteen variable nucleotide positions were identified (4 new and 10 previously reported). We identified 68 diplotypes comprised of 24 predicted haplotypes, with the most common diplotype occurring in 123 individuals. Diplotypes that were found exclusively among positive or negative animals were rare, each occurring in less than 1% of the deer studied. Only one haplotype (C, odds ratio 0.240) and 2 diplotypes (AC and BC, odds ratios of 0.161 and 0.108 respectively) has significant associations with CWD resistance. Each contains mutations (one synonymous nucleotide 555C/T and one nonsynonymous nucleotide 286G/A) at positions reported to be significantly associated with reduced CWD susceptibility. Results suggest that deer populations with higher frequencies of haplotype C or diplotypes AC and BC might have a reduced risk for CWD infection – while populations with lower frequencies may have higher risk for infection. Understanding the genetic basis of CWD has improved our ability to assess herd susceptibility and direct management efforts within CWD infected areas. PMID:26634768

  19. Prion protein gene sequence and chronic wasting disease susceptibility in white-tailed deer (Odocoileus virginianus).

    PubMed

    Brandt, Adam L; Kelly, Amy C; Green, Michelle L; Shelton, Paul; Novakofski, Jan; Mateus-Pinilla, Nohra E

    2015-01-01

    The sequence of the prion protein gene (PRNP) affects susceptibility to spongiform encephalopathies, or prion diseases in many species. In white-tailed deer, both coding and non-coding single nucleotide polymorphisms have been identified in this gene that correlate to chronic wasting disease (CWD) susceptibility. Previous studies examined individual nucleotide or amino acid mutations; here we examine all nucleotide polymorphisms and their combined effects on CWD. A 626 bp region of PRNP was examined from 703 free-ranging white-tailed deer. Deer were sampled between 2002 and 2010 by hunter harvest or government culling in Illinois and Wisconsin. Fourteen variable nucleotide positions were identified (4 new and 10 previously reported). We identified 68 diplotypes comprised of 24 predicted haplotypes, with the most common diplotype occurring in 123 individuals. Diplotypes that were found exclusively among positive or negative animals were rare, each occurring in less than 1% of the deer studied. Only one haplotype (C, odds ratio 0.240) and 2 diplotypes (AC and BC, odds ratios of 0.161 and 0.108 respectively) has significant associations with CWD resistance. Each contains mutations (one synonymous nucleotide 555C/T and one nonsynonymous nucleotide 286G/A) at positions reported to be significantly associated with reduced CWD susceptibility. Results suggest that deer populations with higher frequencies of haplotype C or diplotypes AC and BC might have a reduced risk for CWD infection--while populations with lower frequencies may have higher risk for infection. Understanding the genetic basis of CWD has improved our ability to assess herd susceptibility and direct management efforts within CWD infected areas.

  20. Prion protein gene sequence and chronic wasting disease susceptibility in white-tailed deer (Odocoileus virginianus).

    PubMed

    Brandt, Adam L; Kelly, Amy C; Green, Michelle L; Shelton, Paul; Novakofski, Jan; Mateus-Pinilla, Nohra E

    2015-01-01

    The sequence of the prion protein gene (PRNP) affects susceptibility to spongiform encephalopathies, or prion diseases in many species. In white-tailed deer, both coding and non-coding single nucleotide polymorphisms have been identified in this gene that correlate to chronic wasting disease (CWD) susceptibility. Previous studies examined individual nucleotide or amino acid mutations; here we examine all nucleotide polymorphisms and their combined effects on CWD. A 626 bp region of PRNP was examined from 703 free-ranging white-tailed deer. Deer were sampled between 2002 and 2010 by hunter harvest or government culling in Illinois and Wisconsin. Fourteen variable nucleotide positions were identified (4 new and 10 previously reported). We identified 68 diplotypes comprised of 24 predicted haplotypes, with the most common diplotype occurring in 123 individuals. Diplotypes that were found exclusively among positive or negative animals were rare, each occurring in less than 1% of the deer studied. Only one haplotype (C, odds ratio 0.240) and 2 diplotypes (AC and BC, odds ratios of 0.161 and 0.108 respectively) has significant associations with CWD resistance. Each contains mutations (one synonymous nucleotide 555C/T and one nonsynonymous nucleotide 286G/A) at positions reported to be significantly associated with reduced CWD susceptibility. Results suggest that deer populations with higher frequencies of haplotype C or diplotypes AC and BC might have a reduced risk for CWD infection--while populations with lower frequencies may have higher risk for infection. Understanding the genetic basis of CWD has improved our ability to assess herd susceptibility and direct management efforts within CWD infected areas. PMID:26634768

  1. The adherens junctions control susceptibility to Staphylococcus aureus α-toxin.

    PubMed

    Popov, Lauren M; Marceau, Caleb D; Starkl, Philipp M; Lumb, Jennifer H; Shah, Jimit; Guerrera, Diego; Cooper, Rachel L; Merakou, Christina; Bouley, Donna M; Meng, Wenxiang; Kiyonari, Hiroshi; Takeichi, Masatoshi; Galli, Stephen J; Bagnoli, Fabio; Citi, Sandra; Carette, Jan E; Amieva, Manuel R

    2015-11-17

    Staphylococcus aureus is both a transient skin colonizer and a formidable human pathogen, ranking among the leading causes of skin and soft tissue infections as well as severe pneumonia. The secreted bacterial α-toxin is essential for S. aureus virulence in these epithelial diseases. To discover host cellular factors required for α-toxin cytotoxicity, we conducted a genetic screen using mutagenized haploid human cells. Our screen identified a cytoplasmic member of the adherens junctions, plekstrin-homology domain containing protein 7 (PLEKHA7), as the second most significantly enriched gene after the known α-toxin receptor, a disintegrin and metalloprotease 10 (ADAM10). Here we report a new, unexpected role for PLEKHA7 and several components of cellular adherens junctions in controlling susceptibility to S. aureus α-toxin. We find that despite being injured by α-toxin pore formation, PLEKHA7 knockout cells recover after intoxication. By infecting PLEKHA7(-/-) mice with methicillin-resistant S. aureus USA300 LAC strain, we demonstrate that this junctional protein controls disease severity in both skin infection and lethal S. aureus pneumonia. Our results suggest that adherens junctions actively control cellular responses to a potent pore-forming bacterial toxin and identify PLEKHA7 as a potential nonessential host target to reduce S. aureus virulence during epithelial infections.

  2. The adherens junctions control susceptibility to Staphylococcus aureus α-toxin

    PubMed Central

    Popov, Lauren M.; Marceau, Caleb D.; Starkl, Philipp M.; Lumb, Jennifer H.; Shah, Jimit; Guerrera, Diego; Cooper, Rachel L.; Merakou, Christina; Bouley, Donna M.; Meng, Wenxiang; Kiyonari, Hiroshi; Takeichi, Masatoshi; Galli, Stephen J.; Bagnoli, Fabio; Citi, Sandra; Carette, Jan E.; Amieva, Manuel R.

    2015-01-01

    Staphylococcus aureus is both a transient skin colonizer and a formidable human pathogen, ranking among the leading causes of skin and soft tissue infections as well as severe pneumonia. The secreted bacterial α-toxin is essential for S. aureus virulence in these epithelial diseases. To discover host cellular factors required for α-toxin cytotoxicity, we conducted a genetic screen using mutagenized haploid human cells. Our screen identified a cytoplasmic member of the adherens junctions, plekstrin-homology domain containing protein 7 (PLEKHA7), as the second most significantly enriched gene after the known α-toxin receptor, a disintegrin and metalloprotease 10 (ADAM10). Here we report a new, unexpected role for PLEKHA7 and several components of cellular adherens junctions in controlling susceptibility to S. aureus α-toxin. We find that despite being injured by α-toxin pore formation, PLEKHA7 knockout cells recover after intoxication. By infecting PLEKHA7−/− mice with methicillin-resistant S. aureus USA300 LAC strain, we demonstrate that this junctional protein controls disease severity in both skin infection and lethal S. aureus pneumonia. Our results suggest that adherens junctions actively control cellular responses to a potent pore-forming bacterial toxin and identify PLEKHA7 as a potential nonessential host target to reduce S. aureus virulence during epithelial infections. PMID:26489655

  3. Susceptibility to thyroid autoimmune disease: molecular analysis of HLA-D region genes identifies new markers for goitrous Hashimoto's thyroiditis.

    PubMed

    Badenhoop, K; Schwarz, G; Walfish, P G; Drummond, V; Usadel, K H; Bottazzo, G F

    1990-11-01

    Hashimoto's thyroiditis has been shown to be associated with the HLA-specificities DR4 and DR5. Since former association studies yielded variable results, we used novel molecular typing methods to assess predisposing immunogenetic factors. Gene analysis of the HLA-DR-DQ and tumor necrosis factor region was performed in a group of Hashimoto's thyroiditis patients and randomly chosen controls using standards and nomenclature of the 10th International Histocompatibility Workshop. Genomic DNA of patients and controls was analyzed using a cDNA probe of the DQB1 gene. The resulting restriction fragment patterns allowed the determination of newly defined DQw-types 1-9. We find the strongest relative risk conferred by DQw7 (RR = 4.7), that is observed in 36 of 64 patients (56%) and only 21 of 98 controls (21%) (P corr less than 0.002). Comparison of DNA sequence variation in the DQB1 gene, that is found predominantly in Hashimoto's thyroiditis patients, indicates that codons 45 and 57 are critical features in DQw7 which distinguish it from other DQw specificities. The adjacent DQA1 genes also display a significant association with Hashimoto's thyroiditis (DQA1*0201/*0301 heterozygotes were found in 37% of patients and 15% controls, P less than 0.03). No significant association could be found with polymorphisms of the tumor necrosis factor gene. These results provide a new basis for the concept of genetic susceptibility in Hashimoto's thyroiditis and will help to elucidate the underlying autoimmune mechanisms that lead to disease at the functional level. PMID:1977755

  4. Asthma-susceptibility variants identified using probands in case-control and family-based analyses

    PubMed Central

    2010-01-01

    Background Asthma is a chronic respiratory disease whose genetic basis has been explored for over two decades, most recently via genome-wide association studies. We sought to find asthma-susceptibility variants by using probands from a single population in both family-based and case-control association designs. Methods We used probands from the Childhood Asthma Management Program (CAMP) in two primary genome-wide association study designs: (1) probands were combined with publicly available population controls in a case-control design, and (2) probands and their parents were used in a family-based design. We followed a two-stage replication process utilizing three independent populations to validate our primary findings. Results We found that single nucleotide polymorphisms with similar case-control and family-based association results were more likely to replicate in the independent populations, than those with the smallest p-values in either the case-control or family-based design alone. The single nucleotide polymorphism that showed the strongest evidence for association to asthma was rs17572584, which replicated in 2/3 independent populations with an overall p-value among replication populations of 3.5E-05. This variant is near a gene that encodes an enzyme that has been implicated to act coordinately with modulators of Th2 cell differentiation and is expressed in human lung. Conclusions Our results suggest that using probands from family-based studies in case-control designs, and combining results of both family-based and case-control approaches, may be a way to augment our ability to find SNPs associated with asthma and other complex diseases. PMID:20698975

  5. Influence of protein tyrosine phosphatase gene (PTPN22) polymorphisms on rheumatic heart disease susceptibility in North Indian population.

    PubMed

    Gupta, U; Mir, S S; Chauhan, T; Garg, N; Agarwal, S K; Pande, S; Mittal, B

    2014-11-01

    This study was aimed to assess the association of Protein tyrosine phosphatase non-receptor22 (PTPN22) gene single nucleotide polymorphisms (SNPs) with rheumatic heart disease (RHD) susceptibility in 400 RHD patients and 300 controls. The PTPN22 polymorphisms (rs2476601, rs1217406 and rs3789609) were genotyped using Taqman probes (Applied Biosystems, Foster City, CA). Statistical analysis was performed by spss and haplotype analysis by snpstat. The frequencies of variant alleles were not different between controls and cases (rs2476601: 2.00% & 1.05%; rs1217406: 36.33% & 34.75%; and rs3789609: 38.17% & 40.00%, respectively]. However, G rs2476601 A rs1217406 T rs3789609 haplotype turned out to be a low risk factor for RHD (P = 0.0042) predisposition in females and adult patients. This study suggests PTPN22 haplotype may modulate the risk to RHD in North Indians.

  6. Identification of Susceptibility Genes of Adult Asthma in French Canadian Women

    PubMed Central

    Bérubé, Jean-Christophe; Gaudreault, Nathalie; Lavoie-Charland, Emilie; Sbarra, Laura; Henry, Cyndi; Madore, Anne-Marie; Paré, Peter D.; van den Berge, Maarten; Nickle, David; Laviolette, Michel; Laprise, Catherine; Boulet, Louis-Philippe; Bossé, Yohan

    2016-01-01

    Susceptibility genes of asthma may be more successfully identified by studying subgroups of phenotypically similar asthma patients. This study aims to identify single nucleotide polymorphisms (SNPs) associated with asthma in French Canadian adult women. A pooling-based genome-wide association study was performed in 240 allergic asthmatic and 120 allergic nonasthmatic women. The top associated SNPs were selected for individual genotyping in an extended cohort of 349 asthmatic and 261 nonasthmatic women. The functional impact of asthma-associated SNPs was investigated in a lung expression quantitative trait loci (eQTL) mapping study (n = 1035). Twenty-one of the 38 SNPs tested by individual genotyping showed P values lower than 0.05 for association with asthma. Cis-eQTL analyses supported the functional contribution of rs17801353 associated with C3AR1 (P = 7.90E − 10). The asthma risk allele for rs17801353 is associated with higher mRNA expression levels of C3AR1 in lung tissue. In silico functional characterization of the asthma-associated SNPs also supported the contribution of C3AR1 and additional genes including SYNE1, LINGO2, and IFNG-AS1. This pooling-based GWAS in French Canadian adult women followed by lung eQTL mapping suggested C3AR1 as a functional locus associated with asthma. Additional susceptibility genes were suggested in this homogenous subgroup of asthma patients. PMID:27445529

  7. Identification of Susceptibility Genes of Adult Asthma in French Canadian Women.

    PubMed

    Bérubé, Jean-Christophe; Gaudreault, Nathalie; Lavoie-Charland, Emilie; Sbarra, Laura; Henry, Cyndi; Madore, Anne-Marie; Paré, Peter D; van den Berge, Maarten; Nickle, David; Laviolette, Michel; Laprise, Catherine; Boulet, Louis-Philippe; Bossé, Yohan

    2016-01-01

    Susceptibility genes of asthma may be more successfully identified by studying subgroups of phenotypically similar asthma patients. This study aims to identify single nucleotide polymorphisms (SNPs) associated with asthma in French Canadian adult women. A pooling-based genome-wide association study was performed in 240 allergic asthmatic and 120 allergic nonasthmatic women. The top associated SNPs were selected for individual genotyping in an extended cohort of 349 asthmatic and 261 nonasthmatic women. The functional impact of asthma-associated SNPs was investigated in a lung expression quantitative trait loci (eQTL) mapping study (n = 1035). Twenty-one of the 38 SNPs tested by individual genotyping showed P values lower than 0.05 for association with asthma. Cis-eQTL analyses supported the functional contribution of rs17801353 associated with C3AR1 (P = 7.90E - 10). The asthma risk allele for rs17801353 is associated with higher mRNA expression levels of C3AR1 in lung tissue. In silico functional characterization of the asthma-associated SNPs also supported the contribution of C3AR1 and additional genes including SYNE1, LINGO2, and IFNG-AS1. This pooling-based GWAS in French Canadian adult women followed by lung eQTL mapping suggested C3AR1 as a functional locus associated with asthma. Additional susceptibility genes were suggested in this homogenous subgroup of asthma patients.

  8. Association study of MICA gene polymorphisms with rheumatoid arthritis susceptibility in south Tunisian population.

    PubMed

    Achour, Y; Kammoun, A; Ben Hamad, M; Mahfoudh, N; Chaabane, S; Marzouk, S; Keskes, L; Gaddour, L; Bahloul, Z; Maalej, A

    2014-12-01

    The aim of this study was to investigate the role of major histocompatibility complex (MHC) class I chain-related gene A (MICA) polymorphisms, important in natural killer (NK) cell function, in patients with rheumatoid arthritis (RA). A transmembrane (TM) alanine-encoding GCT repeats, termed A4, A5, A5.1, A6 and A9 in the MICA gene, and single-nucleotide polymorphisms (SNPs): the Met129Val polymorphism (rs1051792) and the nonsynonymously coding SNP (rs1051794) were genotyped in 142 patients with RA and 123 unrelated healthy individuals using, respectively, PCR fluorescent method, nested PCR-RFLP and allele specific PCR (ASP). Association was assessed based on the χ2 test, genotype relative risk (GRR) and odds ratio (OR) with 95% confidence intervals (CIs). Our results show a trend of association of the different MICA genotypes G/G, G/A and A/A (P = 0.029) which did not attain the significance after Bonferroni's correction (pc = 0.08). Although, we revealed a significant association of the genotype A/A of MICA-250 in patients with RA compared to healthy controls (pc = 0.033). In contrast, no significant differences between alleles and genotypes frequencies were found either with MICA-TM or MICA met129 val (P > 0.05) in our sample. Moreover, stratification of patients with RA according to clinical and immunological data for the different polymorphisms studied shows a significant association of both MICA-250 G allele (pc = 0.0075) and MICA-250 GG genotype (pc = 0.008) and both allelic (val) (pc = 0.021) and genotypic (val/val) distribution (pc = 0.0095) for MICA met129 val in the RF-positive subgroup compared to RF-negative patients with RA. In contrast, we found a strong association of the MICA-TM A9 allele in RF-negative patients with RA (pc = 0.0003). This study indicates the involvement of the MICA-250 polymorphism in the genetic susceptibility and severity to RA and suggests that variations in MICA-TM and MICA met129 val may have an effect on RA severity in our

  9. Alu Elements as Novel Regulators of Gene Expression in Type 1 Diabetes Susceptibility Genes?

    PubMed Central

    Kaur, Simranjeet; Pociot, Flemming

    2015-01-01

    Despite numerous studies implicating Alu repeat elements in various diseases, there is sparse information available with respect to the potential functional and biological roles of the repeat elements in Type 1 diabetes (T1D). Therefore, we performed a genome-wide sequence analysis of T1D candidate genes to identify embedded Alu elements within these genes. We observed significant enrichment of Alu elements within the T1D genes (p-value < 10e−16), which highlights their importance in T1D. Functional annotation of T1D genes harboring Alus revealed significant enrichment for immune-mediated processes (p-value < 10e−6). We also identified eight T1D genes harboring inverted Alus (IRAlus) within their 3' untranslated regions (UTRs) that are known to regulate the expression of host mRNAs by generating double stranded RNA duplexes. Our in silico analysis predicted the formation of duplex structures by IRAlus within the 3'UTRs of T1D genes. We propose that IRAlus might be involved in regulating the expression levels of the host T1D genes. PMID:26184322

  10. Alu Elements as Novel Regulators of Gene Expression in Type 1 Diabetes Susceptibility Genes?

    PubMed

    Kaur, Simranjeet; Pociot, Flemming

    2015-07-13

    Despite numerous studies implicating Alu repeat elements in various diseases, there is sparse information available with respect to the potential functional and biological roles of the repeat elements in Type 1 diabetes (T1D). Therefore, we performed a genome-wide sequence analysis of T1D candidate genes to identify embedded Alu elements within these genes. We observed significant enrichment of Alu elements within the T1D genes (p-value < 10e-16), which highlights their importance in T1D. Functional annotation of T1D genes harboring Alus revealed significant enrichment for immune-mediated processes (p-value < 10e-6). We also identified eight T1D genes harboring inverted Alus (IRAlus) within their 3' untranslated regions (UTRs) that are known to regulate the expression of host mRNAs by generating double stranded RNA duplexes. Our in silico analysis predicted the formation of duplex structures by IRAlus within the 3'UTRs of T1D genes. We propose that IRAlus might be involved in regulating the expression levels of the host T1D genes.

  11. The breast cancer susceptibility gene, BRCA2: at the crossroads between DNA replication and recombination?

    PubMed Central

    Venkitaraman, A R

    2000-01-01

    The identification and cloning of the familial breast cancer susceptibility gene, BRCA2, has excited much interest in its biological functions. Here, evidence is reviewed that the protein encoded by BRCA2 has an essential role in DNA repair through its association with mRad51, a mammalian homologue of bacterial and yeast proteins involved in homologous recombination. A model is proposed that the critical requirement for BRCA2 in cell division and the maintenance of chromosome stability stems from its participation in recombinational processes essential for DNA replication. PMID:10724455

  12. Identification of Maize Genes Associated with Host Plant Resistance or Susceptibility to Aspergillus flavus Infection and Aflatoxin Accumulation

    PubMed Central

    Kelley, Rowena Y.; Williams, W. Paul; Mylroie, J. Erik; Boykin, Deborah L.; Harper, Jonathan W.; Windham, Gary L.; Ankala, Arunkanth; Shan, Xueyan

    2012-01-01

    Background Aspergillus flavus infection and aflatoxin contamination of maize pose negative impacts in agriculture and health. Commercial maize hybrids are generally susceptible to this fungus. Significant levels of host plant resistance have been observed in certain maize inbred lines. This study was conducted to identify maize genes associated with host plant resistance or susceptibility to A. flavus infection and aflatoxin accumulation. Results Genome wide gene expression levels with or without A. flavus inoculation were compared in two resistant maize inbred lines (Mp313E and Mp04∶86) in contrast to two susceptible maize inbred lines (Va35 and B73) by microarray analysis. Principal component analysis (PCA) was used to find genes contributing to the larger variances associated with the resistant or susceptible maize inbred lines. The significance levels of gene expression were determined by using SAS and LIMMA programs. Fifty candidate genes were selected and further investigated by quantitative RT-PCR (qRT-PCR) in a time-course study on Mp313E and Va35. Sixteen of the candidate genes were found to be highly expressed in Mp313E and fifteen in Va35. Out of the 31 highly expressed genes, eight were mapped to seven previously identified quantitative trait locus (QTL) regions. A gene encoding glycine-rich RNA binding protein 2 was found to be associated with the host hypersensitivity and susceptibility in Va35. A nuclear pore complex protein YUP85-like gene was found to be involved in the host resistance in Mp313E. Conclusion Maize genes associated with host plant resistance or susceptibility were identified by a combination of microarray analysis, qRT-PCR analysis, and QTL mapping methods. Our findings suggest that multiple mechanisms are involved in maize host plant defense systems in response to Aspergillus flavus infection and aflatoxin accumulation. These findings will be important in identification of DNA markers for breeding maize lines resistant to

  13. 16S rRNA Gene Mutations Associated with Decreased Susceptibility to Tetracycline in Mycoplasma bovis

    PubMed Central

    Amram, E.; Mikula, I.; Schnee, C.; Ayling, R. D.; Nicholas, R. A. J.; Rosales, R. S.; Harrus, S.

    2014-01-01

    Mycoplasma bovis isolates with decreased susceptibilities to tetracyclines are increasingly reported worldwide. The acquired molecular mechanisms associated with this phenomenon were investigated in 70 clinical isolates of M. bovis. Sequence analysis of the two 16S rRNA-encoding genes (rrs3 and rrs4 alleles) containing the primary binding pocket for tetracycline (Tet-1 site) was performed on isolates with tetracycline hydrochloride MICs of 0.125 to 16 μg/ml. Mutations at positions A965T, A967T/C (Escherichia coli numbering) of helix 31, U1199C of helix 34, and G1058A/C were identified. Decreased susceptibilities to tetracycline (MICs, ≥2 μg/ml) were associated with mutations present at two (A965 and A967) or three positions (A965, A967, and G1058) of the two rrs alleles. No tet(M), tet(O), or tet(L) determinants were found in the genome of any of the 70 M. bovis isolates. The data presented correlate (P < 0.0001) the mutations identified in the Tet-1 site of clinical isolates of M. bovis with decreased susceptibility to tetracycline. PMID:25403668

  14. The NRAMPI, VDR and TNF-alpha gene polymorphisms in Iranian tuberculosis patients: the study on host susceptibility.

    PubMed

    Merza, Muayad; Farnia, Parissa; Anoosheh, Sabar; Varahram, Mohammed; Kazampour, Mehdi; Pajand, Omid; Saeif, Shima; Mirsaeidi, Mehdi; Masjedi, Mohammad Reza; Velayati, Ali Akbar; Hoffner, Sven

    2009-08-01

    The natural resistance-associated macrophage protein (NRAMP1), Vitamin-D receptor (VDR) and Tumor necrosis factor (TNF-alpha) have been associated in susceptibility to tuberculosis, but the results have been inconsistent. This study aimed to determine the association of NRAMP1, VDR, and TNF-á variant with development of pulmonary tuberculosis (PTB) among Iranian patients. The single nucleotide polymorphisms (SNPs) at INT4, D543, 3'UTR of NRAMP1 gene, SNPs in restriction sites of BsmI, and FokI of the VDR gene and SNPs of TNF-alpha at -238,-308, -244,857,-863 positions were analyzed by PCR-RFLP among two groups of individual; patients with PTB (n=117) and healthy controls (n=60). Thereafter, the frequencies of extended haplotypes and diplotypes were estimated. No statistically significant differences were observed in allele frequencies of INT4, D543, 3'UTR of NRAMPI, FokI of VDR and TNF-alpha at -238, -244,-863 and -857 position. Although, the frequency of b allele of BsmI [ORs: 0.24 CI95% (0.07-0.67 (p=0.001)] and -308 A variant in TNF-alpha promoter region [ORs:0.26 CI95%( 0.07-0.77) (p=0.006)] were significantly more in PTB patients than healthy controls. The frequency of extended diplotypes of NRAMP [GG TGTG++GA; 0.02(0.001-0.0035)], VDR [FFBB; 0.2(0.6-0.6] and TNF-alpha [CCCCGGGGGG; 0.49(0.25-0.97)] were statistically different in patients and control subjects (p<0.05). This study confirmed the association of SNPs in BsmI (B/b + b/b) of VDR and SNPs in -308A (G/A +G/G) of TNF-alpha genes with susceptibility to tuberculosis in Iranian PTB patients. Furthermore, the extended haplotypes and diplotypes analysis can be considered as an alternative way to determine the host susceptibility to TB. PMID:20231985

  15. Contribution of DNA double-strand break repair gene XRCC3 genotypes to oral cancer susceptibility in Taiwan.

    PubMed

    Tsai, Chia-Wen; Chang, Wen-Shin; Liu, Juhn-Cherng; Tsai, Ming-Hsui; Lin, Cheng-Chieh; Bau, Da-Tian

    2014-06-01

    The DNA repair gene X-ray repair cross complementing protein 3 (XRCC3) is thought to play a major role in double-strand break repair and in maintaining genomic stability. Very possibly, defective double-strand break repair of cells can lead to carcinogenesis. Therefore, a case-control study was performed to reveal the contribution of XRCC3 genotypes to individual oral cancer susceptibility. In this hospital-based research, the association of XRCC3 rs1799794, rs45603942, rs861530, rs3212057, rs1799796, rs861539, rs28903081 genotypes with oral cancer risk in a Taiwanese population was investigated. In total, 788 patients with oral cancer and 956 age- and gender-matched healthy controls were genotyped. The results showed that there was significant differential distribution among oral cancer and controls in the genotypic (p=0.001428) and allelic (p=0.0013) frequencies of XRCC3 rs861539. As for the other polymorphisms, there was no difference between case and control groups. In gene-lifestyle interaction analysis, we have provided the first evidence showing that there is an obvious joint effect of XRCC3 rs861539 genotype with individual areca chewing habits on oral cancer risk. In conclusion, the T allele of XRCC3 rs861539, which has an interaction with areca chewing habit in oral carcinogenesis, may be an early marker for oral cancer in Taiwanese.

  16. Transcriptome outlier analysis implicates schizophrenia susceptibility genes and enriches putatively functional rare genetic variants

    PubMed Central

    Duan, Jubao; Sanders, Alan R.; Moy, Winton; Drigalenko, Eugene I.; Brown, Eric C.; Freda, Jessica; Leites, Catherine; Göring, Harald H. H.; Gejman, Pablo V.

    2015-01-01

    We searched a gene expression dataset comprised of 634 schizophrenia (SZ) cases and 713 controls for expression outliers (i.e., extreme tails of the distribution of transcript expression values) with SZ cases overrepresented compared with controls. These outlier genes were enriched for brain expression and for genes known to be associated with neurodevelopmental disorders. SZ cases showed higher outlier burden (i.e., total outlier events per subject) than controls for genes within copy number variants (CNVs) associated with SZ or neurodevelopmental disorders. Outlier genes were enriched for CNVs and for rare putative regulatory variants, but this only explained a small proportion of the outlier subjects, highlighting the underlying presence of additional genetic and potentially, epigenetic mechanisms. PMID:26022996

  17. Transcriptome outlier analysis implicates schizophrenia susceptibility genes and enriches putatively functional rare genetic variants.

    PubMed

    Duan, Jubao; Sanders, Alan R; Moy, Winton; Drigalenko, Eugene I; Brown, Eric C; Freda, Jessica; Leites, Catherine; Göring, Harald H H; Gejman, Pablo V

    2015-08-15

    We searched a gene expression dataset comprised of 634 schizophrenia (SZ) cases and 713 controls for expression outliers (i.e., extreme tails of the distribution of transcript expression values) with SZ cases overrepresented compared with controls. These outlier genes were enriched for brain expression and for genes known to be associated with neurodevelopmental disorders. SZ cases showed higher outlier burden (i.e., total outlier events per subject) than controls for genes within copy number variants (CNVs) associated with SZ or neurodevelopmental disorders. Outlier genes were enriched for CNVs and for rare putative regulatory variants, but this only explained a small proportion of the outlier subjects, highlighting the underlying presence of additional genetic and potentially, epigenetic mechanisms.

  18. Characterization of Toxin Genes and Antimicrobial Susceptibility of Staphylococcus aureus Isolates in Fishery Products in Iran

    PubMed Central

    Arfatahery, Noushin; Davoodabadi, Abolfazl; Abedimohtasab, Taranehpeimaneh

    2016-01-01

    Staphylococcus aureus is one of the most common causes of seafood-borne diseases worldwide, which are attributable to the contamination of food by preformed enterotoxins. In this study, a total of 206 (34.3%) Staphylococcus aureus strains were obtained from 600 fish and shrimp samples and were tested for their antimicrobial susceptibility. We assessed the prevalence of the genes responsible for the staphylococcal enterotoxins (SEA, SEB) and toxic shock syndrome toxin 1 (TSST-1) genes. The results indicated that 34% of aqua food samples were contaminated with S. aureus, and 23.8% of these isolates were mec-A-positive. Sixty-four percent of the strains isolated from contaminated seafood was enterotoxigenic S. aureus, and 28.2% of SEs were MRSA-positive. The most prevalent genotype was characterized by the presence of the sea gene (45.2%), followed by the seb gene (18.5%), and the tst gene encoding TSST-1 was found in eight strains (3.9%). Of the 206 S. aureus isolates, 189 strains (84.9%) were resistant to at least one antibiotic. Given the frequent outbreaks of enterotoxigenic MRSA, it is necessary to make revisions to mandatory programmes to facilitate improved hygiene practices during fishing, aquaculture, processing, and sales to prevent the contamination of fishery products in Iran. PMID:27694813

  19. Dopamine transporter gene susceptibility to methylation is associated with impulsivity in nonhuman primates

    PubMed Central

    Rajala, Abigail Z.; Zaitoun, Ismail; Henriques, Jeffrey B.; Converse, Alexander K.; Murali, Dhanabalan; Epstein, Miles L.

    2014-01-01

    Impulsivity, the predisposition to act without regard for negative consequences, is a characteristic of several psychiatric disorders and is thought to result in part from genetic variation in the untranslated region of the dopamine transporter (DAT) gene. As the exact link between genetic mutations and impulsivity has not been established, we used oculomotor behavior to characterize rhesus monkeys as impulsive or calm and genetic/epigenetic analysis and positron emission tomography (PET) to correlate phenotype to DAT genotype, DAT gene methylation, and DAT availability. We found three single nucleotide polymorphisms (SNPs) in the 3′-UTR of the DAT gene, one of which provided a potential site for methylation in the impulsive group. Bisulfite analysis showed that the DNA of the impulsive but not the calm subjects was methylated at one SNP. Because genetic/epigenetic modifications could lead to differences in protein expression, we measured DAT availability using [18F]2β-carbomethoxy-3β-(4-chlorophenyl)-8-(2-fluoroethyl)-nortropane ([18F]FECNT) PET and found higher DAT availability in the internal globus pallidus, an output nucleus of the basal ganglia, of the impulsive group. Higher DAT availability lowers dopamine levels, potentially altering neuronal circuits involved in the initiation of action, thus contributing to the impulsive phenotype. The association between increased methylation in the DAT gene and greater DAT availability suggests that mutations to the regulatory portion of the DAT gene lead to a susceptibility to epigenetic modification resulting in a discrete behavioral phenotype. PMID:25122707

  20. Immunogenetic mechanisms leading to thyroid autoimmunity: recent advances in identifying susceptibility genes and regions.

    PubMed

    Brand, Oliver J; Gough, Stephen C L

    2011-12-01

    The autoimmune thyroid diseases (AITD) include Graves' disease (GD) and Hashimoto's thyroiditis (HT), which are characterised by a breakdown in immune tolerance to thyroid antigens. Unravelling the genetic architecture of AITD is vital to better understanding of AITD pathogenesis, required to advance therapeutic options in both disease management and prevention. The early whole-genome linkage and candidate gene association studies provided the first evidence that the HLA region and CTLA-4 represented AITD risk loci. Recent improvements in; high throughput genotyping technologies, collection of larger disease cohorts and cataloguing of genome-scale variation have facilitated genome-wide association studies and more thorough screening of candidate gene regions. This has allowed identification of many novel AITD risk genes and more detailed association mapping. The growing number of confirmed AITD susceptibility loci, implicates a number of putative disease mechanisms most of which are tightly linked with aspects of immune system function. The unprecedented advances in genetic study will allow future studies to identify further novel disease risk genes and to identify aetiological variants within specific gene regions, which will undoubtedly lead to a better understanding of AITD patho-physiology.

  1. Genetic polymorphisms and haplotypes of TRAIL gene correlate with NSCLC susceptibility in a group of Chinese patients.

    PubMed

    Luo, Jun; Xiong, Jinmeng; Wu, Jianghua; Ye, Xujun

    2015-01-01

    The association between genetic polymorphisms and haplotypes of TNF-related apoptosis-inducing ligand (TRAIL) and the NSCLC development was investigated in 592 Chinese patients and the prevalence of G1525A, G1588A, and C1595T gene polymorphisms compared between the NSCLC patients and control group in this study. It was found that the frequencies of variant allele A and genotype GA+AA of G1525A were significantly lower and those of variant alleles A and T of G1588A and C1595T significantly higher in the NSCLC patients compared with those in control. The frequencies of variant allele T and genotype CT+TT of C1595T were significantly higher in stage III and IV than in stage I and II of the patients. Moreover, the frequencies of variant allele A and genotype GA+AA of G1525A were significantly higher in stage III and IV than in stage I and II of the patients. In addition, TRAIL gene variants G1525A/G1588A/C1595T were found to be in complete linkage disequilibrium in all patients. Compared with the healthy people, the frequency of AAT haplotype was significantly lower whereas that of GAT haplotype significantly higher in NSCLC patients. The results indicated that the genetic polymorphisms and haplotypes of TRAIL gene correlated significantly with the NSCLC susceptibility in the group of Chinese patients. PMID:26629137

  2. The variant rs1867277 in FOXE1 gene confers thyroid cancer susceptibility through the recruitment of USF1/USF2 transcription factors.

    PubMed

    Landa, Iñigo; Ruiz-Llorente, Sergio; Montero-Conde, Cristina; Inglada-Pérez, Lucía; Schiavi, Francesca; Leskelä, Susanna; Pita, Guillermo; Milne, Roger; Maravall, Javier; Ramos, Ignacio; Andía, Víctor; Rodríguez-Poyo, Paloma; Jara-Albarrán, Antonino; Meoro, Amparo; del Peso, Cristina; Arribas, Luis; Iglesias, Pedro; Caballero, Javier; Serrano, Joaquín; Picó, Antonio; Pomares, Francisco; Giménez, Gabriel; López-Mondéjar, Pedro; Castello, Roberto; Merante-Boschin, Isabella; Pelizzo, Maria-Rosa; Mauricio, Didac; Opocher, Giuseppe; Rodríguez-Antona, Cristina; González-Neira, Anna; Matías-Guiu, Xavier; Santisteban, Pilar; Robledo, Mercedes

    2009-09-01

    In order to identify genetic factors related to thyroid cancer susceptibility, we adopted a candidate gene approach. We studied tag- and putative functional SNPs in genes involved in thyroid cell differentiation and proliferation, and in genes found to be differentially expressed in thyroid carcinoma. A total of 768 SNPs in 97 genes were genotyped in a Spanish series of 615 cases and 525 controls, the former comprising the largest collection of patients with this pathology from a single population studied to date. SNPs in an LD block spanning the entire FOXE1 gene showed the strongest evidence of association with papillary thyroid carcinoma susceptibility. This association was validated in a second stage of the study that included an independent Italian series of 482 patients and 532 controls. The strongest association results were observed for rs1867277 (OR[per-allele] = 1.49; 95%CI = 1.30-1.70; P = 5.9x10(-9)). Functional assays of rs1867277 (NM_004473.3:c.-283G>A) within the FOXE1 5' UTR suggested that this variant affects FOXE1 transcription. DNA-binding assays demonstrated that, exclusively, the sequence containing the A allele recruited the USF1/USF2 transcription factors, while both alleles formed a complex in which DREAM/CREB/alphaCREM participated. Transfection studies showed an allele-dependent transcriptional regulation of FOXE1. We propose a FOXE1 regulation model dependent on the rs1867277 genotype, indicating that this SNP is a causal variant in thyroid cancer susceptibility. Our results constitute the first functional explanation for an association identified by a GWAS and thereby elucidate a mechanism of thyroid cancer susceptibility. They also attest to the efficacy of candidate gene approaches in the GWAS era.

  3. The Variant rs1867277 in FOXE1 Gene Confers Thyroid Cancer Susceptibility through the Recruitment of USF1/USF2 Transcription Factors

    PubMed Central

    Montero-Conde, Cristina; Inglada-Pérez, Lucía; Schiavi, Francesca; Leskelä, Susanna; Pita, Guillermo; Milne, Roger; Maravall, Javier; Ramos, Ignacio; Andía, Víctor; Rodríguez-Poyo, Paloma; Jara-Albarrán, Antonino; Meoro, Amparo; del Peso, Cristina; Arribas, Luis; Iglesias, Pedro; Caballero, Javier; Serrano, Joaquín; Picó, Antonio; Pomares, Francisco; Giménez, Gabriel; López-Mondéjar, Pedro; Castello, Roberto; Merante-Boschin, Isabella; Pelizzo, Maria-Rosa; Mauricio, Didac; Opocher, Giuseppe; Rodríguez-Antona, Cristina; González-Neira, Anna; Matías-Guiu, Xavier; Santisteban, Pilar; Robledo, Mercedes

    2009-01-01

    In order to identify genetic factors related to thyroid cancer susceptibility, we adopted a candidate gene approach. We studied tag- and putative functional SNPs in genes involved in thyroid cell differentiation and proliferation, and in genes found to be differentially expressed in thyroid carcinoma. A total of 768 SNPs in 97 genes were genotyped in a Spanish series of 615 cases and 525 controls, the former comprising the largest collection of patients with this pathology from a single population studied to date. SNPs in an LD block spanning the entire FOXE1 gene showed the strongest evidence of association with papillary thyroid carcinoma susceptibility. This association was validated in a second stage of the study that included an independent Italian series of 482 patients and 532 controls. The strongest association results were observed for rs1867277 (OR[per-allele] = 1.49; 95%CI = 1.30–1.70; P = 5.9×10−9). Functional assays of rs1867277 (NM_004473.3:c.−283G>A) within the FOXE1 5′ UTR suggested that this variant affects FOXE1 transcription. DNA-binding assays demonstrated that, exclusively, the sequence containing the A allele recruited the USF1/USF2 transcription factors, while both alleles formed a complex in which DREAM/CREB/αCREM participated. Transfection studies showed an allele-dependent transcriptional regulation of FOXE1. We propose a FOXE1 regulation model dependent on the rs1867277 genotype, indicating that this SNP is a causal variant in thyroid cancer susceptibility. Our results constitute the first functional explanation for an association identified by a GWAS and thereby elucidate a mechanism of thyroid cancer susceptibility. They also attest to the efficacy of candidate gene approaches in the GWAS era. PMID:19730683

  4. Repression of the interleukin 6 gene promoter by p53 and the retinoblastoma susceptibility gene product

    SciTech Connect

    Santhanam, U.; Ray, A.; Sehgal, P.B. )

    1991-09-01

    The aberrant overexpression of interleukin 6 (IL-6) is implicated as an autocrine mechanism in the enhanced proliferation of the neoplastic cell elements in various B- and T-cell malignancies and in some carcinomas and sarcomas; many of these neoplasms have been shown to be associated with a mutated p53 gene. The possibility that wild-type (wt) p53, a nuclear tumor-suppressor protein, but not its transforming mutants might serve to repress IL-6 gene expression was investigated in HeLa cells. The authors transiently cotransfected these cells with constitutive cytomegalovirus (CMV) enhancer/promoter expression plasmids overproducing wt or mutant human or murine p53 and with appropriate chloramphenicol acetyltransferase (CAT) reporter plasmids containing the promoter elements of human IL-6, c-fos, or {beta}-actin genes or of porcine major histocompatibility complex (MHC) class I gene in pN-38 to evaluate the effect of the various p53 species on these promoters. These observations identify transcriptional repression as a property of p53 and suggest that p53 and RB may be involved as transcriptional repressors in modulating IL-6 gene expression during cellular differentiation and oncogenesis.

  5. A Rapid Molecular Test for Determining Yersinia pestis Susceptibility to Ciprofloxacin by the Quantification of Differentially Expressed Marker Genes

    PubMed Central

    Steinberger-Levy, Ida; Shifman, Ohad; Zvi, Anat; Ariel, Naomi; Beth-Din, Adi; Israeli, Ofir; Gur, David; Aftalion, Moshe; Maoz, Sharon; Ber, Raphael

    2016-01-01

    Standard antimicrobial susceptibility tests used to determine bacterial susceptibility to antibiotics are growth dependent and time consuming. The long incubation time required for standard tests may render susceptibility results irrelevant, particularly for patients infected with lethal bacteria that are slow growing on agar but progress rapidly in vivo, such as Yersinia pestis. Here, we present an alternative approach for the rapid determination of antimicrobial susceptibility, based on the quantification of the changes in the expression levels of specific marker genes following exposure to growth-inhibiting concentrations of the antibiotic, using Y. pestis and ciprofloxacin as a model. The marker genes were identified by transcriptomic DNA microarray analysis of the virulent Y. pestis Kimberley53 strain after exposure to specific concentrations of ciprofloxacin for various time periods. We identified several marker genes that were induced following exposure to growth-inhibitory concentrations of ciprofloxacin, and we confirmed the marker expression profiles at additional ciprofloxacin concentrations using quantitative RT-PCR. Eleven candidate marker transcripts were identified, of which four mRNA markers were selected for a rapid quantitative RT-PCR susceptibility test that correctly determined the Minimal Inhibitory Concentration (MIC) values and the categories of susceptibility of several Y. pestis strains and isolates harboring various ciprofloxacin MIC values. The novel molecular susceptibility test requires just 2 h of antibiotic exposure in a 7-h overall test time, in contrast to the 24 h of antibiotic exposure required for a standard microdilution test. PMID:27242774

  6. A Rapid Molecular Test for Determining Yersinia pestis Susceptibility to Ciprofloxacin by the Quantification of Differentially Expressed Marker Genes.

    PubMed

    Steinberger-Levy, Ida; Shifman, Ohad; Zvi, Anat; Ariel, Naomi; Beth-Din, Adi; Israeli, Ofir; Gur, David; Aftalion, Moshe; Maoz, Sharon; Ber, Raphael

    2016-01-01

    Standard antimicrobial susceptibility tests used to determine bacterial susceptibility to antibiotics are growth dependent and time consuming. The long incubation time required for standard tests may render susceptibility results irrelevant, particularly for patients infected with lethal bacteria that are slow growing on agar but progress rapidly in vivo, such as Yersinia pestis. Here, we present an alternative approach for the rapid determination of antimicrobial susceptibility, based on the quantification of the changes in the expression levels of specific marker genes following exposure to growth-inhibiting concentrations of the antibiotic, using Y. pestis and ciprofloxacin as a model. The marker genes were identified by transcriptomic DNA microarray analysis of the virulent Y. pestis Kimberley53 strain after exposure to specific concentrations of ciprofloxacin for various time periods. We identified several marker genes that were induced following exposure to growth-inhibitory concentrations of ciprofloxacin, and we confirmed the marker expression profiles at additional ciprofloxacin concentrations using quantitative RT-PCR. Eleven candidate marker transcripts were identified, of which four mRNA markers were selected for a rapid quantitative RT-PCR susceptibility test that correctly determined the Minimal Inhibitory Concentration (MIC) values and the categories of susceptibility of several Y. pestis strains and isolates harboring various ciprofloxacin MIC values. The novel molecular susceptibility test requires just 2 h of antibiotic exposure in a 7-h overall test time, in contrast to the 24 h of antibiotic exposure required for a standard microdilution test. PMID:27242774

  7. Differential susceptibility to maternal expressed emotion in children with ADHD and their siblings? Investigating plasticity genes, prosocial and antisocial behaviour.

    PubMed

    Richards, Jennifer S; Hartman, Catharina A; Franke, Barbara; Hoekstra, Pieter J; Heslenfeld, Dirk J; Oosterlaan, Jaap; Arias Vásquez, Alejandro; Buitelaar, Jan K

    2015-02-01

    The differential susceptibility theory states that children differ in their susceptibility towards environmental experiences, partially due to plasticity genes. Individuals carrying specific variants in such genes will be more disadvantaged in negative but, conversely, more advantaged in positive environments. Understanding gene-environment interactions may help unravel the causal mechanisms involved in multifactorial psychiatric disorders such as Attention-Deficit/Hyperactivity Disorder (ADHD). The differential susceptibility theory was examined by investigating the presence of interaction effects between maternal expressed emotion (EE; warmth and criticism) and the solitary and combined effects of plasticity genes (DAT1, DRD4, 5-HTT) on prosocial and antisocial behaviour (measured with parent- and self-reports) in children with ADHD and their siblings (N = 366, M = 17.11 years, 74.9% male). Maternal warmth was positively associated with prosocial behaviour and negatively with antisocial behaviour, while maternal criticism was positively associated with antisocial behaviour and negatively with prosocial behaviour. No evidence of differential susceptibility was found. The current study found no evidence for differential susceptibility based on the selected plasticity genes, in spite of strong EE-behaviour associations. It is likely that additional factors play a role in the complex relationship between genes, environment and behaviour.

  8. Differential Susceptibility to Maternal Expressed Emotion in Children with ADHD and their Siblings? Investigating Plasticity Genes, Prosocial and Antisocial Behaviour

    PubMed Central

    Richards, Jennifer S.; Hartman, Catharina A.; Franke, Barbara; Hoekstra, Pieter J.; Heslenfeld, Dirk J.; Oosterlaan, Jaap; Vásquez, Alejandro Arias; Buitelaar, Jan K.

    2014-01-01

    Background The differential susceptibility theory states that children differ in their susceptibility towards environmental experiences, partially due to plasticity genes. Individuals carrying specific variants in such genes will be more disadvantaged in negative but, conversely, more advantageous in positive environments. Understanding gene-environment interactions may help unravel the causal mechanisms involved in multifactorial psychiatric disorders such as Attention-Deficit/Hyperactivity Disorder (ADHD). Methods The differential susceptibility theory was examined by investigating the presence of interaction effects between maternal expressed emotion (EE; warmth and criticism) and the solitary and combined effects of plasticity genes (DAT1, DRD4, 5-HTT) on prosocial and antisocial behaviour (measured with parent- and self-reports) in children with ADHD and their siblings (N=366, M=17.11 years, 74.9 % male). Results Maternal warmth was positively associated with prosocial behaviour and negatively with antisocial behaviour, while maternal criticism was positively associated with antisocial behaviour and negatively with prosocial behaviour. No evidence of differential susceptibility was found. Conclusions The current study found no evidence for differential susceptibility based on the selected plasticity genes, in spite of strong EE-behaviour associations. It is likely that additional factors play a role in the complex relationship between genes, environment and behaviour. PMID:24929324

  9. Toxoplasmosis and Polygenic Disease Susceptibility Genes: Extensive Toxoplasma gondii Host/Pathogen Interactome Enrichment in Nine Psychiatric or Neurological Disorders

    PubMed Central

    Carter, C. J.

    2013-01-01

    Toxoplasma gondii is not only implicated in schizophrenia and related disorders, but also in Alzheimer's or Parkinson's disease, cancer, cardiac myopathies, and autoimmune disorders. During its life cycle, the pathogen interacts with ~3000 host genes or proteins. Susceptibility genes for multiple sclerosis, Alzheimer's disease, schizophrenia, bipolar disorder, depression, childhood obesity, Parkinson's disease, attention deficit hyperactivity disorder (P  from  8.01E − 05  (ADHD)  to  1.22E − 71) (multiple sclerosis), and autism (P = 0.013), but not anorexia or chronic fatigue are highly enriched in the human arm of this interactome and 18 (ADHD) to 33% (MS) of the susceptibility genes relate to it. The signalling pathways involved in the susceptibility gene/interactome overlaps are relatively specific and relevant to each disease suggesting a means whereby susceptibility genes could orient the attentions of a single pathogen towards disruption of the specific pathways that together contribute (positively or negatively) to the endophenotypes of different diseases. Conditional protein knockdown, orchestrated by T. gondii proteins or antibodies binding to those of the host (pathogen derived autoimmunity) and metabolite exchange, may contribute to this disruption. Susceptibility genes may thus be related to the causes and influencers of disease, rather than (and as well as) to the disease itself. PMID:23533776

  10. The relationship between polymorphisms in the glutamate cysteine ligase gene and asthma susceptibility.

    PubMed

    Polonikov, A V; Ivanov, V P; Solodilova, M A; Khoroshaya, I V; Kozhuhov, M A; Panfilov, V I

    2007-11-01

    The present study was designed to investigate an association of common -588C/T and -23G/T polymorphisms within glutamate cysteine ligase modifier subunit gene with susceptibility to bronchial asthma. A total of 435 ethnically Russian subjects were recruited in this study, including 221 patients with asthma and 214 sex and age matched healthy subjects. As previously reported, the -588C/T and -23G/T polymorphisms were completely linked. The -588TT/-23TT genotype was found to be associated with decreased risk of allergic asthma after adjustment for age, gender and smoking status using multivariate logistic regression analysis (OR=0.33 95% CI 0.15-0.70, p=0.036). However, the -588CT/-23GT genotype was associated with increased risk of non-allergic asthma (OR=2.03 95% CI 1.05-3.90, p=0.06). This is a first study reporting the association between genetic variations in the glutamate cysteine ligase gene and susceptibility to bronchial asthma. PMID:17643973

  11. Down-regulation of promoter methylation level of CD4 gene after MDV infection in MD-susceptible chicken line

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Marek’s disease virus (MDV) is an oncovirus that induces lymphoid tumors in susceptible chickens, and may affect the epigenetic stability of the CD4 gene. The purpose of this study was to find how the effect of MDV infection on DNA methylation status of the CD4 gene differed between MD-resistant (L6...

  12. Two variants on T2DM susceptible gene HHEX are associated with CRC risk in a Chinese population

    PubMed Central

    Gao, Chang; Xiong, Ying-Ying; Li, Min; Wang, Ya-Ping; Su, Yan-Wei; Lin, Mei; Jiang, An-Li; Xiong, Ling-Fan; Xie, Yan; Feng, Jue-Ping

    2016-01-01

    Increasing amounts of evidence has demonstrated that T2DM (Type 2 Diabetes Mellitus) patients have increased susceptibility to CRC (colorectal cancer). As HHEX is a recognized susceptibility gene in T2DM, this work was focused on two SNPs in HHEX, rs1111875 and rs7923837, to study their association with CRC. T2DM patients without CRC (T2DM-only, n=300), T2DM with CRC (T2DM/CRC, n=135), cancer-free controls (Control, n=570), and CRC without T2DM (CRC-only, n=642) cases were enrolled. DNA samples were extracted from the peripheral blood leukocytes of the patients and sequenced by direct sequencing. The χ2 test was used to compare categorical data. We found that in T2DM patients, rs1111875 but not the rs7923837 in HHEX gene was associated with the occurrence of CRC (p= 0.006). for rs1111875, TC/CC patients had an increased risk of CRC (p=0.019, OR=1.592, 95%CI=1.046-2.423). Moreover, our results also indicated that the two variants of HEEX gene could be risk factors for CRC in general population, independent on T2DM (p< 0.001 for rs1111875, p=0.001 for rs7923837). For rs1111875, increased risk of CRC was observed in TC or TC/CC than CC individuals (p<0.001, OR= 1.780, 95%CI= 1.385-2.287; p<0.001, OR= 1.695, 95%CI= 1.335-2.152). For rs7923837, increased CRC risk was observed in AG, GG, and AG/GG than AA individuals (p< 0.001, OR= 1.520, 95%CI= 1.200-1.924; p=0.036, OR= 1.739, 95%CI= 0.989-3.058; p< 0.001, OR= 1.540, 95%CI= 1.225-1.936). This finding highlights the potentially functional alteration with HHEX rs1111875 and rs7923837 polymorphisms may increase CRC susceptibility. Risk effects and the functional impact of these polymorphisms need further validation. PMID:27105501

  13. Maternal Self-Efficacy: Illusory Control and Its Effect on Susceptibility to Learned Helplessness.

    ERIC Educational Resources Information Center

    Donovan, Wilberta L.; And Others

    1990-01-01

    Mothers who exhibited high illusory control showed increased susceptibility to learned helplessness when they tried to solve a child-care task. The early attributional and behavioral style characteristic of high illusory control may be a precursor to overcontrolling, interfering behaviors during the toddler years. (RH)

  14. Haplotype mapping and sequence analysis of the mouse Nramp gene predict susceptibility to infection with intracellular parasites

    SciTech Connect

    Malo, D.; Hu, Jinxin; Schurr, E.

    1994-09-01

    The mouse chromosome 1 locus Bcg (Ity, Lsh) controls the capacity of the tissue macrophage to restrict the replication of antigenically unrelated intracellular parasites and therefore determines the natural resistance (BCG-R, dominant) or susceptibility (BCG-S, recessive) of inbred mouse strains to infection with diverse pathogens. We have used a positional cloning strategy based on genetic and physical mapping, YAC cloning, and exon trapping to isolate a candidate gene for Beg (Nramp) that encodes a predicted macrophage-specific transport protein. We have analyzed a total of 27 inbred mouse strains of BCG-R and BCG-S phenotypes for the presence of nucleotide sequence variations within the coding portion of Nramp and have carried out haplotype typing of the corresponding chromosome 1 region in these mice, using 11 additional polymorphic markers mapping in the immediate vicinity of Nramp. cDNA cloning and nucleotide sequencing identified 5 nucleotide sequence variations within Nramp in the inbred strains.

  15. The breast cancer susceptibility genes (BRCA) in breast and ovarian cancers

    PubMed Central

    Paul, Arindam; Paul, Soumen

    2015-01-01

    The Breast Cancer Susceptibility Genes, BRCA1 and BRCA2, are the dynamic regulators of genomic integrity. Inherited mutations in these genes are associated with the development of cancer in multiple organs including the breast and ovary. Mutations of BRCA1/2 genes greatly increase lifetime risk to develop breast and ovarian cancer and these mutations are frequently observed in hereditary breast and ovarian cancers. In addition, misregulation and altered expressions of BRCA1/2 proteins potentiate sporadic forms of breast cancer. In particular, both genes contribute to DNA repair and transcriptional regulation in response to DNA damage. Thus, deficiencies of BRCA1/2 functions lead to the accumulation of genetic alterations and ultimately influence the development of cancer. Studies since identification of both BRCA1 and BRCA2 have provided strong evidences for their tumor suppressor activities specifically for breast and ovarian cancer and this article aims to review the current state of knowledge regarding the BRCAs and associated cancer risk. PMID:24389207

  16. Susceptibility to Theiler's virus-induced demyelination. Mapping of the gene within the H-2D region.

    PubMed

    Rodriguez, M; Leibowitz, J; David, C S

    1986-03-01

    Demyelination induced by Theiler's virus was examined in mouse strains with congeneic recombinant haplotypes. Light and electron microscopy of spinal cord sections from mice with s, q, v, p, and f H-2D alleles showed perivascular inflammation and primary demyelination. The presence of susceptible haplotypes in the K or I region did not correlate with pathologic abnormalities. The Qa, Tla, PgK, and UpG genes did not appear to be critical in determining susceptibility to disease. However, mutation in the H-2D genes altered the susceptibility to virus-induced demyelination. B10.D2dm1 mice, which have deletions in the 3' end of Dd and the 5' end of Ld, showed prominent demyelination and clinical deficits. In contrast, BALB/c-dm2, which have a deletion of the entire L gene, showed no pathologic changes. Central nervous system virus titers correlated with susceptibility to demyelination; both resistant and susceptible strains had a strong humoral immune response to the virus. The findings in the congeneic recombinant mice and in mice mutant in the H-2D region strongly suggest that at least one of the genes critical for determining virus-induced demyelination maps to the 3' end of the H-2D gene.

  17. Differential Susceptibility in Early Literacy Instruction through Computer Games: The Role of the Dopamine D4 Receptor Gene (DRD4)

    ERIC Educational Resources Information Center

    Kegel, Cornelia A. T.; Bus, Adriana G.; van IJzendoorn, Marinus H.

    2011-01-01

    Not every child seems equally susceptible to the same parental, educational, or environmental influences even if cognitive level is similar. This study is the first randomized controlled trial to apply the differential susceptibility paradigm to education in relation to children's genotype and early literacy skills. A randomized pretest-posttest…

  18. Genome-Wide Screening Identifies Six Genes That Are Associated with Susceptibility to Escherichia coli Microcin PDI.

    PubMed

    Zhao, Zhe; Eberhart, Lauren J; Orfe, Lisa H; Lu, Shao-Yeh; Besser, Thomas E; Call, Douglas R

    2015-10-01

    The microcin PDI inhibits a diverse group of pathogenic Escherichia coli strains. Coculture of a single-gene knockout library (BW25113; n=3,985 mutants) against a microcin PDI-producing strain (E. coli 25) identified six mutants that were not susceptible (ΔatpA, ΔatpF, ΔdsbA, ΔdsbB, ΔompF, and ΔompR). Complementation of these genes restored susceptibility in all cases, and the loss of susceptibility was confirmed through independent gene knockouts in E. coli O157:H7 Sakai. Heterologous expression of E. coli ompF conferred susceptibility to Salmonella enterica and Yersinia enterocolitica strains that are normally unaffected by microcin PDI. The expression of chimeric OmpF and site-directed mutagenesis revealed that the K47G48N49 region within the first extracellular loop of E. coli OmpF is a putative binding site for microcin PDI. OmpR is a transcriptional regulator for ompF, and consequently loss of susceptibility by the ΔompR strain most likely is related to this function. Deletion of AtpA and AtpF, as well as AtpE and AtpH (missed in the original library screen), resulted in the loss of susceptibility to microcin PDI and the loss of ATP synthase function. Coculture of a susceptible strain in the presence of an ATP synthase inhibitor resulted in a loss of susceptibility, confirming that a functional ATP synthase complex is required for microcin PDI activity. In trans expression of ompF in the ΔdsbA and ΔdsbB strains did not restore a susceptible phenotype, indicating that these proteins are probably involved with the formation of disulfide bonds for OmpF or microcin PDI.

  19. Interpretive standards and quality control limits for susceptibility tests with ampicillin-sulbactam combination disks.

    PubMed Central

    Barry, A L; Jones, R N; Thornsberry, C

    1984-01-01

    In vitro studies were performed to evaluate susceptibility tests with disks containing 10 micrograms of ampicillin plus 10 micrograms of sulbactam. Interpretive zone standards of less than or equal to 11 mm (resistant), 12 to 13 mm (intermediate), and greater than or equal to 14 mm (susceptible) are proposed. A nine-laboratory coordinated study was performed to establish tentative zone size limits for quality control of ampicillin-sulbactam disks. This included data with a new control strain selected to monitor performance of such combination disks. PMID:6321543

  20. Analysis of ADRB2 (Arg16Gly) Gene Variant with Susceptibility, Pharmacogenetic Response and Disease Severity in South Indian Asthmatics.

    PubMed

    Bandaru, Srinivas; Akka, Jyothy; Marri, Vijaya Kumar; Alvala, Mallika; Ponnala, Deepika; Mundluru, Hema Prasad

    2015-12-01

    β2-Adrenergic receptor (β2-AR) plays a crucial role in asthma pathophysiology by regulating, processes of the lung function, and clinical response to bronchodilators. The +46G>A- Gly16Arg polymorphism in the gene encoding β2 adrenergic receptor (ADRB2) has been associated with receptor non-responsiveness after β2-agonist exposure. In the present study, we sought to evaluate the possible association of Gly16Arg polymorphism with asthma susceptibility, pharmacogenetic response to Salbutamol, and varying degrees of disease severity. Three hundred ninety-eight clinically diagnosed patients and 456 healthy controls were enrolled for the study. Patients were classified into severity classes according to Global Initiative for Asthma guidelines. To assess bronchodilator response, spirometry was performed before and 15 min after Salbutamol (200 μg) delivery. Responders to Salbutamol were categorized if percentage reversibility was greater than or equal to 12% in them, while those showing reversibility less than 12% were classified as non-responders. Genotyping was carried out by ARMS-PCR technique. Statistical methods were applied to test for the significance of the results. In the present study, there was lack of significant association of polymorphism with disease susceptibility as well as with bronchodilator response. The polymorphism was not associated with mild and moderate asthma subtypes; however, there was a notable association with severe asthma subtype. In addition, the polymorphism was associated with severe asthma compared to subtypes of mild and moderate asthma combined. In a South Indian population, the ADRB2 Arg/Gly may not form a susceptible variant to develop asthma nor can be a standard predictive marker to bronchodilator response; nevertheless, the patterns in asthma severity can be predicted by analyzing this variant.

  1. NOS2 Variants Reveal a Dual Genetic Control of Nitric Oxide Levels, Susceptibility to Plasmodium Infection, and Cerebral Malaria

    PubMed Central

    Trovoada, Maria de Jesus; Martins, Madalena; Ben Mansour, Riadh; Sambo, Maria do Rosário; Fernandes, Ana B.; Antunes Gonçalves, Lígia; Borja, Artur; Moya, Roni; Almeida, Paulo; Costa, João; Marques, Isabel; Macedo, M. Paula; Coutinho, António; Narum, David L.

    2014-01-01

    Nitric oxide (NO) is a proposed component of malaria pathogenesis, and the inducible nitric oxide synthase gene (NOS2) has been associated to malaria susceptibility. We analyzed the role of NOS2 polymorphisms on NO bioavailability and on susceptibility to infection, Plasmodium carrier status and clinical malaria. Two distinct West African sample collections were studied: a population-based collection of 1,168 apparently healthy individuals from the Príncipe Island and a hospital-based cohort of 269 Angolan children. We found that two NOS2 promoter single-nucleotide polymorphism (SNP) alleles associated to low NO plasma levels in noninfected individuals were also associated to reduced risk of pre-erythrocytic infection as measured anti-CSP antibody levels (6.25E–04 < P < 7.57E–04). In contrast, three SNP alleles within the NOS2 cistronic region conferring increased NO plasma levels in asymptomatic carriers were strongly associated to risk of parasite carriage (8.00E–05 < P < 7.90E–04). Notwithstanding, three SNP alleles in this region protected from cerebral malaria (7.90E–4 < P < 4.33E–02). Cohesively, the results revealed a dual regimen in the genetic control of NO bioavailability afforded by NOS2 depending on the infection status. NOS2 promoter variants operate in noninfected individuals to decrease both NO bioavailability and susceptibility to pre-erythrocytic infection. Conversely, NOS2 cistronic variants (namely, rs6505469) operate in infected individuals to increase NO bioavailability and confer increased susceptibility to unapparent infection but protect from cerebral malaria. These findings corroborate the hypothesis that NO anti-inflammatory properties impact on different steps of malaria pathogenesis, explicitly by favoring infection susceptibility and deterring severe malaria syndromes. PMID:24379293

  2. NOS2 variants reveal a dual genetic control of nitric oxide levels, susceptibility to Plasmodium infection, and cerebral malaria.

    PubMed

    Trovoada, Maria de Jesus; Martins, Madalena; Ben Mansour, Riadh; Sambo, Maria do Rosário; Fernandes, Ana B; Antunes Gonçalves, Lígia; Borja, Artur; Moya, Roni; Almeida, Paulo; Costa, João; Marques, Isabel; Macedo, M Paula; Coutinho, António; Narum, David L; Penha-Gonçalves, Carlos

    2014-03-01

    Nitric oxide (NO) is a proposed component of malaria pathogenesis, and the inducible nitric oxide synthase gene (NOS2) has been associated to malaria susceptibility. We analyzed the role of NOS2 polymorphisms on NO bioavailability and on susceptibility to infection, Plasmodium carrier status and clinical malaria. Two distinct West African sample collections were studied: a population-based collection of 1,168 apparently healthy individuals from the Príncipe Island and a hospital-based cohort of 269 Angolan children. We found that two NOS2 promoter single-nucleotide polymorphism (SNP) alleles associated to low NO plasma levels in noninfected individuals were also associated to reduced risk of pre-erythrocytic infection as measured anti-CSP antibody levels (6.25E-04 < P < 7.57E-04). In contrast, three SNP alleles within the NOS2 cistronic region conferring increased NO plasma levels in asymptomatic carriers were strongly associated to risk of parasite carriage (8.00E-05 < P < 7.90E-04). Notwithstanding, three SNP alleles in this region protected from cerebral malaria (7.90E-4 < P < 4.33E-02). Cohesively, the results revealed a dual regimen in the genetic control of NO bioavailability afforded by NOS2 depending on the infection status. NOS2 promoter variants operate in noninfected individuals to decrease both NO bioavailability and susceptibility to pre-erythrocytic infection. Conversely, NOS2 cistronic variants (namely, rs6505469) operate in infected individuals to increase NO bioavailability and confer increased susceptibility to unapparent infection but protect from cerebral malaria. These findings corroborate the hypothesis that NO anti-inflammatory properties impact on different steps of malaria pathogenesis, explicitly by favoring infection susceptibility and deterring severe malaria syndromes.

  3. Polymorphism of VEGF gene in susceptibility to chronic immune-mediated inflammatory diseases: a meta-analysis.

    PubMed

    Wei, Ni; Chen, Zijia; Xue, Zhifeng; Zhu, Yuelan

    2015-08-01

    Background Vascular endothelial growth factor (VEGF) is an important angiogenic factor and may be connected with chronic immune-mediated inflammatory diseases (IMIDs) to some extent. However, previous researches about the relationship between the +405G>C (dbSNP: rs2010963) polymorphism in VEGF gene and the risk of IMIDs are controversial and inconsistent. So we conducted this meta-analysis to assess whether the relationship between the +405G>C polymorphism in the 5'-UTR region of VEGF gene and IMID susceptibility exists. Methods Our literature search was conducted on the PubMed, Embase, Web of science, Chinese National Knowledge Infrastructure, and Chinese Biomedical databases to retrieve for eligible studies. Odds ratios as well as their 95 % confidence intervals were utilized to deduce the possible relationship. Results A total number of 5175 patients with IMIDs and 7069 healthy controls from 27 case-control studies were included. For the overall eligible data collected in our meta-analysis, there was no marked relationship between +405G>C polymorphism and the risk of IMIDs. However, subgroup analysis by ethnicity suggested that +405C allele could be a protective factor for IMIDs in Asians, whereas an opposite conclusion was drawn in Caucasians. Conclusion Thus, we may come to the conclusion that the VEGF +405G>C polymorphism could be associated with IMIDs, and the correlation might vary with ethnic groups. PMID:26007152

  4. Systematic screening of lysyl oxidase-like (LOXL) family genes demonstrates that LOXL2 is a susceptibility gene to intracranial aneurysms.

    PubMed

    Akagawa, Hiroyuki; Narita, Akira; Yamada, Haruhiko; Tajima, Atsushi; Krischek, Boris; Kasuya, Hidetoshi; Hori, Tomokatsu; Kubota, Motoo; Saeki, Naokatsu; Hata, Akira; Mizutani, Tohru; Inoue, Ituro

    2007-05-01

    Four lysyl oxidase family genes (LOXL1, LOXL2, LOXL3, and LOXL4), which catalyze cross-linking of collagen and elastin, were considered to be functional candidates for intracranial aneurysms (IA) and were extensively screened for genetic susceptibility in Japanese IA patients. Total RNA was isolated from four paired ruptured IA and superficial temporal artery (STA) tissue and examined by real-time RT-PCR. The expression of LOXL2 in the paired IA and STA tissues was elevated in the IA tissue. A total of 55 single nucleotide polymorphisms (SNPs) of LOXL1-4 were genotyped for an allelic association study in 402 Japanese IA patients and 462 Japanese non-IA controls. Allelic associations were evaluated with the chi-square test and the permutation test especially designed for adjustment of multiple testing. SNPs of LOXL1 and LOXL4 were not significantly associated with IA, while several SNPs of LOXL2 and LOXL3 showed nominally significant associations in IA patients. We detected an empirically significant association with one SNP of LOXL2 in familial IA patients after adjustment for multiple testing [chi(2) = 10.23, empirical P = 0.023, OR (95% CI) = 1.49 (1.17, 1.90)]. Furthermore, multilocus interaction was evaluated by multifactor dimensionality reduction analysis. We found that the SNPs of LOXL2 have an interactive effect with elastin (ELN) and LIM kinase 1 (LIMK1) that have been previously found to be associated with IA. In conclusion, one SNP of LOXL2 showed a significant association with IA individually, and we also detected a gene-gene interaction of LOXL2 with ELN/LIMK1, which may play an important role in susceptibility to IA.

  5. Localization of a Susceptibility Gene for Common Forms of Stroke to 5q12

    PubMed Central

    Gretarsdottir, Solveig; Sveinbjörnsdottir, Sigurlaug; Jonsson, Hjörtur H.; Jakobsson, Finnbogi; Einarsdottir, Elisabet; Agnarsson, Uggi; Shkolny, Dana; Einarsson, Gisli; Gudjonsdottir, Herdis M.; Valdimarsson, Einar M.; Einarsson, Olafur B.; Thorgeirsson, Gudmundur; Hadzic, Radinka; Jonsdottir, Sif; Reynisdottir, Sigridur Th.; Bjarnadottir, Sigrun M.; Gudmundsdottir, Thorunn; Gudlaugsdottir, Gudrun J.; Gill, Ramanjit; Lindpaintner, Klaus; Sainz, Jesus; Hannesson, Helgi H.; Sigurdsson, Gunnar Th.; Frigge, Michael L.; Kong, Augustine; Gudnason, Vilmundur; Stefansson, Kari; Gulcher, Jeffrey R.

    2002-01-01

    Stroke is one of the most complex diseases, with several subtypes, as well as secondary risk factors, such as hypertension, hyperlipidemia, and diabetes, which, in turn, have genetic and environmental risk factors of their own. Here, we report the results of a genomewide search for susceptibility genes for the common forms of stroke. We cross-matched a population-based list of patients with stroke in Iceland with an extensive computerized genealogy database clustering 476 patients with stroke within 179 extended pedigrees. Linkage to 5q12 was detected, and the LOD score at this locus meets the criteria for genomewide significance (multipoint allele-sharing LOD score of 4.40, P=3.9×10-6). A 20-cM region on 5q was physically and genetically mapped to obtain accurate marker order and intermarker distances. This locus on 5q12, which we have designated as “STRK1,” does not correspond to known susceptibility loci for stroke or for its risk factors and represents the first mapping of a locus for common stroke. PMID:11833004

  6. Polymorphisms in inflammation-related genes are associated with susceptibility to major depression and antidepressant response

    PubMed Central

    Dong, C; Maestre-Mesa, J; Licinio, J

    2009-01-01

    There are clinical parallels between the nature and course of depressive symptoms in major depressive disorder (MDD) and those of inflammatory disorders. However, the characterization of a possible immune system dysregulation in MDD has been challenging. Emerging data support the role of T-cell dysfunction. Here we report the association of MDD and antidepressant response to genes important in the modulation of the hypothalamic-pituitary-adrenal axis and immune functions in Mexican Americans with major depression. Specifically, single nucleotide polymorphisms (SNPs) in two genes critical for T-cell function are associated with susceptibility to MDD: PSMB4 (proteasome β4 subunit), important for antigen processing, and TBX21 (T bet), critical for differentiation. Our analyses revealed a significant combined allele dose-effect: individuals who had one, two and three risk alleles were 2.3, 3.2 and 9.8 times more likely to have the diagnosis of MDD, respectively. We found associations of several SNPs and antidepressant response; those genes support the role of T cell (CD3E, PRKCH, PSMD9 and STAT3) and hypothalamic-pituitary-adrenal axis (UCN3) functions in treatment response. We also describe in MDD increased levels of CXCL10/IP-10, which decreased in response to antidepressants. This further suggests predominance of type 1 T-cell activity in MDD. T-cell function variations that we describe here may account for 47.8% of the attributable risk in Mexican Americans with moderate MDD. Immune function genes are highly variable; therefore, different genes might be implicated in distinct population groups. PMID:18504423

  7. Identification of Novel Candidate Genes for Early-Onset Colorectal Cancer Susceptibility

    PubMed Central

    Weren, Robbert D. A.; Mensenkamp, Arjen R.; Gilissen, Christian; van Zelst-Stams, Wendy A.; Spruijt, Liesbeth; Kets, C. Marleen; Zhang, Junxiao; Venselaar, Hanka; Vreede, Lilian; Schubert, Nil; Tychon, Marloes; Derks, Ronny; Schackert, Hans K.; Geurts van Kessel, Ad; Hoogerbrugge, Nicoline; Ligtenberg, Marjolijn J. L.; Kuiper, Roland P.

    2016-01-01

    Approximately 25–30% of colorectal cancer (CRC) cases are expected to result from a genetic predisposition, but in only 5–10% of these cases highly penetrant germline mutations are found. The remaining CRC heritability is still unexplained, and may be caused by a hitherto-undefined set of rare variants with a moderately penetrant risk. Here we aimed to identify novel risk factors for early-onset CRC using whole-exome sequencing, which was performed on a cohort of CRC individuals (n = 55) with a disease onset before 45 years of age. We searched for genes that were recurrently affected by rare variants (minor allele frequency ≤0.001) with potentially damaging effects and, subsequently, re-sequenced the candidate genes in a replication cohort of 174 early-onset or familial CRC individuals. Two functionally relevant genes with low frequency variants with potentially damaging effects, PTPN12 and LRP6, were found in at least three individuals. The protein tyrosine phosphatase PTP-PEST, encoded by PTPN12, is a regulator of cell motility and LRP6 is a component of the WNT-FZD-LRP5-LRP6 complex that triggers WNT signaling. All variants in LRP6 were identified in individuals with an extremely early-onset of the disease (≤30 years of age), and two of the three variants showed increased WNT signaling activity in vitro. In conclusion, we present PTPN12 and LRP6 as novel candidates contributing to the heterogeneous susceptibility to CRC. PMID:26901136

  8. A susceptibility gene for premature ovarian failure (POF) maps to proximal Xq28.

    PubMed

    Rossetti, Francesca; Rizzolio, Flavio; Pramparo, Tiziano; Sala, Cinzia; Bione, Silvia; Bernardi, Franca; Goegan, Mara; Zuffardi, Orsetta; Toniolo, Daniela

    2004-10-01

    Terminal deletions of the long arm of the human X chromosome have been described in women with premature ovarian failure (POF). We report here the molecular characterization of an inherited deletion in two affected women and in their mother. The two daughters presented secondary amenorrhea at 17 or 22 years respectively, while the mother was fertile. She had four children, but she eventually had premature menopause at 43 years of age. The fine molecular analysis of the deletion showed that the three women carried an identical deletion. We conclude that the phenotypic difference within the family must be attributed to genetic or environmental factors and not to the presence of different extent deletions. By comparison with other deletions in the region, we map a susceptibility gene for POF to 4.5 Mb, in the distal part of Xq.

  9. A breast-ovarian cancer susceptibility gene maps to chromosome 17q21

    SciTech Connect

    Feunteun, J. ); Narod, S.A.; Parboosingh, J. ); Lynch, H.T.; Watson, P.; Conway, T.; Lynch, J. ); O'Connell, P.; White, R. ); Lenoir, G.M. )

    1993-04-01

    Nineteen North American Caucasian families that contain a minimum of four confirmed cases of breast or ovarian cancer have been studied. Four polymorphisms (cLB17.1, D17S579, D17S588, and D17S74), which span a region of approximately 15 cM on chromosome 17q12, were typed. The data confirm the location of a dominant gene conferring susceptibility to breast and ovarian cancer (maximum lod = 9.78) and suggest that the breast-ovarian cancer syndrome is genetically heterogeneous. Two recombinants in one large family suggest that the breast-ovarian cancer locus lies between D17S588 and D17S579. 14 refs., 3 figs., 3 tabs.

  10. The role of the BRCA2 gene in susceptibility to prostate cancer revisited.

    PubMed

    Ostrander, Elaine A; Udler, Miriam S

    2008-08-01

    Prostate cancer is a genetically complex disease with multiple predisposing factors affecting presentation, progression, and outcome. Epidemiologic studies have long shown an aggregation of breast and prostate cancer in some families. More recently, studies have reported an apparent excess of prostate cancer cases among BRCA2 mutation-carrying families. Additionally, population-based screens of early-onset prostate cancer patients have suggested that the prevalence of deleterious BRCA2 mutations in this group is 1% to 2%, imparting a significantly increased risk of the disease compared with noncarrier cases. However, studies of high-risk prostate cancer families suggest that BRCA2 plays at most a minimal role in these individuals, highlighting the potential genetic heterogeneity of the disease. In this commentary, we review the current literature and hypotheses surrounding the relationship between BRCA2 mutations and susceptibility to prostate cancer and speculate on the potential for involvement of additional genes.

  11. Interleukin-12B gene polymorphism frequencies in Egyptians and sex-related susceptibility to hepatitis C infection.

    PubMed

    Youssef, Samar Samir; Abd El Aal, Asmaa Mostafa; Nasr, Amal Soliman; el Zanaty, Taher; Seif, Sameh Mohamed

    2013-08-01

    Hepatitis C virus (HCV) infection is a major health problem worldwide. Egypt is the country with the highest HCV infection epidemic in the world. Interleukin (IL)-12 is a cytokine that has been shown to have a potent role as an antiviral cytokine. IL-12 is a heterodimer of the polypeptides p35 and p40. IL-12 B, the gene encoding IL-12 p40, is polymorphic, and a functional single-nucleotide polymorphism (SNP) of the 3'-untranslated region at position rs3212227 was associated with apparent resistance to HCV. The genotype distribution of this polymorphism differs by race. This study is sought to identify the genotype distribution of the IL-12 SNP rs3212227 polymorphism in Egyptians and to assess its role in susceptibility to chronic HCV infection alone or in a sex-dependent way. The study included 238 subjects: 100 healthy controls and 138 patients with HCV infection. The IL-12 SNP rs3212227 was genotyped by the polymerase chain reaction-restriction fragment length polymorphism method (PCR-RFLP). Results showed a genotype frequency of 46%, 39%, and 15% for AA, AC, and CC IL-12 genotypes, respectively. No significant result (P=0.5) was shown in the differential distribution of the IL-12 SNP genotypes between controls and patients with HCV infection. Nonetheless, this difference in the IL-12 genotype distribution was significant (0.005) when it was stratified according to sex; moreover, the C allele distribution in men and women differed with a statistically high significance (P=0.0001) in controls versus HCV patients. In conclusion, the IL-12 SNP rs3212227 polymorphism confers a susceptibility to HCV infection in a sex-dependent way in Egyptians.

  12. Complex genetic control of susceptibility to malaria: positional cloning of the Char9 locus

    PubMed Central

    Min-Oo, Gundula; Fortin, Anny; Pitari, Giuseppina; Tam, Mifong; Stevenson, Mary M.; Gros, Philippe

    2007-01-01

    Mouse strains AcB55 and AcB61 are resistant to malaria by virtue of a mutation in erythrocyte pyruvate kinase (PklrI90N). Linkage analysis in [AcB55 × A/J] F2 mice detected a second locus (Char9; logarithm of odds = 4.74) that regulates the blood-stage replication of Plasmodium chabaudi AS independently of Pklr. We characterized the 77 genes of the Char9 locus for tissue-specific expression, strain-specific alterations in gene expression, and polymorphic variants that are possibly associated with differential susceptibility. We identified Vnn1/Vnn3 as the likely candidates responsible for Char9. Vnn3/Vnn1 map within a conserved haplotype block and show expression levels that are strictly cis-regulated by this haplotype. The absence of Vnn messenger RNA expression and lack of pantetheinase protein activity in tissues are associated with susceptibility to malaria and are linked to a complex rearrangement in the Vnn3 promoter region. The A/J strain also carries a unique nonsense mutation that leads to a truncated protein. Vanin genes code for a pantetheinase involved in the production of cysteamine, a key regulator of host responses to inflammatory stimuli. Administration of cystamine in vivo partially corrects susceptibility to malaria in A/J mice, as measured by reduced blood parasitemia and decreased mortality. These studies suggest that pantetheinase is critical for the host response to malaria. PMID:17312006

  13. Availability of type II diabetic families for detection of diabetes susceptibility genes.

    PubMed

    Cook, J T; Page, R C; O'Rahilly, S; Levy, J; Holman, R; Barrow, B; Hattersley, A T; Shaw, A G; Wainscoat, J S; Turner, R C

    1993-10-01

    Type II diabetes is a familial disorder, as evidenced by the increased prevalence in monozygotic cotwins and first-degree relatives of affected subjects; however, its genetic etiology is largely unknown. Well-characterized pedigrees are an essential resource for the study of susceptibility genes for type II diabetes. This study describes a 5-yr search for type II diabetic families in Oxfordshire, U.K. We interviewed 950 type II diabetic subjects concerning the availability of first-degree relatives; 127 Caucasian families ascertained through a proband with type II diabetes were studied, and 589 first-degree relatives were characterized. Three large pedigrees with maturity-onset diabetes of the young, and 8 multiplex multigenerational type II diabetic pedigrees were identified. We identified 12 sib-pairs in which both siblings had type II diabetes; however, only 7 sib-pairs had both parents alive, and 2 of these had both parents affected. If one also considers one sib having diabetes and one sib having glucose intolerance as being an affected sib-pair, we identified 30 sib-pairs of which 7 had both parents affected and probably had bilineal inheritance. We identified 76 complete nuclear families with both parents and offspring available for study, but only 6 were of optimal structure for linkage analysis. In conclusion, multiplex pedigrees and type II diabetic sib-pairs with living parents are uncommon, and their ascertainment requires a substantial investment of resources. Large-scale collaborative multicenter initiatives would be needed to collect a large resource of family material for the study of susceptibility genes for type II diabetes.

  14. A TagSNP in SIRT1 Gene Confers Susceptibility to Myocardial Infarction in a Chinese Han Population

    PubMed Central

    Cheng, Jie; Cho, Miook; Cen, Jin-ming; Cai, Meng-yun; Xu, Shun; Ma, Ze-wei; Liu, Xinguang; Yang, Xi-li; Chen, Can; Suh, Yousin; Xiong, Xing-dong

    2015-01-01

    SIRT1 exerts protective effects against endothelial cells dysfunction, inflammation and atherosclerosis, indicating an important role on myocardial infarction (MI) pathogenesis. Nonetheless, the effects of SIRT1 variants on MI risk remain poorly understood. Here we aimed to investigate the influence of SIRT1 polymorphisms on individual susceptibility to MI. Genotyping of three tagSNPs (rs7069102, rs3818292 and rs4746720) in SIRT1 gene was performed in a Chinese Han population, consisting of 287 MI cases and 654 control subjects. In a logistic regression analysis, we found that G allele of rs7069102 had increased MI risk with odds ratio (OR) of 1.57 [95% confidence interval (CI) = 1.15–2.16, Bonferroni corrected P (Pc) = 0.015] after adjustment for conventional risk factors compared to C allele. Similarly, the combined CG/GG genotypes was associated with the increased MI risk (OR = 1.64, 95% CI = 1.14–2.35, Pc = 0.021) compared to the CC genotype. Further stratified analysis revealed a more significant association with MI risk among younger subjects (≤ 55 years old). Consistent with these results, the haplotype rs7069102G-rs3818292A-rs4746720T containing the rs7069102 G allele was also associated with the increased MI risk (OR = 1.41, 95% CI = 1.09–1.84, Pc = 0.040). However, we did not detect any association of rs3818292 and rs4746720 with MI risk. Our study provides the first evidence that the tagSNP rs7069102 and haplotype rs7069102G-rs3818292A-rs4746720T in SIRT1 gene confer susceptibility to MI in the Chinese Han population. PMID:25706717

  15. RANGE: Gene Transfer of Reversibly Controlled Polycistronic Genes

    PubMed Central

    Chen, Yiwei; Cao, Liji; Luo, Chonglin; Ditzel, Désirée AW; Peter, Jörg; Sprengel, Rolf

    2013-01-01

    We developed a single vector recombinant adeno-associated viral (rAAV) expression system for spatial and reversible control of polycistronic gene expression. Our approach (i) integrates the advantages of the tetracycline (Tet)-controlled transcriptional silencer tTSKid and the self-cleaving 2A peptide bridge, (ii) combines essential regulatory components as an autoregulatory loop, (iii) simplifies the gene delivery scheme, and (iv) regulates multiple genes in a synchronized manner. Controlled by an upstream Tet-responsive element (TRE), both the ubiquitous chicken β-actin promoter (CAG) and the neuron-specific synapsin-1 promoter (Syn) could regulate expression of tTSKid together with two 2A-linked reporter genes. Transduction in vitro exhibited maximally 50-fold regulation by doxycycline (Dox). Determined by gene delivery method as well as promoter, highly specific tissues were transduced in vivo. Bioluminescence imaging (BLI) visualized reversible “ON/OFF” gene switches over repeated “Doxy-Cycling” in living mice. Thus, the reversible rAAV-mediated N-cistronic gene expression system, termed RANGE, may serve as a versatile tool to achieve reversible polycistronic gene regulation for the study of gene function as well as gene therapy. PMID:23571608

  16. Identification of candidate MLO powdery mildew susceptibility genes in cultivated Solanaceae and functional characterization of tobacco NtMLO1.

    PubMed

    Appiano, Michela; Pavan, Stefano; Catalano, Domenico; Zheng, Zheng; Bracuto, Valentina; Lotti, Concetta; Visser, Richard G F; Ricciardi, Luigi; Bai, Yuling

    2015-10-01

    Specific homologs of the plant Mildew Locus O (MLO) gene family act as susceptibility factors towards the powdery mildew (PM) fungal disease, causing significant economic losses in agricultural settings. Thus, in order to obtain PM resistant phenotypes, a general breeding strategy has been proposed, based on the selective inactivation of MLO susceptibility genes across cultivated species. In this study, PCR-based methodologies were used in order to isolate MLO genes from cultivated solanaceous crops that are hosts for PM fungi, namely eggplant, potato and tobacco, which were named SmMLO1, StMLO1 and NtMLO1, respectively. Based on phylogenetic analysis and sequence alignment, these genes were predicted to be orthologs of tomato SlMLO1 and pepper CaMLO2, previously shown to be required for PM pathogenesis. Full-length sequence of the tobacco homolog NtMLO1 was used for a heterologous transgenic complementation assay, resulting in its characterization as a PM susceptibility gene. The same assay showed that a single nucleotide change in a mutated NtMLO1 allele leads to complete gene loss-of-function. Results here presented, also including a complete overview of the tobacco and potato MLO gene families, are valuable to study MLO gene evolution in Solanaceae and for molecular breeding approaches aimed at introducing PM resistance using strategies of reverse genetics.

  17. Identification of candidate MLO powdery mildew susceptibility genes in cultivated Solanaceae and functional characterization of tobacco NtMLO1.

    PubMed

    Appiano, Michela; Pavan, Stefano; Catalano, Domenico; Zheng, Zheng; Bracuto, Valentina; Lotti, Concetta; Visser, Richard G F; Ricciardi, Luigi; Bai, Yuling

    2015-10-01

    Specific homologs of the plant Mildew Locus O (MLO) gene family act as susceptibility factors towards the powdery mildew (PM) fungal disease, causing significant economic losses in agricultural settings. Thus, in order to obtain PM resistant phenotypes, a general breeding strategy has been proposed, based on the selective inactivation of MLO susceptibility genes across cultivated species. In this study, PCR-based methodologies were used in order to isolate MLO genes from cultivated solanaceous crops that are hosts for PM fungi, namely eggplant, potato and tobacco, which were named SmMLO1, StMLO1 and NtMLO1, respectively. Based on phylogenetic analysis and sequence alignment, these genes were predicted to be orthologs of tomato SlMLO1 and pepper CaMLO2, previously shown to be required for PM pathogenesis. Full-length sequence of the tobacco homolog NtMLO1 was used for a heterologous transgenic complementation assay, resulting in its characterization as a PM susceptibility gene. The same assay showed that a single nucleotide change in a mutated NtMLO1 allele leads to complete gene loss-of-function. Results here presented, also including a complete overview of the tobacco and potato MLO gene families, are valuable to study MLO gene evolution in Solanaceae and for molecular breeding approaches aimed at introducing PM resistance using strategies of reverse genetics. PMID:25947088

  18. Allele-specific expression of mutated in colorectal cancer (MCC) gene and alternative susceptibility to colorectal cancer in schizophrenia.

    PubMed

    Wang, Yang; Cao, Yanfei; Huang, Xiaoye; Yu, Tao; Wei, Zhiyun; McGrath, John; Xu, Fei; Bi, Yan; Li, Xingwang; Yang, Fengping; Li, Weidong; Zou, Xia; Peng, Zhihai; Xiao, Yanzeng; Zhang, Yan; He, Lin; He, Guang

    2016-01-01

    Evidence has indicated that the incidence of colorectal cancer (CRC) among schizophrenia is lower than normal. To explore this potential protective effect, we employed an innovative strategy combining association study with allele-specific expression (ASE) analysis in MCC gene. We first genotyped four polymorphisms within MCC in 312 CRC patients, 270 schizophrenia patients and 270 controls. Using the MassArray technique, we performed ASE measurements in a second sample series consisting of 50 sporadic CRC patients, 50 schizophrenia patients and 52 controls. Rs2227947 showed significant differences between schizophrenia cases and controls, and haplotype analysis reported some significant discrepancies among these three subject groups. ASE values of rs2227948 and rs2227947 presented consistently differences between CRC (or schizophrenia) patients and controls. Of the three groups, highest frequencies of ASE in MCC were concordantly found in CRC group, whereas lowest frequencies of ASE were observed in schizophrenia group. Similar trends were confirmed in both haplotype frequencies and ASE frequencies (i.e. CRC > control > schizophrenia). We provide a first indication that MCC might confer alterative genetic susceptibility to CRC in individuals with schizophrenia promising to shed more light on the relationship between schizophrenia and cancer progression. PMID:27226254

  19. European genome-wide association study identifies SLC14A1 as a new urinary bladder cancer susceptibility gene

    PubMed Central

    Rafnar, Thorunn; Vermeulen, Sita H.; Sulem, Patrick; Thorleifsson, Gudmar; Aben, Katja K.; Witjes, J. Alfred; Grotenhuis, Anne J.; Verhaegh, Gerald W.; Hulsbergen-van de Kaa, Christina A.; Besenbacher, Soren; Gudbjartsson, Daniel; Stacey, Simon N.; Gudmundsson, Julius; Johannsdottir, Hrefna; Bjarnason, Hjordis; Zanon, Carlo; Helgadottir, Hafdis; Jonasson, Jon Gunnlaugur; Tryggvadottir, Laufey; Jonsson, Eirikur; Geirsson, Gudmundur; Nikulasson, Sigfus; Petursdottir, Vigdis; Bishop, D. Timothy; Chung-Sak, Sei; Choudhury, Ananya; Elliott, Faye; Barrett, Jennifer H.; Knowles, Margaret A.; de Verdier, Petra J.; Ryk, Charlotta; Lindblom, Annika; Rudnai, Peter; Gurzau, Eugene; Koppova, Kvetoslava; Vineis, Paolo; Polidoro, Silvia; Guarrera, Simonetta; Sacerdote, Carlotta; Panadero, Angeles; Sanz-Velez, José I.; Sanchez, Manuel; Valdivia, Gabriel; Garcia-Prats, Maria D.; Hengstler, Jan G.; Selinski, Silvia; Gerullis, Holger; Ovsiannikov, Daniel; Khezri, Abdolaziz; Aminsharifi, Alireza; Malekzadeh, Mahyar; van den Berg, Leonard H.; Ophoff, Roel A.; Veldink, Jan H.; Zeegers, Maurice P.; Kellen, Eliane; Fostinelli, Jacopo; Andreoli, Daniele; Arici, Cecilia; Porru, Stefano; Buntinx, Frank; Ghaderi, Abbas; Golka, Klaus; Mayordomo, José I.; Matullo, Giuseppe; Kumar, Rajiv; Steineck, Gunnar; Kiltie, Anne E.; Kong, Augustine; Thorsteinsdottir, Unnur; Stefansson, Kari; Kiemeney, Lambertus A.

    2011-01-01

    Three genome-wide association studies in Europe and the USA have reported eight urinary bladder cancer (UBC) susceptibility loci. Using extended case and control series and 1000 Genomes imputations of 5 340 737 single-nucleotide polymorphisms (SNPs), we searched for additional loci in the European GWAS. The discovery sample set consisted of 1631 cases and 3822 controls from the Netherlands and 603 cases and 37 781 controls from Iceland. For follow-up, we used 3790 cases and 7507 controls from 13 sample sets of European and Iranian ancestry. Based on the discovery analysis, we followed up signals in the urea transporter (UT) gene SLC14A. The strongest signal at this locus was represented by a SNP in intron 3, rs17674580, that reached genome-wide significance in the overall analysis of the discovery and follow-up groups: odds ratio = 1.17, P = 7.6 × 10−11. SLC14A1 codes for UTs that define the Kidd blood group and are crucial for the maintenance of a constant urea concentration gradient in the renal medulla and, through this, the kidney's ability to concentrate urine. It is speculated that rs17674580, or other sequence variants in LD with it, indirectly modifies UBC risk by affecting urine production. If confirmed, this would support the ‘urogenous contact hypothesis’ that urine production and voiding frequency modify the risk of UBC. PMID:21750109

  20. European genome-wide association study identifies SLC14A1 as a new urinary bladder cancer susceptibility gene.

    PubMed

    Rafnar, Thorunn; Vermeulen, Sita H; Sulem, Patrick; Thorleifsson, Gudmar; Aben, Katja K; Witjes, J Alfred; Grotenhuis, Anne J; Verhaegh, Gerald W; Hulsbergen-van de Kaa, Christina A; Besenbacher, Soren; Gudbjartsson, Daniel; Stacey, Simon N; Gudmundsson, Julius; Johannsdottir, Hrefna; Bjarnason, Hjordis; Zanon, Carlo; Helgadottir, Hafdis; Jonasson, Jon Gunnlaugur; Tryggvadottir, Laufey; Jonsson, Eirikur; Geirsson, Gudmundur; Nikulasson, Sigfus; Petursdottir, Vigdis; Bishop, D Timothy; Chung-Sak, Sei; Choudhury, Ananya; Elliott, Faye; Barrett, Jennifer H; Knowles, Margaret A; de Verdier, Petra J; Ryk, Charlotta; Lindblom, Annika; Rudnai, Peter; Gurzau, Eugene; Koppova, Kvetoslava; Vineis, Paolo; Polidoro, Silvia; Guarrera, Simonetta; Sacerdote, Carlotta; Panadero, Angeles; Sanz-Velez, José I; Sanchez, Manuel; Valdivia, Gabriel; Garcia-Prats, Maria D; Hengstler, Jan G; Selinski, Silvia; Gerullis, Holger; Ovsiannikov, Daniel; Khezri, Abdolaziz; Aminsharifi, Alireza; Malekzadeh, Mahyar; van den Berg, Leonard H; Ophoff, Roel A; Veldink, Jan H; Zeegers, Maurice P; Kellen, Eliane; Fostinelli, Jacopo; Andreoli, Daniele; Arici, Cecilia; Porru, Stefano; Buntinx, Frank; Ghaderi, Abbas; Golka, Klaus; Mayordomo, José I; Matullo, Giuseppe; Kumar, Rajiv; Steineck, Gunnar; Kiltie, Anne E; Kong, Augustine; Thorsteinsdottir, Unnur; Stefansson, Kari; Kiemeney, Lambertus A

    2011-11-01

    Three genome-wide association studies in Europe and the USA have reported eight urinary bladder cancer (UBC) susceptibility loci. Using extended case and control series and 1000 Genomes imputations of 5 340 737 single-nucleotide polymorphisms (SNPs), we searched for additional loci in the European GWAS. The discovery sample set consisted of 1631 cases and 3822 controls from the Netherlands and 603 cases and 37 781 controls from Iceland. For follow-up, we used 3790 cases and 7507 controls from 13 sample sets of European and Iranian ancestry. Based on the discovery analysis, we followed up signals in the urea transporter (UT) gene SLC14A. The strongest signal at this locus was represented by a SNP in intron 3, rs17674580, that reached genome-wide significance in the overall analysis of the discovery and follow-up groups: odds ratio = 1.17, P = 7.6 × 10(-11). SLC14A1 codes for UTs that define the Kidd blood group and are crucial for the maintenance of a constant urea concentration gradient in the renal medulla and, through this, the kidney's ability to concentrate urine. It is speculated that rs17674580, or other sequence variants in LD with it, indirectly modifies UBC risk by affecting urine production. If confirmed, this would support the 'urogenous contact hypothesis' that urine production and voiding frequency modify the risk of UBC.

  1. Association of NOS2 and NOS3 gene polymorphisms with susceptibility to type 2 diabetes mellitus and diabetic nephropathy in the Chinese Han population.

    PubMed

    Chen, Feng; Li, Yu-Mei; Yang, Lin-Qing; Zhong, Cai-Gao; Zhuang, Zhi-Xiong

    2016-07-01

    Inducible nitric oxide synthase (NOS2) and endothelial nitric oxide synthase (NOS3) gene play important roles in the susceptibility to type 2 diabetes mellitus (T2DM). The present study aims to detect the potential association of NOS2 and NOS3 gene polymorphisms with the susceptibility toT2DM and diabetic nephropathy (DN) in the Chinese Han population. Four hundred and ninety T2DM patients and 485 healthy controls were enrolled in this case-control study. The genotypes of NOS2 and NOS3 gene polymorphisms were analyzed by the polymerase chain reaction (PCR)-ligase detection reaction (LDR) method. Our data demonstrated that the NOS2 rs2779248 and NOS2 rs1137933 genetic polymorphisms were significantly associated with the increased susceptibility to T2DM in the heterozygote comparison, dominant model, and allele contrast; and NOS3 rs3918188 genetic polymorphism was significantly associated with the increased susceptibility to T2DM in the homozygote comparison and recessive model. The allele-C and genotype-TC of NOS2 rs2779248, allele-A and genotype-GA of NOS2 rs1137933 and genotype-AA of NOS3 rs3918188 genetic polymorphisms might be the risk factors for increasing the susceptibility to T2DM. And a significant haplotype effect of NOS2 rs10459953/C- rs1137933/G- rs2779248/T was found between T2DM cases and controls. Moreover, NOS3 rs1800783 polymorphism was significantly associated with the increased susceptibility to DN in the heterozygote comparison, recessive model and allele contrast. At last, a positive correlation of family history of diabetes with NOS3 rs11771443 polymorphism was found in DN. These preliminary findings indicate that the NOS2 rs2779248, NOS2 rs1137933, and NOS3 rs3918188 genetic polymorphisms are potentially related to the susceptibility to T2DM, and the rs1800783 polymorphism might be considered as genetic risk factors for diabetic nephropathy, and family history of diabetes was closely associated with rs11771443 polymorphism in DN, and the

  2. Genetic association of KCNJ10 rs1130183 with seizure susceptibility and computational analysis of deleterious non-synonymous SNPs of KCNJ10 gene.

    PubMed

    Phani, Nagaraja M; Acharya, Shreeshakala; Xavy, Seethu; Bhaskaranand, Nalini; Bhat, Manoj K; Jain, Aditya; Rai, Padmalatha S; Satyamoorthy, Kapaettu; Kapaettu, Satyamoorthy

    2014-02-25

    Establishing genetic basis of Idiopathic generalized epilepsies (IGE) is challenging because of their complex inheritance pattern and genetic heterogeneity. Kir4.1 inwardly rectifying channel (KCNJ10) is one of the independent genes reported to be associated with seizure susceptibility. In the current study we have performed a comprehensive in silico analysis of genetic variants in KCNJ10 gene at functional and structural level along with a case-control analysis for the association of rs1130183 (R271C) polymorphism in Indian patients with IGE. Age and sex matched 108 epileptic patients and normal healthy controls were examined. Genotyping of KCNJ10rs1130183 variation was performed using PCR-RFLP method. The risk association was determined by using odds ratio and 95% confidence interval. Functional effects of non-synonymous SNPs (nsSNPs) in KCNJ10 gene were analyzed using SIFT PolyPhen-2, I-Mutant 2.0, PANTHER and FASTSNP. Subsequently, homology modeling of protein three dimensional (3D) structures was performed using Modeller tool (9.10v) and compared the native protein with mutant for assessment of structure and stability. SIFT, PolyPhen-2, I-Mutant 2.0 and PANTHER collectively showed rs1130183, rs1130182 and rs137853073 SNPs inKCNJ10 gene affect protein structure and function. There was a considerable variation in the Root Mean Square Deviation (RMSD) value between the native and mutant structure (1.17Ǻ). Association analysis indicate KCNJ10rs1130183 did not contribute to risk of seizure susceptibility in Indian patients with IGE (OR- 0.38; 95%CI, 0.07-2.05) and T allele frequency (0.02%) was in concordance with dbSNP reports. This study identifies potential SNPs that may contribute to seizure susceptibility and further studies with the selected SNPs in larger number of samples and their functional analysis is required for understanding the variants of KCNJ10 with seizure susceptibility.

  3. Breast cancer risk associated with genotype polymorphism of the catechol estrogen-metabolizing genes: a multigenic study on cancer susceptibility.

    PubMed

    Cheng, Ting-Chih; Chen, Shou-Tung; Huang, Chiun-Sheng; Fu, Yi-Ping; Yu, Jyh-Cherng; Cheng, Chun-Wen; Wu, Pei-Ei; Shen, Chen-Yang

    2005-01-20

    Estrogen has been suggested to trigger breast cancer development via an initiating mechanism involving its metabolite, catechol estrogen (CE). To examine this hypothesis, we carried out a multigenic case-control study of 469 incident breast cancer patients and 740 healthy controls to define the role of important genes involved in the different metabolic steps that protect against the potentially harmful effects of CE metabolism. We studied the 3 genes involved in CE detoxification by conjugation reactions involving methylation (catechol-O-methyltransferase, COMT), sulfation (sulfotransferase 1A1, SULT1A1), or glucuronidation (UDP-glucuronosyltransferase 1A1, UGT1A1), one (manganese superoxide dismutase, MnSOD) involved in protection against reactive oxidative species-mediated oxidation during the conversion of CE-semiquinone (CE-SQ) to CE-quinone (CE-Q), and 2 of the glutathione S-transferase superfamily, GSTM1 and GSTT1, involved in CE-Q metabolism. Support for this hypothesis came from the observations that (i) there was a trend toward an increased risk of breast cancer in women harboring a greater number of putative high-risk genotypes of these genes (p < 0.05); (ii) this association was stronger and more significant in those women who were more susceptible to estrogen [no history of pregnancy or older (> or =26 years) at first full-term pregnancy (FFTP)]; and (iii) the risks associated with having one or more high-risk genotypes were not the same in women having experienced different menarche-to-FFTP intervals, being more significant in women having been exposed to estrogen for a longer period (> or =12 years) before FFTP. Furthermore, because CE-Q can attack DNA, leading to the formation of double-strand breaks (DSB), we examined whether the relationship between cancer risk and the genotypic polymorphism of CE-metabolizing genes was modified by the genotypes of DSB repair genes, and found that a joint effect of CE-metabolizing genes and one of the two DSB

  4. Parameter Space of Fixed Points of the Damped Driven Pendulum Susceptible to Control of Chaos Algorithms

    NASA Astrophysics Data System (ADS)

    Dittmore, Andrew; Trail, Collin; Olsen, Thomas; Wiener, Richard J.

    2003-11-01

    We have previously demonstrated the experimental control of chaos in a Modified Taylor-Couette system with hourglass geometry( Richard J. Wiener et al), Phys. Rev. Lett. 83, 2340 (1999).. Identifying fixed points susceptible to algorithms for the control of chaos is key. We seek to learn about this process in the accessible numerical model of the damped, driven pendulum. Following Baker(Gregory L. Baker, Am. J. Phys. 63), 832 (1995)., we seek points susceptible to the OGY(E. Ott, C. Grebogi, and J. A. Yorke, Phys. Rev. Lett. 64), 1196 (1990). algorithm. We automate the search for fixed points that are candidates for control. We present comparisons of the space of candidate fixed points with the bifurcation diagrams and Poincare sections of the system. We demonstrate control at fixed points which do not appear on the attractor. We also show that the control algorithm may be employed to shift the system between non-communicating branches of the attractor.

  5. A Distinct and Replicable Squamous Cell Carcinoma Gene INPPA5 Variant Modifies Susceptibility of Arsenic-Associated Skin Lesions in Bangladesh

    PubMed Central

    Seow, Wei Jie; Pan, Wen-Chi; Kile, Molly L.; Lin, Tong; Baccarelli, Andrea; Quamruzzaman, Quazi; Rahman, Mahmuder; Mostofa, Golam; Rakibuz-Zaman, Muhammad; Kibriya, Muhammad; Ahsan, Habibul; Lin, Xihong; Christiani, David C.

    2015-01-01

    Background Single nucleotide polymorphisms (SNPs) in inflammation, one-carbon metabolism and skin cancer genes might influence susceptibility to arsenic-induced skin lesions. Methods A case-control study was conducted in Pabna, Bangladesh (2001-2003) and drinking water arsenic concentration was measured for each participant. A panel of twenty-five candidate SNPs was analyzed in 540 cases and 400 controls. Logistic regression was used to estimate the association between each SNP and the potential for gene-environment interactions in skin lesion risk adjusting for relevant covariates. Replication testing was conducted in an independent Bangladesh population with 488 cases and 2,794 controls. Results In the discovery population, genetic variants in the one-carbon metabolism genes PEMT (rs2278952, P for interaction = 0.004; rs897453, P for interaction = 0.05) and DHFR (rs1650697, P for interaction = 0.02), inflammation gene IL10 (rs3024496, P for interaction = 0.04), and skin cancer genes INPP5A (rs1133400, P for interaction = 0.03) and XPC (rs2228000, P for interaction = 0.01) significantly modified the association between arsenic and skin lesions after adjusting for multiple comparisons. The significant gene-environment interaction between a SNP in INPP5A gene (rs1133400) and water arsenic on skin lesion risk was successfully replicated in an independent population (P for interaction = 0.03). Conclusion Minor allele carriers of skin cancer gene INPP5A modified odds of arsenic-induced skin lesions in both main and replicative populations. Genetic variation in INPP5A appears to have a role in susceptibility to arsenic toxicity. PMID:25759212

  6. [Transcriptional control of ciliary genes].

    PubMed

    Vieillard, Jennifer; Jerber, Julie; Durand, Bénédicte

    2014-11-01

    Cilia are found in many eukaryotic species and share a common microtubule architecture that can nonetheless show very diverse features within one animal. The genesis of cilia and their diversity require the expression of different specific genes. At least two classes of transcription factors are involved in ciliogenesis: the RFX family, essential for the assembly of most cilia and the FOXJ1 transcription factors that are key regulators of motile cilia assembly. These two different families of transcription factors have both specific and common target genes and they can also cooperate for the formation of cilia. In collaboration with cell type specific factors, they also contribute to the specialisation of cilia. As a consequence, the identification of RFX and FOXJ1 target genes has emerged as an efficient strategy to identify novel ciliary genes, and in particular genes potentially implicated in ciliopathies.

  7. Molecular network, pathway, and functional analysis of time-dependent gene changes associated with pancreatic cancer susceptibility to oncolytic vaccinia virotherapy

    PubMed Central

    Haddad, Dana; Socci, Nicholas; Chen, Chun-Hao; Chen, Nanhai G; Zhang, Qian; Carpenter, Susanne G; Mittra, Arjun; Szalay, Aladar A; Fong, Yuman

    2016-01-01

    Background: Pancreatic cancer is a fatal disease associated with resistance to conventional therapies. This study aimed to determine changes in gene expression patterns associated with infection and susceptibility of pancreatic cancer cells to an oncolyticvaccinia virus, GLV-1h153, carrying the human sodium iodide symporter for deep tissue imaging of virotherapy. Methods: Replication and susceptibility of pancreatic adenocarcinoma PANC-1 cells to GLV-1h153 was confirmed with replication and cytotoxicity assays. PANC-1 cells were then infected with GLV-1h153 and near-synchronous infection confirmed via flow cytometry of viral-induced green fluorescent protein (GFP) expression. Six and 24 hours after infection, three samples of each time point were harvested, and gene expression patterns assessed using HG-U133A cDNA microarray chips as compared to uninfected control. Differentially expressed genes were identified using Bioconductor LIMMA statistical analysis package. A fold change of 2.0 or above was used as a cutoff, with a P value of 0.01. The gene list was then analyzed using Ingenuity Pathways Analysis software. Results: Differential gene analysis revealed a total of 12,412 up- and 11,065 downregulated genes at 6 and 24 hours postinfection with GLV-1h153 as compared to control. At 6 hours postinfection. A total of 139 genes were either up or downregulated >twofold (false discovery rate < 0.05), of which 124 were mapped by Ingenuity Pathway Analysis (IPA). By 24 hours postinfection, a total of 5,698 genes were identified and 5,563 mapped by IPA. Microarray revealed gene expression changes, with gene networks demonstrating downregulation of processes such as cell death, cell cycle, and DNA repair, and upregulation of infection mechanisms (P < 0.01). Six hours after infection, gene changes involved pathways such as HMGB-1, interleukin (IL)-2, IL-6, IL-8, janus kinase/signal tranducer and activator of transcription (JAK/STAT), interferon, and ERK 5 signaling (P < 0

  8. Comparison of adhesin genes and antimicrobial susceptibilities between uropathogenic and intestinal commensal Escherichia coli strains.

    PubMed

    Qin, Xiaohua; Hu, Fupin; Wu, Shi; Ye, Xinyu; Zhu, Demei; Zhang, Ying; Wang, Minggui

    2013-01-01

    The presence of adhesins is arguably an important determinant of pathogenicity for Uropathogenic Escherichia coli (UPEC). Antimicrobial susceptibilities were tested by agar dilution method, fifteen adhesin genes were detected by polymerase chain reaction, and multilocus sequence typing (MLST) was analyzed in 70 UPEC isolates and 41 commensal E. coli strains. Extended-spectrum β-lactamase (ESBL) was determined with confirmatory test. The prevalence of ESBL-producers in UPEC (53%, 37/70) was higher than the commensal intestinal isolates (7%, 3/41), and 97% (36/37) of the ESBL-producing UPEC harbored bla CTX-M genes. afa was present in 36% (10/28) UPEC isolates from recurrent lower urinary tract infection (UTI), and none in the acute pyelonephritis, acute uncomplicated cystitis or commensal strains (P<0.0001). papG was detected in 28% (20/70) of UPEC isolates, while 5% (2/41) of the commensal strains were papG positive (P = 0.0025), and the prevalence of papG was significantly higher in acute pyelonephritis group (71%) than the other two UTI groups (P<0.0001). The prevalence of flu, yqi, yadN and ygiL was significantly higher in UPEC isolates than in the commensal strains. ESBL-producing UPEC showed a lower prevalence of adhesin genes compared with non-ESBL-producing strains. The MLST profiles were different between UPEC and commensal strains, with ST131 (19%, 13/70) and ST10 (20%, 8/41) being the most common MLSTs, respectively. This study demonstrated that several adhesin genes were more prevalent in UPEC isolates than in commensal E. coli, and afa may be associated with recurrent lower UTI whereas papG is more frequently associated with acute pyelonephritis.

  9. Mechanisms of control of gene expression

    SciTech Connect

    Cullen, B.; Gage, L.P.; Siddiqui, M.A.Q.; Skalka, A.M.; Weissbach, H.

    1987-01-01

    This book examines an array of topics on the regulation of gene expression, including an examination of DNA-protein interactions and the role of oncogene proteins in normal and abnormal cellular responses. The book focuses on the control of mRNA transcription in eykaryotes and delineates other areas including gene regulation in prokaryotes and control of stable RNA synthesis.

  10. The Circadian Rhythm Gene Arntl2 Is a Metastasis Susceptibility Gene for Estrogen Receptor-Negative Breast Cancer

    PubMed Central

    Ha, Ngoc-Han; Long, Jirong; Cai, Qiuyin; Shu, Xiao Ou

    2016-01-01

    Breast cancer mortality is primarily due to metastasis rather than primary tumors, yet relatively little is understood regarding the etiology of metastatic breast cancer. Previously, using a mouse genetics approach, we demonstrated that inherited germline polymorphisms contribute to metastatic disease, and that these single nucleotide polymorphisms (SNPs) could be used to predict outcome in breast cancer patients. In this study, a backcross between a highly metastatic (FVB/NJ) and low metastatic (MOLF/EiJ) mouse strain identified Arntl2, a gene encoding a circadian rhythm transcription factor, as a metastasis susceptibility gene associated with progression, specifically in estrogen receptor-negative breast cancer patients. Integrated whole genome sequence analysis with DNase hypersensitivity sites reveals SNPs in the predicted promoter of Arntl2. Using CRISPR/Cas9-mediated substitution of the MOLF promoter, we demonstrate that the SNPs regulate Arntl2 transcription and affect metastatic burden. Finally, analysis of SNPs associated with ARNTL2 expression in human breast cancer patients revealed reproducible associations of ARNTL2 expression quantitative trait loci (eQTL) SNPs with disease-free survival, consistent with the mouse studies. PMID:27656887

  11. Interaction of KIR genes and G1M immunoglobulin allotypes confer susceptibility to type 2 diabetes in Puerto Rican Americans.

    PubMed

    Zuniga, Joaquin; Romero, Viviana; Azocar, Jose; Stern, Joel N H; Clavijo, Olga; Almeciga, Ingrid; Encinales, Liliana; Avendano, Angel; Fridkis-Hareli, Masha; Pandey, Janardan P; Yunis, Edmond J

    2006-11-01

    The susceptibility to type 2 diabetes (T2D) involves genetic factors. We studied the distribution of KIR and MHC class I ligands phenotype and genotype frequencies, as well as immunoglobulin KM and GM allotype frequencies in a group of patients (N = 95) with T2D and ethnically matched healthy controls (N = 74) with Puerto Rican ethnic background. We found a slight increase of the 2DL3/2DL3 homozygous genotype in T2D. Moreover, the association between 2DL3/2DL3 genotype was significant in the presence of 2DS4 (pC = 0.01). Also, we observed an epistatic effect of the interaction of 2DL3/2DL3, 2DS4 with allele z of G1M in T2D (pC = 0.004, OR = 3.60, 95% CI, 1.62-8.10). This genetic interaction between KIR and G1M allotypes, associated with T2D, was also significant by multiple logistic regression analysis (p < 0.0001, OR = 4.90, 95% CI, 2.12-11.3). We did not detect population stratification using unlinked short tandem repeat (STR) markers, demonstrating that the patients and controls were ethnically matched. Hence, we have demonstrated in this study an epistatic interaction between KIR genes and the G1M allotype that influences the susceptibility to T2D in Puerto Rican Americans. Our findings are important for understanding the autoimmune or innate immune inflammatory-mediated mechanisms involved in the pathogenesis of T2D.

  12. Vascular endothelial growth factor gene polymorphisms and psoriasis susceptibility: a meta-analysis.

    PubMed

    Lee, Y H; Song, G G

    2015-01-01

    The aim of this study was to explore whether vascular endothelial growth factor (VEGF) polymorphisms confer susceptibility to psoriasis. Meta-analyses were conducted to examine the associations between the +405 C/G, -460 C/T, -1154 A/G, and -2578 A/C polymorphisms of VEGF and psoriasis using allele contrast and recessive, dominant, and additive models. Seven studies on VEGF polymorphisms and psoriasis involving 1956 subjects (psoriasis patients 665, controls 1291) were included in this meta-analysis. We observed no association between psoriasis and the VEGF +405 C allele in all study subjects (odds ratio = 0.984, 95% confidence interval = 0.754-1.285, P = 0.906), but stratification by ethnicity indicated a significant association between the VEGF +405 C allele and psoriasis in Asians (odds ratio = 0.762, 95% confidence interval = 0.628-0.923, P = 0.005). In addition, we observed a significant association between the VEGF -460 C allele and psoriasis in Europeans (odds ratio = 0.807, 95% confidence interval = 0.672-0.968, P = 0.021). Meta-analyses of the -1154 A/G polymorphism also revealed a significant association with psoriasis in Europeans. However, the VEGF -2578 A/C polymorphism showed no association in all subjects or in Europeans or Asians. This meta-analysis suggests the VEGF +405 C/G polymorphism confers susceptibility to psoriasis in Asians, and that the -460 C/T and -1154 A/G polymorphisms confer susceptibility to psoriasis in Europeans. PMID:26600499

  13. A modifier screen identifies DNAJB6 as a cardiomyopathy susceptibility gene

    PubMed Central

    Ding, Yonghe; Long, Pamela A.; Bos, J. Martijn; Shih, Yu-Huan; Ma, Xiao; Sundsbak, Rhianna S.; Chen, Jianhua; Jiang, Yiwen; Zhao, Liqun; Hu, Xinyang; Wang, Jianan; Shi, Yongyong; Ackerman, Michael J.; Lin, Xueying; Ekker, Stephen C.; Redfield, Margaret M.; Olson, Timothy M.; Xu, Xiaolei

    2016-01-01

    Mutagenesis screening is a powerful forward genetic approach that has been successfully applied in lower-model organisms to discover genetic factors for biological processes. This phenotype-based approach has yet to be established in vertebrates for probing major human diseases, largely because of the complexity of colony management. Herein, we report a rapid strategy for identifying genetic modifiers of cardiomyopathy (CM). Based on the application of doxorubicin stress to zebrafish insertional cardiac (ZIC) mutants, we identified 4 candidate CM-modifying genes, of which 3 have been linked previously to CM. The long isoform of DnaJ (Hsp40) homolog, subfamily B, member 6b (dnajb6b(L)) was identified as a CM susceptibility gene, supported by identification of rare variants in its human ortholog DNAJB6 from CM patients. Mechanistic studies indicated that the deleterious, loss-of-function modifying effects of dnajb6b(L) can be ameliorated by inhibition of ER stress. In contrast, overexpression of dnajb6(L) exerts cardioprotective effects on both fish and mouse CM models. Together, our findings establish a mutagenesis screening strategy that is scalable for systematic identification of genetic modifiers of CM, feasible to suggest therapeutic targets, and expandable to other major human diseases.

  14. Disentangling fetal and maternal susceptibility for pre-eclampsia: a British multicenter candidate-gene study.

    PubMed

    2005-07-01

    The Genetics of Pre-Eclampsia (GOPEC) collaboration aims to identify genetic factors in U.K. families affected by pre-eclampsia. A number of genetic studies have reported associations with pre-eclampsia, but attempts to replicate these findings have yielded inconsistent results. We describe the results of extensive genotyping of seven candidate genes previously reported as conferring susceptibility to pre-eclampsia. Six hundred fifty-seven women affected by pre-eclampsia and their families were genotyped at 28 single-nucleotide polymorphisms in the genes encoding angiotensinogen, the angiotensin receptors, factor V Leiden variant, methylene tetrahydrofolate reductase, nitric oxide synthase, and TNFalpha. Genotypes were analyzed by the transmission/disequilibrium test. Genotype risk ratios (GRRs) associated with maternal genotypes had a range of 0.70-1.16; GRRs associated with fetal genotypes had a range of 0.72-1.11. No GRR achieved the prespecified criteria for statistical significance (posterior probability >.05). We conclude that none of the genetic variants tested in this large study of strictly defined pre-eclamptic pregnancies confers a high risk of disease. The results emphasize the importance of conducting rigorously designed studies of adequate size to provide precise genetic risks with narrow confidence intervals, if overreporting of false-positive results is to be avoided.

  15. A modifier screen identifies DNAJB6 as a cardiomyopathy susceptibility gene

    PubMed Central

    Ding, Yonghe; Long, Pamela A.; Bos, J. Martijn; Shih, Yu-Huan; Ma, Xiao; Sundsbak, Rhianna S.; Chen, Jianhua; Zhao, Liqun; Hu, Xinyang; Wang, Jianan; Shi, Yongyong; Ackerman, Michael J.; Lin, Xueying; Ekker, Stephen C.; Redfield, Margaret M.; Olson, Timothy M.

    2016-01-01

    Mutagenesis screening is a powerful forward genetic approach that has been successfully applied in lower-model organisms to discover genetic factors for biological processes. This phenotype-based approach has yet to be established in vertebrates for probing major human diseases, largely because of the complexity of colony management. Herein, we report a rapid strategy for identifying genetic modifiers of cardiomyopathy (CM). Based on the application of doxorubicin stress to zebrafish insertional cardiac (ZIC) mutants, we identified 4 candidate CM-modifying genes, of which 3 have been linked previously to CM. The long isoform of DnaJ (Hsp40) homolog, subfamily B, member 6b (dnajb6b(L)) was identified as a CM susceptibility gene, supported by identification of rare variants in its human ortholog DNAJB6 from CM patients. Mechanistic studies indicated that the deleterious, loss-of-function modifying effects of dnajb6b(L) can be ameliorated by inhibition of ER stress. In contrast, overexpression of dnajb6(L) exerts cardioprotective effects on both fish and mouse CM models. Together, our findings establish a mutagenesis screening strategy that is scalable for systematic identification of genetic modifiers of CM, feasible to suggest therapeutic targets, and expandable to other major human diseases. PMID:27642634

  16. Enhanced disease susceptibility 1 and salicylic acid act redundantly to regulate resistance gene-mediated signaling.

    PubMed

    Venugopal, Srivathsa C; Jeong, Rae-Dong; Mandal, Mihir K; Zhu, Shifeng; Chandra-Shekara, A C; Xia, Ye; Hersh, Matthew; Stromberg, Arnold J; Navarre, DuRoy; Kachroo, Aardra; Kachroo, Pradeep

    2009-07-01

    Resistance (R) protein-associated pathways are well known to participate in defense against a variety of microbial pathogens. Salicylic acid (SA) and its associated proteinaceous signaling components, including enhanced disease susceptibility 1 (EDS1), non-race-specific disease resistance 1 (NDR1), phytoalexin deficient 4 (PAD4), senescence associated gene 101 (SAG101), and EDS5, have been identified as components of resistance derived from many R proteins. Here, we show that EDS1 and SA fulfill redundant functions in defense signaling mediated by R proteins, which were thought to function independent of EDS1 and/or SA. Simultaneous mutations in EDS1 and the SA-synthesizing enzyme SID2 compromised hypersensitive response and/or resistance mediated by R proteins that contain coiled coil domains at their N-terminal ends. Furthermore, the expression of R genes and the associated defense signaling induced in response to a reduction in the level of oleic acid were also suppressed by compromising SA biosynthesis in the eds1 mutant background. The functional redundancy with SA was specific to EDS1. Results presented here redefine our understanding of the roles of EDS1 and SA in plant defense.

  17. Circadian Gene Variants and Susceptibility to Type 2 Diabetes: A Pilot Study

    PubMed Central

    Kelly, M. Ann; Rees, Simon D.; Hydrie, M. Zafar I.; Shera, A. Samad; Bellary, Srikanth; O’Hare, J. Paul; Kumar, Sudhesh; Taheri, Shahrad; Basit, Abdul; Barnett, Anthony H.

    2012-01-01

    Background Disruption of endogenous circadian rhythms has been shown to increase the risk of developing type 2 diabetes, suggesting that circadian genes might play a role in determining disease susceptibility. We present the results of a pilot study investigating the association between type 2 diabetes and selected single nucleotide polymorphisms (SNPs) in/near nine circadian genes. The variants were chosen based on their previously reported association with prostate cancer, a disease that has been suggested to have a genetic link with type 2 diabetes through a number of shared inherited risk determinants. Methodology/Principal Findings The pilot study was performed using two genetically homogeneous Punjabi cohorts, one resident in the United Kingdom and one indigenous to Pakistan. Subjects with (N = 1732) and without (N = 1780) type 2 diabetes were genotyped for thirteen circadian variants using a competitive allele-specific polymerase chain reaction method. Associations between the SNPs and type 2 diabetes were investigated using logistic regression. The results were also combined with in silico data from other South Asian datasets (SAT2D consortium) and white European cohorts (DIAGRAM+) using meta-analysis. The rs7602358G allele near PER2 was negatively associated with type 2 diabetes in our Punjabi cohorts (combined odds ratio [OR] = 0.75 [0.66–0.86], p = 3.18×10−5), while the BMAL1 rs11022775T allele was associated with an increased risk of the disease (combined OR = 1.22 [1.07–1.39], p = 0.003). Neither of these associations was replicated in the SAT2D or DIAGRAM+ datasets, however. Meta-analysis of all the cohorts identified disease associations with two variants, rs2292912 in CRY2 and rs12315175 near CRY1, although statistical significance was nominal (combined OR = 1.05 [1.01–1.08], p = 0.008 and OR = 0.95 [0.91–0.99], p = 0.015 respectively). Conclusions/significance None of the selected circadian gene

  18. Dogs and Humans Share a Common Susceptibility Gene SRBD1 for Glaucoma Risk

    PubMed Central

    Kanemaki, Nobuyuki; Tchedre, Kissaou T.; Imayasu, Masaki; Kawarai, Shinpei; Sakaguchi, Masahiro; Yoshino, Atsushi; Itoh, Norihiko; Meguro, Akira; Mizuki, Nobuhisa

    2013-01-01

    Glaucoma is a degenerative optic neuropathy that is associated with elevated intraocular pressure. Primary open angle glaucoma is the most common type of glaucoma in canines, and its highest incidence among dog breeds has been reported in Shiba-Inus, followed by Shih-Tzus. These breeds are known to have an abnormal iridocorneal angle and dysplastic prectinate ligament. However, the hereditary and genetic backgrounds of these dogs have not yet been clarified. In this study, we investigated the association between polymorphisms of the glaucoma candidate genes, SRBD1, ELOVL5, and ADAMTS10, and glaucoma in Shiba-Inus and Shih-Tzus. We analyzed 11 polymorphisms in these three genes using direct DNA sequencing. Three SRBD1 SNPs, rs8655283, rs22018514 and rs22018513 were significantly associated with glaucoma in Shiba-Inus, while rs22018513, a synonymous SNP in exon 4, showed the strongest association (P = 0.00039, OR = 3.03). Conditional analysis revealed that rs22018513 could account for most of the association of these SNPs with glaucoma in Shiba-Inus. In Shih-Tzus, only rs9172407 in the SRBD1 intron 1 was significantly associated with glaucoma (P = 0.0014, OR = 5.25). There were no significant associations between the ELOVL5 or ADAMTS10 polymorphisms and glaucoma in Shiba-Inus and Shih-Tzus. The results showed that SRBD1 polymorphisms play an important role in glaucoma pathology in both Shiba-Inus and Shih-Tzus. SRBD1 polymorphisms have also been associated with normal- and high-tension glaucomas in humans. Therefore, SRBD1 may be a common susceptibility gene for glaucoma in humans and dogs. We anticipate that the nucleotide sequencing data from this study can be used in genetic testing to determine for the first time, the genetic status and susceptibility of glaucoma in dogs, with high precision. Moreover, canine glaucoma resulting from SRBD1 polymorphisms could be a useful animal model to study human glaucoma. PMID:24040232

  19. Phenotypic antimicrobial susceptibility and occurrence of selected resistance genes in gram-positive mastitis pathogens isolated from Wisconsin dairy cows.

    PubMed

    Ruegg, P L; Oliveira, L; Jin, W; Okwumabua, O

    2015-07-01

    In the United States, few intramammary antimicrobials exist that are approved for treatment of bovine mastitis; thus, ensuring judicious use of these products is a priority. The objectives of this study were to determine phenotypic susceptibility and presence of selected antimicrobial resistance genes from staphylococci, streptococci, and streptococcal-like organisms recovered from cases of clinical mastitis occurring in cows on large Wisconsin farms. Staphylococcus aureus (n=35 from 19 herds), coagulase-negative staphylococci (n=51 from 30 herds), Streptococcus spp. (n=78 from 36 herds), and streptococcal-like organisms (n=31 from 19 herds) were used in this study. All Staphylococcus spp. were susceptible to ceftiofur, cephalothin, and the combination of penicillin and novobiocin. Of all staphylococci, only a single Staphylococcus epidermidis exhibited phenotypic resistance to oxacillin. Phenotypic susceptibility to erythromycin was observed in only 8.6 and 15.7% of Staphylococcus aureus and coagulase-negative staphylococci, respectively. Approximately 20% of staphylococci and 13 to 22% of streptococci and streptococcal-like organisms exhibited phenotypic resistance to pirlimycin. All Streptococcus spp. exhibited phenotypic susceptibility to ceftiofur, cephalothin, and oxacillin. The proportion of isolates exhibiting phenotypic susceptibility to pirlimycin and sulfadimethoxine differed among Streptococcus dysgalactiae and Streptococcus uberis. All streptococcal-like organisms exhibited phenotypic susceptibility to ceftiofur, cephalothin, oxacillin, penicillin, and the combination of penicillin and novobiocin. Of all organisms tested, 36.9% did not carry any of the resistance genes (ermC, blaZ, tetK, or tetM), 35.4% carried 1 gene, and 27.7% carried multiple genes (usually blaZ in combination with a tet gene). Eighteen (51.4%) Staph. aureus and 12 (48.0%) Staphylococcus chromogenes carried multiple resistance genes. Six (12.2%) Strep. dysgalactiae and no Strep

  20. Association between plasminogen activator inhibitor-1 4G/5G gene polymorphism and immunoglobulin A nephropathy susceptibility.

    PubMed

    Zhou, Tian-Biao; Jiang, Zong-Pei

    2015-02-01

    The association between plasminogen activator inhibitor-1 (PAI-1) 4 G/5 G gene polymorphism and immunoglobulin A nephropathy (IgAN) risk is still controversial. A meta-analysis was performed to evaluate the association between PAI-1 4 G/5 G gene polymorphism and IgAN susceptibility. A predefined literature search and selection of eligible relevant studies were performed to collect data from electronic database. Four articles were identified for the analysis of association between PAI-1 4 G/5 G gene polymorphism and IgAN risk. 4 G allele was not associated with IgAN susceptibility in overall populations and in Asians. Furthermore, 4 G/4 G and 5 G/5 G genotype were not associated with IgAN for overall populations, Asians. In conclusion, PAI-1 4 G/5 G gene polymorphism was not associated with IgAN risk in overall populations and in Asians. However, more studies should be performed in the future.

  1. Simulated microgravity affects ciprofloxacin susceptibility and expression of acrAB-tolC genes in E. coli ATCC25922

    PubMed Central

    Xu, Bingxin; Li, Chenglin; Zheng, Yanhua; Si, Shaoyan; Shi, Yuhua; Huang, Yuling; Zhang, Jianzhong; Cui, Yan; Cui, Yimin

    2015-01-01

    As a representative fluoroquinolone antibacterial, ciprofloxacin is frequently used to treat infections caused by bacteria such as E. coli. It is much meaningful to explore ciprofloxacin susceptibility and investigate a possible mechanism of drug susceptibility changes in E. coli ATCC25922 exposed to the environmental stress of simulated microgravity. The subculture of E. coli lasted for 7 days under simulated microgravity conditions (SMG) and normal microgravity (NG) conditions. On the 8th day, the cultures were divided into three groups: (1) NG group (continuous NG cultures); (2) SMG group (continuous SMG cultures); (3) SMCNG group (simulated microgravity change into normal gravity cultures). Ciprofloxacin (a final concentration of 0.125 μg/ml) sensitivity and expression of acrAB-tolC genes were detected in E. coli cells. The count and percentage of viable cells in the SMG cultures bacteria exposed to ciprofloxacin were higher than that in NG cultures and reduced to the levels of NG group when they were subcultivated from SMG to NG. The expressions of efflux pump genes (acrA, acrB and tolC) were upregulated in SMG culture and downregulated to the levels of NG group when they were subcultivated from SMG to NG. Susceptibility to ciprofloxacin and expression of acrAB-tolC genes in E. coli could be reversibly affected by SMG conditions. Over expression of efflux pump genes acrAB-tolC perhaps played an important role in decreased CIP susceptibility under SMG. PMID:26339360

  2. cDNA microarray analysis of gene expression in insecticide-susceptible and –resistant Tarnished Plant bug

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Insecticide resistance in the tarnished plant bug is most likely associated with increased detoxification gene expression. To better understand the molecular mechanisms of insecticide resistance, an insecticide-susceptible laboratory colony and several resistant field-collected strains of Lygus line...

  3. Identification of susceptibility genes in non-syndromic cleft lip with or without cleft palate using whole-exome sequencing

    PubMed Central

    Liu, Ya-Peng; Xu, Li-Fang; Wang, Qi; Zhou, Xiao-Long; Zhou, Ji-Long; Pan, Chen; Zhang, Jin-Peng; Wu, Qin-Rong; Li, Yi-Qun; Xia, Yu-Juan; Peng, Xiu; Zhang, Mei-Rong; Yu, Hong-Min

    2015-01-01

    Background Non-syndromic cleft lip with or without cleft palate (NSCL/P) is among the most common congenital malformations. The etiology of NSCL/P remains poorly characterized owing to its complex genetic heterogeneity. The objective of this study was to identify genetic variants that increase susceptibility to NSCL/P. Material and Methods Whole-exome sequencing (WES) was performed in 8 fetuses with NSCL/P in China. Bioinformatics analysis was performed using commercially available software. Variants detected by WES were validated by Sanger sequencing. Results By filtering out synonymous variants in exons, we identified average 8575 nonsynonymous single nucleotide variants (SNVs). We subsequently compared the SNVs against public databases including NCBI dbSNP build 135 and 1000 Genomes Project and obtained an average of 203 SNVs. Total 12 reported candidate genes were verified by Sanger sequencing. Sanger sequencing also confirmed 16 novel SNVs shared by two or more samples. Conclusions We have found and confirmed 16 susceptibility genes responsible for NSCL/P, which may play important role in the etiology of NSCL/P. The susceptibility genes identified in this study will not only be useful in revealing the etiology of NSCL/P but also in diagnosis and treatment of the patients with NSCL/P. Key words:Non-syndromic cleft lip with or without cleft palate, whole-exome sequencing, sanger sequencing, susceptibility gene, single nucleotide variants (SNVs). PMID:26449438

  4. Presence of the KPC carbapenemase gene in Enterobacteriaceae causing bacteremia, and the correlation with in vitro carbapenem susceptibility

    Technology Transfer Automated Retrieval System (TEKTRAN)

    During six months, we obtained Enterobacteriaceae isolates from patients with Gram-negative bacteremia at a 1250-bed teaching hospital in St. Louis, Missouri, and compared carbapenem susceptibility with the presence of blaKPC, a transferable carbapenemase gene. Three (1.2%) out of 243 isolates were ...

  5. 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

  6. The null polymorphism of the GSTM1/T1 gene is not associated with susceptibility to systemic lupus erythematosus: a meta-analysis.

    PubMed

    Lu, Lechun; Lei, Dongyun; Nong, Xiang; Guo, Meihua; Ma, Jiaqing; He, Li

    2015-02-01

    Previous studies have suggested that the null polymorphism of the glutathione S-transferases M1/T1 (GSTM1/T1) gene may be associated with the risk of developing systemic lupus erythematosus (SLE). We further explored this potential association using a meta-analysis. A systematic literature search was carried out in the scientific literature databases and we used odds ratios (OR) and 95 % confidence intervals (CIs) to evaluate the strength of this association. All statistical analyses were calculated using Stata software 11.0, and Bonferroni correction was used to adjust the p values. Nine eligible articles with 1,850 patients and 2,826 controls were identified. Our results showed the null polymorphism of the GSTM1 gene was associated with SLE in East Asians (OR 1.32, 95 % CI 1.04-1.69, p = 0.024), but not in Europeans and Africans. However, when Bonferroni corrections were applied (p = 0.05/2 = 0.025), we could not be sure of this association. We further analysed the associations between the GSTT1 gene null polymorphism and the risk of SLE. The results of this investigation showed that this null polymorphism was not associated with susceptibility to SLE in all included populations. In conclusion, the null polymorphism of GSTM1/T1 gene may not be associated with the risk of SLE. More studies are needed to confirm this lack of association between key oxidative defense genes and susceptibility to SLE in the future. PMID:25628002

  7. Candidate genes for obesity-susceptibility show enriched association within a large genome-wide association study for BMI

    PubMed Central

    Vimaleswaran, Karani S.; Tachmazidou, Ioanna; Zhao, Jing Hua; Hirschhorn, Joel N.; Dudbridge, Frank; Loos, Ruth J.F.

    2012-01-01

    Before the advent of genome-wide association studies (GWASs), hundreds of candidate genes for obesity-susceptibility had been identified through a variety of approaches. We examined whether those obesity candidate genes are enriched for associations with body mass index (BMI) compared with non-candidate genes by using data from a large-scale GWAS. A thorough literature search identified 547 candidate genes for obesity-susceptibility based on evidence from animal studies, Mendelian syndromes, linkage studies, genetic association studies and expression studies. Genomic regions were defined to include the genes ±10 kb of flanking sequence around candidate and non-candidate genes. We used summary statistics publicly available from the discovery stage of the genome-wide meta-analysis for BMI performed by the genetic investigation of anthropometric traits consortium in 123 564 individuals. Hypergeometric, rank tail-strength and gene-set enrichment analysis tests were used to test for the enrichment of association in candidate compared with non-candidate genes. The hypergeometric test of enrichment was not significant at the 5% P-value quantile (P = 0.35), but was nominally significant at the 25% quantile (P = 0.015). The rank tail-strength and gene-set enrichment tests were nominally significant for the full set of genes and borderline significant for the subset without SNPs at P < 10−7. Taken together, the observed evidence for enrichment suggests that the candidate gene approach retains some value. However, the degree of enrichment is small despite the extensive number of candidate genes and the large sample size. Studies that focus on candidate genes have only slightly increased chances of detecting associations, and are likely to miss many true effects in non-candidate genes, at least for obesity-related traits. PMID:22791748

  8. Candidate genes for obesity-susceptibility show enriched association within a large genome-wide association study for BMI.

    PubMed

    Vimaleswaran, Karani S; Tachmazidou, Ioanna; Zhao, Jing Hua; Hirschhorn, Joel N; Dudbridge, Frank; Loos, Ruth J F

    2012-10-15

    Before the advent of genome-wide association studies (GWASs), hundreds of candidate genes for obesity-susceptibility had been identified through a variety of approaches. We examined whether those obesity candidate genes are enriched for associations with body mass index (BMI) compared with non-candidate genes by using data from a large-scale GWAS. A thorough literature search identified 547 candidate genes for obesity-susceptibility based on evidence from animal studies, Mendelian syndromes, linkage studies, genetic association studies and expression studies. Genomic regions were defined to include the genes ±10 kb of flanking sequence around candidate and non-candidate genes. We used summary statistics publicly available from the discovery stage of the genome-wide meta-analysis for BMI performed by the genetic investigation of anthropometric traits consortium in 123 564 individuals. Hypergeometric, rank tail-strength and gene-set enrichment analysis tests were used to test for the enrichment of association in candidate compared with non-candidate genes. The hypergeometric test of enrichment was not significant at the 5% P-value quantile (P = 0.35), but was nominally significant at the 25% quantile (P = 0.015). The rank tail-strength and gene-set enrichment tests were nominally significant for the full set of genes and borderline significant for the subset without SNPs at P < 10(-7). Taken together, the observed evidence for enrichment suggests that the candidate gene approach retains some value. However, the degree of enrichment is small despite the extensive number of candidate genes and the large sample size. Studies that focus on candidate genes have only slightly increased chances of detecting associations, and are likely to miss many true effects in non-candidate genes, at least for obesity-related traits.

  9. DNA repair gene ERCC1 polymorphisms and glioma susceptibility among Chinese population: a meta-analysis

    PubMed Central

    Jiang, Chunming; Shen, Fang; Du, Jianmin; Wang, Xiaohua; Su, Jin; Liu, Zhanli; Huang, Xianmei

    2015-01-01

    Background: Excision repair cross complementation group 1 (ERCC1) has been shown to be involved in the progression of glioma susceptibility. However, the results remain conflict. The aim of this study was to systematically review and evaluate the role of ERCC1 C118T and C8092A polymorphisms in glioma risk among Chinese population. Methods: Related case-control studies were searched in online electronic databases. Odds ratio (OR) with its 95% confidence interval (CI) were employed to calculate the extracted data. Results: Total seven articles were retrieved, including 4426 subjects (1926 were glioma patients and 2500 were matched controls). No significant heterogeneity was found between studies (I2=0%, P>0.01). Our results demonstrated that A allele and AA genotype of ERCC1 C8092A polymorphism have a positive association with increasing the risk of glioma in the fixed-effect model (A vs. C: OR=1.13, 95% CI=1.02-1.25, P=0.02; AA vs. CC: OR=1.29, 95% CI=1.04-1.61, P=0.02; AA vs. CA+CC: OR=1.25, 95% CI=1.01-1.55, P=0.04). However, no significant relationship was found between C118T variant and glioma susceptibility. Conclusions: Our results indicated that ERCC1 C8092A, not C118T polymorphism might be a biomarker for patients with glioma among Chinese population. Future studies with more ethnicities are needed to explore the precise association. PMID:26379816

  10. Analysis of the gyrA Gene of Clinical Yersinia ruckeri Isolates with Reduced Susceptibility to Quinolones

    PubMed Central

    Gibello, Alicia; Porrero, M. Concepción; Blanco, M. Mar; Vela, Ana I.; Liébana, Pilar; Moreno, Miguel A.; Fernández-Garayzábal, José F.; Domínguez, Lucas

    2004-01-01

    Antimicrobial susceptibility of seven clinical strains of Yersinia ruckeri representative of those isolated between 1994 and 2002 from a fish farm with endemic enteric redmouth disease was studied. All isolates displayed indistinguishable pulsed-field gel electrophoresis restriction patterns, indicating that they represented a single strain. However, considering both inhibition zone diameters (IZD) and MICs, the isolates recovered in 2001-2002 formed a separate cluster with lower levels of susceptibility to all the quinolones tested, especially nalidixic acid (NA) and oxolinic acid (OA), compared with the isolates recovered between 1994 and 1998. Analysis of the PCR product of the quinolone resistance-determining region of the gyrA gene from clinical isolates of Y. ruckeri with reduced susceptibility to OA and NA revealed a single amino acid substitution, Ser-83 to Arg-83 (Escherichia coli numbering). Identical substitution was observed in induced OA-resistant mutant strains, which displayed IZD and MICs of quinolones similar to those of the clinical isolates of Y. ruckeri with reduced susceptibility to these antimicrobial agents. These data indicate in that for Y. ruckeri, the substitution of Ser by Arg at position 83 of the gyrA gene is associated with reduced susceptibility to quinolones. PMID:14711693

  11. Analysis of the gyrA gene of clinical Yersinia ruckeri isolates with reduced susceptibility to quinolones.

    PubMed

    Gibello, Alicia; Porrero, M Concepción; Blanco, M Mar; Vela, Ana I; Liébana, Pilar; Moreno, Miguel A; Fernández-Garayzábal, José F; Domínguez, Lucas

    2004-01-01

    Antimicrobial susceptibility of seven clinical strains of Yersinia ruckeri representative of those isolated between 1994 and 2002 from a fish farm with endemic enteric redmouth disease was studied. All isolates displayed indistinguishable pulsed-field gel electrophoresis restriction patterns, indicating that they represented a single strain. However, considering both inhibition zone diameters (IZD) and MICs, the isolates recovered in 2001-2002 formed a separate cluster with lower levels of susceptibility to all the quinolones tested, especially nalidixic acid (NA) and oxolinic acid (OA), compared with the isolates recovered between 1994 and 1998. Analysis of the PCR product of the quinolone resistance-determining region of the gyrA gene from clinical isolates of Y. ruckeri with reduced susceptibility to OA and NA revealed a single amino acid substitution, Ser-83 to Arg-83 (Escherichia coli numbering). Identical substitution was observed in induced OA-resistant mutant strains, which displayed IZD and MICs of quinolones similar to those of the clinical isolates of Y. ruckeri with reduced susceptibility to these antimicrobial agents. These data indicate in that for Y. ruckeri, the substitution of Ser by Arg at position 83 of the gyrA gene is associated with reduced susceptibility to quinolones.

  12. In utero exposure of rats to high-fat diets perturbs gene expression profiles and cancer susceptibility of prepubertal mammary glands.

    PubMed

    Govindarajah, Vinothini; Leung, Yuet-Kin; Ying, Jun; Gear, Robin; Bornschein, Robert L; Medvedovic, Mario; Ho, Shuk-Mei

    2016-03-01

    Human studies suggest that high-fat diets (HFDs) increase the risk of breast cancer. The 7,12-dimethylbenz[a]anthracene (DMBA)-induced mammary carcinogenesis rat model is commonly used to evaluate the effects of lifestyle factors such as HFD on mammary tumor risk. Past studies focused primarily on the effects of continuous maternal exposure on the risk of offspring at the end of puberty (PND50). We assessed the effects of prenatal HFD exposure on cancer susceptibility in prepubertal mammary glands and identified key gene networks associated with such disruption. During pregnancy, dams were fed AIN-93G-based diets with isocaloric high olive oil, butterfat or safflower oil. The control group received AIN-93G. Female offspring were treated with DMBA on PND21. However, a significant increase in tumor volume and a trend of shortened tumor latency were observed in rats with HFD exposure against the controls (P=.048 and P=.067, respectively). Large-volume tumors harbored carcinoma in situ. Transcriptome profiling identified 43 differentially expressed genes in the mammary glands of the HFBUTTER group as compared with control. Rapid hormone signaling was the most dysregulated pathway. The diet also induced aberrant expression of Dnmt3a, Mbd1 and Mbd3, consistent with potential epigenetic disruption. Collectively, these findings provide the first evidence supporting susceptibility of prepubertal mammary glands to DMBA-induced tumorigenesis that can be modulated by dietary fat that involves aberrant gene expression and likely epigenetic dysregulation. PMID:26895667

  13. Common Variants in Interleukin-1-Beta Gene Are Associated with Intracranial Hemorrhage and Susceptibility to Brain Arteriovenous Malformation

    PubMed Central

    Kim, Helen; Hysi, Pirro G.; Pawlikowska, Ludmila; Poon, Annie; Burchard, Esteban González; Zaroff, Jonathan G.; Sidney, Stephen; Ko, Nerissa U.; Achrol, Achal S.; Lawton, Michael T.; McCulloch, Charles E.; Kwok, Pui-Yan; Young, William L.

    2009-01-01

    Background Polymorphisms in the proinflammatory cytokine interleukin (IL)-1β gene have been associated with systemic atherogenesis, thrombosis and rupture. The aim of this study was to investigate associations between single nucleotide polymorphisms (SNPs) in IL-1β and intracranial hemorrhage (ICH) in the natural course of brain arteriovenous malformation (BAVM) patients. Method Two IL-1β promoter SNPs (−511C→T, −31T→C) and 1 synonymous coding SNP in exon 5 at +3953C→T (Phe) were genotyped in 410 BAVM patients. We performed a survival analysis of time to subsequent ICH, censoring cases at first treatment, death or last follow-up. A Cox regression analysis was performed to obtain hazard ratios (HRs) for genotypes adjusted for age, sex, Caucasian race/ethnicity and hemorrhagic presentation. Results Subjects with the −31 CC genotype (HR = 2.7; 95% CI 1.1–6.6; p = 0.029) or the −511 TT genotype (HR = 2.6; 95% CI 1.1–6.5; p = 0.039) had a greater risk of subsequent ICH compared with reference genotypes, adjusting for covariates. The +3953C→T SNP was not significantly associated with an increased ICH risk (p = 0.22). The IL-1β promoter polymorphisms were also associated with BAVM susceptibility among a subset of 235 BAVM cases and 255 healthy controls of Caucasian race/ethnicity (p < 0.001). Conclusion IL-1β promoter polymorphisms were associated with an increased risk of ICH in BAVM clinical course and with BAVM susceptibility. These results suggest that inflammatory pathways, including the IL-1β cytokine, may play an important role in ICH. PMID:19092239

  14. Contributions of Ea(z) and Eb(z) MHC genes to lupus susceptibility in New Zealand mice.

    PubMed

    Vyse, T J; Rozzo, S J; Drake, C G; Appel, V B; Lemeur, M; Izui, S; Palmer, E; Kotzin, B L

    1998-03-15

    Unlike parental New Zealand Black (NZB) or New Zealand White (NZW) mice, (NZB x NZW)F1 mice exhibit a lupus-like disease characterized by IgG autoantibody production and severe immune complex-mediated nephritis. In studies of the genetic susceptibility to disease in this F1 model, the NZW MHC (H2z) has been strongly linked with the development of disease, and it was hypothesized that class II MHC genes, particularly Ez genes, may underlie this genetic contribution. In the present study, we bred transgenic B6 mice expressing I-Ez or congenic B6 mice carrying H2z with NZB mice and used a backcross analysis to test the hypothesis that Ea(z) and/or Eb(z) genes account for the effect of H2z on disease. The genetic analysis of different backcross combinations showed that unlike mice carrying H2z, mice inheriting Ez transgenes do not demonstrate increased IgG autoantibody production or increased incidence of nephritis. Surprisingly, in the same transgenic backcross mice, inheritance of the endogenous H2b from the B6 strain was strongly linked with the production of IgG autoantibodies, but not with disease. Additional experiments suggested that the level of IgG3 autoantibody production, which is controlled by H2, may be important in the pathogenesis of renal disease. Contributions to autoantibody production were also detected from an NZB locus on distal chromosome 1 (previously named Nba2). Together, these studies provide new insight into the role of MHC in lupus-like autoimmunity.

  15. Case-control study for colorectal cancer genetic susceptibility in EPICOLON: previously identified variants and mucins

    PubMed Central

    2011-01-01

    Background Colorectal cancer (CRC) is the second leading cause of cancer death in developed countries. Familial aggregation in CRC is also important outside syndromic forms and, in this case, a polygenic model with several common low-penetrance alleles contributing to CRC genetic predisposition could be hypothesized. Mucins and GALNTs (N-acetylgalactosaminyltransferase) are interesting candidates for CRC genetic susceptibility and have not been previously evaluated. We present results for ten genetic variants linked to CRC risk in previous studies (previously identified category) and 18 selected variants from the mucin gene family in a case-control association study from the Spanish EPICOLON consortium. Methods CRC cases and matched controls were from EPICOLON, a prospective, multicenter, nationwide Spanish initiative, comprised of two independent stages. Stage 1 corresponded to 515 CRC cases and 515 controls, whereas stage 2 consisted of 901 CRC cases and 909 controls. Also, an independent cohort of 549 CRC cases and 599 controls outside EPICOLON was available for additional replication. Genotyping was performed for ten previously identified SNPs in ADH1C, APC, CCDN1, IL6, IL8, IRS1, MTHFR, PPARG, VDR and ARL11, and 18 selected variants in the mucin gene family. Results None of the 28 SNPs analyzed in our study was found to be associated with CRC risk. Although four SNPs were significant with a P-value < 0.05 in EPICOLON stage 1 [rs698 in ADH1C (OR = 1.63, 95% CI = 1.06-2.50, P-value = 0.02, recessive), rs1800795 in IL6 (OR = 1.62, 95% CI = 1.10-2.37, P-value = 0.01, recessive), rs3803185 in ARL11 (OR = 1.58, 95% CI = 1.17-2.15, P-value = 0.007, codominant), and rs2102302 in GALNTL2 (OR = 1.20, 95% CI = 1.00-1.44, P-value = 0.04, log-additive 0, 1, 2 alleles], only rs3803185 achieved statistical significance in EPICOLON stage 2 (OR = 1.34, 95% CI = 1.06-1.69, P-value = 0.01, recessive). In the joint analysis for both stages, results were only significant for rs

  16. Characterization of Arabidopsis Transcriptional Responses to Different Aphid Species Reveals Genes that Contribute to Host Susceptibility and Non-host Resistance

    PubMed Central

    Jaouannet, Maëlle; Morris, Jenny A.; Hedley, Peter E.; Bos, Jorunn I. B.

    2015-01-01

    Aphids are economically important pests that display exceptional variation in host range. The determinants of diverse aphid host ranges are not well understood, but it is likely that molecular interactions are involved. With significant progress being made towards understanding host responses upon aphid attack, the mechanisms underlying non-host resistance remain to be elucidated. Here, we investigated and compared Arabidopsis thaliana host and non-host responses to aphids at the transcriptional level using three different aphid species, Myzus persicae, Myzus cerasi and Rhopalosiphum pisum. Gene expression analyses revealed a high level of overlap in the overall gene expression changes during the host and non-host interactions with regards to the sets of genes differentially expressed and the direction of expression changes. Despite this overlap in transcriptional responses across interactions, there was a stronger repression of genes involved in metabolism and oxidative responses specifically during the host interaction with M. persicae. In addition, we identified a set of genes with opposite gene expression patterns during the host versus non-host interactions. Aphid performance assays on Arabidopsis mutants that were selected based on our transcriptome analyses identified novel genes contributing to host susceptibility, host defences during interactions with M. persicae as well to non-host resistance against R. padi. Understanding how plants respond to aphid species that differ in their ability to infest plant species, and identifying the genes and signaling pathways involved, is essential for the development of novel and durable aphid control in crop plants. PMID:25993686

  17. New susceptible variant of COQ2 gene in Japanese patients with sporadic multiple system atrophy

    PubMed Central

    Sun, Zhuoran; Ohta, Yasuyuki; Yamashita, Toru; Sato, Kota; Takemoto, Mami; Hishikawa, Nozomi

    2016-01-01

    Objective: The aim of this study was to analyze the association between the variations of coenzyme Q2 4-hydroxybenzoate polyprenyltransferase gene (COQ2) and Japanese patients with multiple system atrophy (MSA). Methods: We investigated the genetic variations in exons 1, 2, 6, and 7 of the COQ2 gene in 133 Japanese patients with MSA and 200 controls and analyzed the association between the variations and MSA. Results: Six DNA variations (G21S, L25V, V66L, P157S, V393A, and X422K) were found in the 133 patients with MSA, and G21S and X422K were new variations that had never been reported. V66L was a common variation that was found in all 133 patients with MSA. G21S, P157S, V393A, and X422K did not show gene frequency differences between patients with MSA and controls. On the other hand, L25V was newly proven to be the only risk factor of sporadic MSA with predominant olivopontocerebellar ataxia. Conclusions: The present study suggests L25V variant of COQ2 gene as a genetic risk factor in Japanese patients with MSA with cerebellar ataxia. PMID:27123473

  18. Possible contribution of GSTP1 and other xenobiotic metabolizing genes to vitiligo susceptibility.

    PubMed

    Minashkin, Mikhail M; Salnikova, Lubov E; Lomonosov, Konstantin M; Korobko, Igor V; Tatarenko, Andrey O

    2013-04-01

    Vitiligo is an acquired pigmentary disorder with several proposed pathogenesis mechanisms and complex multifactorial genetic predisposition. We analyzed 65 polymorphisms in genes potentially relevant to vitiligo pathogenesis mechanism to reveal novel and confirm reported genetic risk factors in general Russian population. We found that polymorphism rs1138272 (TC + CC) in GSTP1 gene encoding enzyme involved in xenobiotic metabolism is associated with vitiligo (Bonferroni adjusted P value 0.0015) with extraordinary high odds ratio 13.03, and haplotype analysis confirmed association of GSTP1 gene with vitiligo risk. Moreover, analysis of variations in several genes encoding enzymes of xenobiotic metabolism showed that higher risk of vitiligo is associated with higher number of risk alleles. This finding reveals possible contribution of genetic background to observed imbalance of oxidative stress control in vitiligo through cumulative effect of multiple genetic variations in xenobiotic metabolizing genes, supporting the concept of multigenic nature of vitiligo with multiple low-risk alleles cumulatively contributing to vitiligo risk.

  19. Gene-gene and gene-environment interplay represent specific susceptibility for different types of ischaemic stroke and leukoaraiosis.

    PubMed

    Szolnoki, Zoltán; Melegh, Béla

    2006-01-01

    Stroke is a very frequent entity. It is the third leading cause of death and the leading cause of adult disability in the developed world. At a population level, the common sporadic form of ischaemic stroke is underpinned by both environmental and genetic risk factors. Typically, in clinical practice, environmental risk factors such as hypertension, diabetes mellitus, smoking, alcohol consumption, and other factors, are usually considered to be more important than genetic factors. However, it is the interplay of both environmental and common genetic factors [such as the Leiden V, methylenetetrahydrofolate reductase C677T, apolipopotein E 4, endothelial nitric oxide synthase G894T, angiotensin-converting enzyme I/D and angiotensin II type 1 receptor A1166C mutations and polymorphisms] that leads to the development of ischaemic stroke. Indeed, a complex network of interactions between genetic factors and clinical risk factors can be supposed. This review evaluates the possible roles of gene-gene and gene-environment interactions concerning the above genetic factors in the evolution of ischaemic stroke and leukoaraiosis. A knowledge of the specific genetic patterns which are associated with a significant risk of ischaemic stroke or leukoaraiosis may also draw attention to a large population at an increased risk of circulatory disorders. This may facilitate the choice of more effective and specific prevention on the basis of the genotype.

  20. Reading Genomes and Controlling Gene Expression

    NASA Astrophysics Data System (ADS)

    Libchaber, Albert

    2000-03-01

    Molecular recognition of DNA sequences is achieved by DNA hybridization of complementary sequences. We present various scenarios for optimization, leading to microarrays and global measurement. Gene expression can be controlled using gene constructs immobilized on a template with micron scale temperature heaters. We will discuss and present results on protein microarrays.

  1. Bilirubin UDP-glucuronosyltransferase 1A1 gene polymorphisms: susceptibility to oxidative damage and cancer?

    PubMed

    Grant, D J; Bell, D A

    2000-12-01

    The UDP-glucuronosyltransferase 1A1 (UGT1A1) gene product catalyzes the glucuronidation of serum bilirubin as part of normal heme catabolism. Recently, TA repeat polymorphisms containing five, six, seven, and eight TA dinucleotides in a putative TATA box in the promoter region of the UGT1A1 gene have been described. TA repeat number modulates UGT1A1 transcriptional activity and the quantity of enzyme available to conjugate serum bilirubin. Serum bilirubin is a known antioxidant, and low serum bilirubin has been associated with increased risk for coronary artery disease and inhibition of reactive oxygen species (ROS)-induced damage to erythrocytes in vitro. We hypothesize that the UGT1A1 TA repeats or other functional polymorphisms resulting in lower serum bilirubin levels may be predictive of genetic susceptibility to oxidative damage and cancer. Exposure-related or endogenous production of ROS may impact the integrity of cellular macromolecules and infrastructure, lead to DNA base changes or chromosomal aberrations, and induce toxicity or apoptosis. ROS damage to lipoproteins may be a factor in formation of atherogenic plaques in coronary heart disease. Thus, cellular oxidative stress could contribute to tumorigenesis through mutagenic or epigenetic pathways, and higher serum bilirubin levels should inhibit this process. No definitive studies have been performed, but in a small prospective study of colon cancer, serum bilirubin levels were observed to be lower in these cases. Another study has suggested a link between UGT1A1 alleles, estrogen metabolism, and risk in breast cancer. Epidemiologic studies examining variation in ROS metabolism, ROS damage, bilirubin, and cancer risk will demonstrate the value of this hypothesis. PMID:11170257

  2. A Systems Genetics Approach Identifies CXCL14, ITGAX, and LPCAT2 as Novel Aggressive Prostate Cancer Susceptibility Genes

    PubMed Central

    Andreas, Jonathan; Patel, Shashank J.; Zhang, Suiyuan; Chines, Peter; Elkahloun, Abdel; Chandrasekharappa, Settara; Gutkind, J. Silvio; Molinolo, Alfredo A.; Crawford, Nigel P. S.

    2014-01-01

    Although prostate cancer typically runs an indolent course, a subset of men develop aggressive, fatal forms of this disease. We hypothesize that germline variation modulates susceptibility to aggressive prostate cancer. The goal of this work is to identify susceptibility genes using the C57BL/6-Tg(TRAMP)8247Ng/J (TRAMP) mouse model of neuroendocrine prostate cancer. Quantitative trait locus (QTL) mapping was performed in transgene-positive (TRAMPxNOD/ShiLtJ) F2 intercross males (n = 228), which facilitated identification of 11 loci associated with aggressive disease development. Microarray data derived from 126 (TRAMPxNOD/ShiLtJ) F2 primary tumors were used to prioritize candidate genes within QTLs, with candidate genes deemed as being high priority when possessing both high levels of expression-trait correlation and a proximal expression QTL. This process enabled the identification of 35 aggressive prostate tumorigenesis candidate genes. The role of these genes in aggressive forms of human prostate cancer was investigated using two concurrent approaches. First, logistic regression analysis in two human prostate gene expression datasets revealed that expression levels of five genes (CXCL14, ITGAX, LPCAT2, RNASEH2A, and ZNF322) were positively correlated with aggressive prostate cancer and two genes (CCL19 and HIST1H1A) were protective for aggressive prostate cancer. Higher than average levels of expression of the five genes that were positively correlated with aggressive disease were consistently associated with patient outcome in both human prostate cancer tumor gene expression datasets. Second, three of these five genes (CXCL14, ITGAX, and LPCAT2) harbored polymorphisms associated with aggressive disease development in a human GWAS cohort consisting of 1,172 prostate cancer patients. This study is the first example of using a systems genetics approach to successfully identify novel susceptibility genes for aggressive prostate cancer. Such approaches will

  3. 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

  4. Nuclear factor erythroid 2-related factor gene variants and susceptibility of arsenic-related skin lesions.

    PubMed

    Cordova, E J; Valenzuela, O L; Sánchez-Peña, L C; Escamilla-Guerrero, G; Hernández-Zavala, A; Orozco, L; Del Razo, L M

    2014-06-01

    Inorganic arsenic (iAs) is an important pollutant associated with various chronic-degenerative diseases. The cytoprotective protein nuclear factor erythroid 2-related factor (NRF2) has been proposed as an important responsive mechanism against iAs exposure. The aim of this study was to determine whether the risk of skin lesions in people exposed to iAs-contaminated water could be modified by the presence of single nucleotide polymorphisms in the NRF2 coding gene. We studied 117 individuals with long-term iAs exposure and 120 nonexposed individuals. Total As was determined in water, meanwhile iAs and its metabolites were measured in urine. The iAs-induced skin lesion status was evaluated by expert dermatologists. We sequenced the promoter region of NRF2 in a sample of 120 healthy donors. We found four polymorphisms previously reported and one novel polymorphism in the 5' regulatory region of the NRF2. In this study, we did not find allelic and genotype association of NRF2 polymorphisms with iAs-related skin lesion. However, the analysis of haplotypes composed by -653GA, and -617CA NRF2 single nucleotide polymorphisms showed a significant association with protection against skin lesions in the low-As exposure group. This is the first report studying the association between NRF2 polymorphisms and susceptibility of As-related skin lesions. Increasing the sample size will allow us to confirm this data. PMID:24107458

  5. Nuclear factor erythroid 2-related factor gene variants and susceptibility of arsenic-related skin lesions.

    PubMed

    Cordova, E J; Valenzuela, O L; Sánchez-Peña, L C; Escamilla-Guerrero, G; Hernández-Zavala, A; Orozco, L; Del Razo, L M

    2014-06-01

    Inorganic arsenic (iAs) is an important pollutant associated with various chronic-degenerative diseases. The cytoprotective protein nuclear factor erythroid 2-related factor (NRF2) has been proposed as an important responsive mechanism against iAs exposure. The aim of this study was to determine whether the risk of skin lesions in people exposed to iAs-contaminated water could be modified by the presence of single nucleotide polymorphisms in the NRF2 coding gene. We studied 117 individuals with long-term iAs exposure and 120 nonexposed individuals. Total As was determined in water, meanwhile iAs and its metabolites were measured in urine. The iAs-induced skin lesion status was evaluated by expert dermatologists. We sequenced the promoter region of NRF2 in a sample of 120 healthy donors. We found four polymorphisms previously reported and one novel polymorphism in the 5' regulatory region of the NRF2. In this study, we did not find allelic and genotype association of NRF2 polymorphisms with iAs-related skin lesion. However, the analysis of haplotypes composed by -653GA, and -617CA NRF2 single nucleotide polymorphisms showed a significant association with protection against skin lesions in the low-As exposure group. This is the first report studying the association between NRF2 polymorphisms and susceptibility of As-related skin lesions. Increasing the sample size will allow us to confirm this data.

  6. Revisiting the Thrifty Gene Hypothesis via 65 Loci Associated with Susceptibility to Type 2 Diabetes

    PubMed Central

    Ayub, Qasim; Moutsianas, Loukas; Chen, Yuan; Panoutsopoulou, Kalliope; Colonna, Vincenza; Pagani, Luca; Prokopenko, Inga; Ritchie, Graham R.S.; Tyler-Smith, Chris; McCarthy, Mark I.; Zeggini, Eleftheria; Xue, Yali

    2014-01-01

    We have investigated the evidence for positive selection in samples of African, European, and East Asian ancestry at 65 loci associated with susceptibility to type 2 diabetes (T2D) previously identified through genome-wide association studies. Selection early in human evolutionary history is predicted to lead to ancestral risk alleles shared between populations, whereas late selection would result in population-specific signals at derived risk alleles. By using a wide variety of tests based on the site frequency spectrum, haplotype structure, and population differentiation, we found no global signal of enrichment for positive selection when we considered all T2D risk loci collectively. However, in a locus-by-locus analysis, we found nominal evidence for positive selection at 14 of the loci. Selection favored the protective and risk alleles in similar proportions, rather than the risk alleles specifically as predicted by the thrifty gene hypothesis, and may not be related to influence on diabetes. Overall, we conclude that past positive selection has not been a powerful influence driving the prevalence of T2D risk alleles. PMID:24412096

  7. Localization of type 1 diabetes susceptibility to the MHC class I genes HLA-B and HLA-A

    PubMed Central

    Nejentsev, Sergey; Howson, Joanna M. M.; Walker, Neil M.; Szeszko, Jeffrey; Field, Sarah F.; Stevens, Helen E.; Reynolds, Pamela; Hardy, Matthew; King, Erna; Masters, Jennifer; Hulme, John; Maier, Lisa M.; Smyth, Deborah; Bailey, Rebecca; Cooper, Jason D.; Ribas, Gloria; Campbell, R. Duncan; Clayton, David G.; Todd, John A.

    2009-01-01

    The major histocompatibility complex (MHC) on chromosome 6 is associated with susceptibility to more common diseases than any other region of the human genome, including almost all disorders classified as autoimmune. In type 1 diabetes the major genetic susceptibility determinants have been mapped to the MHC class II genes HLA-DQB1 and HLA-DRB1 (refs 1-3), but these genes cannot completely explain the association between type 1 diabetes and the MHC region4-11. Owing to the region’s extreme gene density, the multiplicity of disease-associated alleles, strong associations between alleles, limited genotyping capability, and inadequate statistical approaches and sample sizes, which, and how many, loci within the MHC determine susceptibility remains unclear. Here, in several large type 1 diabetes data sets, we analyse a combined total of 1,729 polymorphisms, and apply statistical methods—recursive partitioning and regression—to pinpoint disease susceptibility to the MHC class I genes HLA-B and HLA-A (risk ratios>1.5; Pcombined=2.01×10-19 and 2.35×10-13, respectively) in addition to the established associations of the MHC class II genes. Other loci with smaller and/or rarer effects might also be involved, but to find these, future searches must take into account both the HLA class II and class I genes and use even larger samples. Taken together with previous studies4-8,10-16, we conclude that MHC-class-I-mediated events, principally involving HLA-B*39, contribute to the aetiology of type 1 diabetes. PMID:18004301

  8. An exon variant in insulin receptor gene is associated with susceptibility to colorectal cancer in women.

    PubMed

    Mahmoudi, Touraj; Majidzadeh-A, Keivan; Karimi, Khatoon; Karimi, Negar; Farahani, Hamid; Dabiri, Reza; Nobakht, Hossein; Dolatmoradi, Hesamodin; Arkani, Maral; Zali, Mohammad Reza

    2015-05-01

    Given the role of insulin resistance in colorectal cancer (CRC), we explored whether genetic variants in insulin (INS), insulin receptor (INSR), insulin receptor substrate 1 (IRS1), insulin receptor substrate 2 (IRS2), insulin-like growth factor 1 (IGF1), and insulin-like growth factor binding protein 3 (IGFBP3) genes were associated with CRC risk. A total of 600 subjects, including 261 cases with CRC and 339 controls, were enrolled in this case-control study. Six polymorphisms in INS (rs689), INSR (rs1799817), IRS1 (rs1801278), IRS2 (rs1805097), IGF1 (rs5742612), and IGFBP3 (rs2854744) genes were genotyped using PCR-RFLP method. No significant difference was observed for INS, INSR, IRS1, IRS2, IGF1, and IGFBP3 genes between the cases and controls. However, the INSR rs1799817 "TT + CT" genotype and "CT" genotype compared with "CC" genotype occurred more frequently in the women with CRC than women controls (P = 0.007; OR = 1.93, 95 %CI = 1.20-3.11 and P = 0.002, OR = 2.15, 95 %CI = 1.31-3.53, respectively), and the difference remained significant after adjustment for confounding factors including age, BMI, smoking status, NSAID use, and family history of CRC (P = 0.018; OR = 1.86, 95 %CI = 1.11-3.10 and P = 0.004, OR = 2.18, 95 %CI = 1.28-3.71, respectively). In conclusion, to our knowledge, this study indicated for the first time that the INSR rs1799817 TT + CT genotype and CT genotype compared with the CC genotype had 1.86-fold and 2.18-fold increased risks for CRC among women, respectively. Furthermore, this finding is in line with previous studies which found significant associations between other variants of the INSR gene and CRC risk. Nevertheless, further studies are required to confirm our findings.

  9. Whole-Exome Sequencing Suggests LAMB3 as a Susceptibility Gene for Morbid Obesity.

    PubMed

    Jiao, Hong; Kulyté, Agné; Näslund, Erik; Thorell, Anders; Gerdhem, Paul; Kere, Juha; Arner, Peter; Dahlman, Ingrid

    2016-10-01

    Identification of rare sequencing variants with a larger functional impact has the potential to highlight new pathways contributing to obesity. Using whole-exome sequencing followed by genotyping, we have identified a low-frequency coding variant rs2076349 (V527M) in the laminin subunit β3 (LAMB3) gene showing strong association with morbid obesity and thereby risk of type 2 diabetes. We exome-sequenced 200 morbidly obese subjects and 100 control subjects with pooled DNA samples. After several filtering steps, we retained 439 obesity-enriched low-frequency coding variants. Associations between genetic variants and obesity were validated sequentially in two case-control cohorts. In the final analysis of 1,911 morbidly obese and 1,274 control subjects, rs2076349 showed strong association with obesity (P = 9.67 × 10(-5); odds ratio 1.84). This variant was also associated with BMI and fasting serum leptin. Moreover, LAMB3 expression in adipose tissue was positively correlated with BMI and adipose morphology (few but large fat cells). LAMB3 knockdown by small interfering RNA in human adipocytes cultured in vitro inhibited adipogenesis. In conclusion, we identified a previously not reported low-frequency coding variant that was associated with morbid obesity in the LAMB3 gene. This gene may be involved in the development of excess body fat. PMID:27431458

  10. Association of functional polymorphisms in the MxA gene with susceptibility to enterovirus 71 infection.

    PubMed

    Zhang, Xiaoai; Xu, Hongmei; Chen, Xiaodan; Li, Xiujun; Wang, Xianjun; Ding, Shujun; Zhang, Renli; Liu, Lijuan; He, Cui; Zhuang, Lu; Li, Hao; Zhang, Panhe; Yang, Hong; Li, Tingyu; Liu, Wei; Cao, Wuchun

    2014-02-01

    Myxovirus resistance A (MxA) is an antiviral protein induced by type I interferons α and β (IFN-α and IFN-β) that can inhibit virus replication. We examined whether the MxA polymorphisms were related to the risk and severity of enterovirus 71 (EV71) infection in Chinese populations. The MxA C-123A and G-88T polymorphisms were genotyped in two independent case-control populations in China by polymerase chain reaction-based restriction fragment length polymorphism (PCR-RFLP) analysis. Multivariate logistic regression analysis was used to calculate adjusted odds ratios (ORs) and 95% confidence intervals (95% CIs). MxA messenger RNA was quantified by real-time quantitative PCR in peripheral blood mononuclear cells (PBMCs) from 45 healthy children and 19 patients with EV71 infection. Significantly decreased susceptibility to EV71 infection was observed for the -123A allele and -88T allele carriers, with ORs (95% CIs) estimated as 0.56 (0.39-0.81) and 0.64 (0.47-0.88), respectively, in the northern population. This association was confirmed in the southern population, with ORs (95% CIs) estimated as 0.58 (0.38-0.89) and 0.67(0.47-0.95), respectively. The A- 123T- 88 haplotype was also significantly associated with lower risk of EV71 infection in both the northern (OR = 0.62; 95% CI = 0.44-0.85) and the southern population (OR = 0.63; 95% CI = 0.43-0.92). Furthermore, we observed higher MxA messenger RNA levels in IFNβ1a-stimulated PBMCs from the -123A or -88T allele carriers compared with that from nocarriers. Our findings suggest that polymorphisms in the MxA promoter may play a role in mediating the susceptibility to EV71 infection in Chinese population.

  11. HLA and interleukin 1 gene polymorphisms in primary biliary cirrhosis: associations with disease progression and disease susceptibility

    PubMed Central

    Donaldson, P; Agarwal, K; Craggs, A; Craig, W; James, O; Jones, D

    2001-01-01

    BACKGROUND AND AIMS—Twin and family studies suggest that there is a genetic component to primary biliary cirrhosis (PBC) but the genetic associations which have been described are weak with marked variations between centres. PBC is heterogeneous and genetic associations with disease progression may be obscured when the PBC population is analysed only as a whole and not subdivided.
METHODS—We have investigated two candidate gene loci in 164 well characterised patients, 88 (54%) of whom had advanced disease.
RESULTS—There was an increased frequency of the HLA DRB1*0801-DQA1*0401-DQB1*0402 haplotype in patients who had progressed to late stage disease (23% v 2% of controls; p=0000044; odds ratio (OR) 15.5, 95% confidence interval (CI) 3.52-68.4) but not in those with early stage disease (4% v 2%). Patients had a higher frequency of the IL-1B*1,1 genotype and lower frequencies of the IL-1B*1,2 and *2,2 genotypes (p=0.00078; OR 2.37, 95% CI 1.38-4.06), and higher frequency of the IL-1RN*1,1 genotype and lower frequency of the IL-1RN*1,2 genotype (p=0.0011; OR 2.28, 95% CI 1.34-3.89). The difference in the IL-1B*1,1 genotype distribution was most marked in patients with early stage disease (77% v 43% of controls; p=0.000003; OR 4.8, 95% CI 2.31-10) but the IL-1RN genotype distribution was similar in patients with early and late stage disease.
CONCLUSIONS—These data indicate a complex relationship between immunoregulatory genes and PBC. While the IL-1 genes are markers of both disease susceptibility and progression, HLA genes appear to be principally associated with disease progression.


Keywords: human leucocyte antigens; primary biliary cirrhosis; interleukin 1 PMID:11171832

  12. Frequency of biocide-resistant genes and susceptibility to chlorhexidine in high-level mupirocin-resistant, methicillin-resistant Staphylococcus aureus (MuH MRSA).

    PubMed

    Liu, Qingzhong; Zhao, Huanqiang; Han, Lizhong; Shu, Wen; Wu, Qiong; Ni, Yuxing

    2015-08-01

    The aim of this study was to determine the prevalence of biocide-resistant determinants and the susceptibility to chlorhexidine in high-level mupirocin-resistant, methicillin-resistant Staphylococcus aureus (MuH MRSA). Fifty-three MuH MRSA isolates were analyzed for plasmid-borne genes (qacA/B, smr, qacG, qacH, and qacJ) by polymerase chain reaction (PCR); for chromosome-mediated genes (norA, norB, norC, mepA, mdeA, sepA, and sdrM) by PCR and quantitative reverse transcription-PCR (qRT-PCR); and for susceptibility to chlorhexidine by MIC and minimum bactericidal concentration (MBC). Furthermore, disinfectant efficacy was tested in the presence of 3.0% bovine serum albumin (BSA) in MBC detection. The plasmid-borne genes qacA/B (83.0%) and smr (77.4%) and overexpressions of chromosome-mediated genes norA (49.0%) and norB (28.8%) were predominantly found in isolates studied, and 90.6% of the isolates revealed tolerance to chlorhexidine. In the presence of BSA, the average MBC of chlorhexidine for these isolates rose to 256 μg/mL. Altogether, our results suggest that surveillance of sensitivity to biocides among MuH MRSA isolates is essential for hospital infection control.

  13. Effect of polymorphisms of the MTHFR and APOE genes on susceptibility to diabetes and severity of diabetic retinopathy in Brazilian patients.

    PubMed

    Errera, F I V; Silva, M E R; Yeh, E; Maranduba, C M C; Folco, B; Takahashi, W; Pereira, A C; Krieger, J E; Passos-Bueno, M R

    2006-07-01

    Diabetes mellitus (DM) is a highly prevalent complex genetic disorder. There has been a worldwide effort in the identification of susceptibility genes for DM and its complications, and the 5-10-methylenetetrahydrofolate reductase (MTHFR) and apolipoprotein-E (APOE) genes have been considered good candidate susceptibility genes to this condition. The objectives of the present study were to determine if the 677T MTHFR and epsilon2/epsilon3/epsilon4 APOE alleles are risk factors for DM and for severity of diabetic retinopathy (DR). A total of 248 individuals were studied: 107 healthy individuals and 141 diabetic patients (46 with type 1 diabetes and 95 with type 2 diabetes), who also had DR (81 with non-proliferative DR and 60 with proliferative DR). The polymorphisms were analyzed by PCR followed by digestion with restriction enzyme or the single-nucleotide primer extension method. No evidence of association between the 677TT genotype of MTHFR gene and DM [cases: TT = 10/95 (10.6%); controls: TT = 14/107 (13%)] or with severity of DR was observed [cases: TT = 5/60 (8.5%); controls: TT = 9/81 (11.1%); P > 0.05]. We also did not find evidence of an association between APOE alleles and proliferative DR (epsilon2, epsilon3 and epsilon4 in cases: 9, 76, and 15%, and in controls: 5, 88, and 12%, respectively) but the carriers of epsilon2 allele were more frequent among patients with type 2 DM and DR than in controls [cases: 15/95 (15.8%); controls: 7/107 (6.5%); P < 0.05]. Therefore, our results suggest that the epsilon2 allele/APOE might be a risk factor for diabetes in the Brazilian population.

  14. Impact of gene patents and licensing practices on access to genetic testing for inherited susceptibility to cancer: comparing breast and ovarian cancers with colon cancers.

    PubMed

    Cook-Deegan, Robert; DeRienzo, Christopher; Carbone, Julia; Chandrasekharan, Subhashini; Heaney, Christopher; Conover, Christopher

    2010-04-01

    Genetic testing for inherited susceptibility to breast and ovarian cancer can be compared with similar testing for colorectal cancer as a "natural experiment." Inherited susceptibility accounts for a similar fraction of both cancers and genetic testing results guide decisions about options for prophylactic surgery in both sets of conditions. One major difference is that in the United States, Myriad Genetics is the sole provider of genetic testing, because it has sole control of relevant patents for BRCA1 and BRCA2 genes, whereas genetic testing for familial colorectal cancer is available from multiple laboratories. Colorectal cancer-associated genes are also patented, but they have been nonexclusively licensed. Prices for BRCA1 and 2 testing do not reflect an obvious price premium attributable to exclusive patent rights compared with colorectal cancer testing, and indeed, Myriad's per unit costs are somewhat lower for BRCA1/2 testing than testing for colorectal cancer susceptibility. Myriad has not enforced patents against basic research and negotiated a Memorandum of Understanding with the National Cancer Institute in 1999 for institutional BRCA testing in clinical research. The main impact of patenting and licensing in BRCA compared with colorectal cancer is the business model of genetic testing, with a sole provider for BRCA and multiple laboratories for colorectal cancer genetic testing. Myriad's sole-provider model has not worked in jurisdictions outside the United States, largely because of differences in breadth of patent protection, responses of government health services, and difficulty in patent enforcement.

  15. Polymorphisms of cell cycle regulator genes CCND1 G870A and TP53 C215G: Association with colorectal cancer susceptibility risk in a Malaysian population

    PubMed Central

    ZAHARY, MOHD NIZAM; AHMAD AIZAT, ABDUL AZIZ; KAUR, GURJEET; YEONG YEH, LEE; MAZUWIN, MAYA; ANKATHIL, RAVINDRAN

    2015-01-01

    Colorectal cancer (CRC) occurs as a more common sporadic form and a less common familial form. Our earlier analysis of germline mutations of mismatch repair genes confirmed only 32% of familial CRC cases as Lynch syndrome cases. It was hypothesized that the remaining familial aggregation may be ‘polygenic’ due to single nucleotide polymorphisms (SNPs) of low penetrance genes involved in cancer predisposition pathways, such as cell cycle regulation and apoptosis pathways. The current case-control study involving 104 CRC patients (52 sporadic and 52 familial) and 104 normal healthy controls investigated the contribution of the SNPs cyclin D1 (CCND1) G870A and tumor protein p53 (TP53) C215G in modulating familial and sporadic CRC susceptibility risk. DNA was extracted from peripheral blood and the polymorphisms were genotyped by employing a polymerase chain reaction-restriction fragment length polymorphism method. The association between these polymorphisms and CRC susceptibility risk was calculated using a binary logistic regression analysis and deriving odds ratios (ORs). The A/A variant genotype of CCND1 and G/G variant genotype of TP53 exhibited a significantly greater association with the risk of sporadic CRC [CCND1: OR, 3.471; 95% confidence interval (CI), 1.443–8.350; P=0.005. TP53: OR, 2.829; CI, 1.119–7.152; P=0.026] as well as familial CRC susceptibility (CCND1: OR, 3.086; CI, 1.270–7.497; P=0.019. TP53: OR, 3.048; CI, 1.147–8.097; P=0.030). The results suggest a potential role of the SNPs CCND1 G870A and TP53 C215G in the modulation of sporadic and familial CRC susceptibility risk. PMID:26722315

  16. Whole genome association study in a homogenous population in Shandong peninsula of China reveals JARID2 as a susceptibility gene for schizophrenia.

    PubMed

    Liu, Yang; Chen, Gang; Norton, Nadine; Liu, Wenmin; Zhu, Haining; Zhou, Peng; Luan, Meng; Yang, Shulin; Chen, Xing; Carroll, Liam; Williams, Nigel M; O'Donovan, Michael C; Kirov, George; Owen, Michael J

    2009-01-01

    DNA pooling can provide an economic and efficient way to detect susceptibility loci to complex diseases. We carried out a genome screen with 400 microsatellite markers spaced at approximately 10 cm in two DNA pools consisting of 119 schizophrenia (SZ) patients and 119 controls recruited from a homogenous population in the Chang Le area of the Shandong peninsula of China. Association of D6S289, a dinucleotide repeat polymorphism in the JARID2 gene with SZ, was found and confirmed by individual genotyping (X(2) = 17.89; P = .047). In order to refine the signal, we genotyped 14 single nucleotide polymorphisms (SNPs) covering JARID2 and the neighboring gene, DNTBP1, in an extended sample of 309 cases and 309 controls from Shandong peninsula (including the samples from the pools). However, rs2235258 and rs9654600 in JARID2 showed association in allelic, genotypic and haplotypic tests with SZ patients from Chang Le area. This was not replicates in the extended sample, we conclude that JARID2 could be a susceptibility gene for SZ.

  17. Alterations in penicillin binding protein gene of Streptococcus pneumoniae and their correlation with susceptibility patterns.

    PubMed

    Ohsaki, Yoshinobu; Tachibana, Mineji; Nakanishi, Kyoko; Nakao, Shoko; Saito, Kumiko; Toyoshima, Eri; Sato, Maki; Takahashi, Toru; Osanai, Shinobu; Itoh, Yoshihisa; Kikuchi, Kenjiro

    2003-08-01

    Penicillin binding protein (pbp) gene alterations of 328 clinical isolates of Streptococcus pneumoniae were examined for a correlation with their antibiotic-resistance. The frequency of penicillin G (PEN-G) resistance was determined to clarify susceptibility to several antibiotics, namely PEN-G, ampicillin, sulbactam/ampicillin, cefozopram, panipenem (PAPM), clarithromycin (CLR), azithromycin (AZM) and levofloxacin (LVX). Oligonucleotide primers for three pbp genes (pbp1a, pbp2x and pbp2b) were used to detect mutations in pbp. Of the strains, 25.9% were classified as Pen-Gs, 68.0% as Pen-Gir and 6.1% as Pen-Gr. The polymerase chain reaction product for wild-type pbp1a was found in 185 isolates, that for wild-type pbp2x was found in 66 isolates and that for wild-type pbp2b was found in 213 isolates. None of these three genes was detectable in 100 isolates while all of them were detected in 64 isolates (1aw/2xw/2bw). Of those 64 isolates with 1aw/2xw/2bw, the minimum inhibitory concentration (MIC) of PEN-G was < or =0.06 mg/l for 54 isolates and 0.12 mg/l for 10 isolates. Of the 272 strains for which the MIC of PAPM was < or =0.03 mg/l, there were 85 Pen-Gs, 184 Pen-Gir and three Pen-Gr isolates. Three strains for which the MIC of LVX was > or =4.0 mg/l included one Pen-Gs and two Pen-Gir isolates. The MICs of CLR correlated significantly with those of AZM. The MIC of CLR was > or =1 mg/l for 216 isolates, and the MIC of AZM was > or =1 mg/l for 244 of them. These data suggested that PAPM may be effective against S. pneumoniae infection, although acquisition of resistance should be considered. LVX also seemed to be effective against S. pneumoniae.

  18. Absence of genetic divergence between western corn rootworms (Coleoptera: Chrysomelidae) resistant and susceptible to control by crop rotation.

    PubMed

    Miller, N J; Kim, K S; Ratcliffe, S T; Estoup, A; Bourguet, D; Guillemaud, T

    2006-06-01

    The western corn rootworm, Diabrotica virgifera virgifera LeConte (Coleoptera: Chrysomelidae), is a major pest of corn, Zea mays L., in North America that has recently invaded Europe. A loss of ovipositional fidelity to cornfields has allowed the species to circumvent crop rotation as a means of control in part of its range in the United States. Analyses of variation at eight microsatellite loci provided no evidence for general genetic differentiation between samples of western corn rootworm collected in soybean, Glycine max (L.) Merr., fields and those collected in cornfields both inside and outside the rotation-resistance problem area. This result suggests that few or no barriers to gene flow exist between rotation-resistant and -susceptible rootworm populations. The implications of this result for the management of western corn rootworm in North America and Europe are discussed.

  19. Fine mapping of the gene for susceptibility to black spot disease in Japanese pear (Pyrus pyrifolia Nakai)

    PubMed Central

    Terakami, Shingo; Moriya, Shigeki; Adachi, Yoshihiko; Kunihisa, Miyuki; Nishitani, Chikako; Saito, Toshihiro; Abe, Kazuyuki; Yamamoto, Toshiya

    2016-01-01

    Black spot disease, which is caused by the Japanese pear pathotype of the filamentous fungus Alternaria alternata (Fries) Keissler, is one of the most harmful diseases in Japanese pear cultivation. We mapped a gene for susceptibility to black spot disease in the Japanese pear (Pyrus pyrifolia Nakai) cultivar ‘Kinchaku’ (Aki gene) at the top of linkage group 11, similar to the positions of the susceptibility genes Ani in ‘Osa Nijisseiki’ and Ana in ‘Nansui’. Using synteny-based marker enrichment, we developed novel apple SSR markers in the target region. We constructed a fine map of linkage group 11 of ‘Kinchaku’ and localized the Aki locus within a 1.5-cM genome region between SSR markers Mdo.chr11.28 and Mdo.chr11.34. Marker Mdo.chr11.30 co-segregated with Aki in all 621 F1 plantlets of a ‘Housui’ × ‘Kinchaku’ cross. The physical size of the Aki region, which includes three markers (Mdo.chr11.28, Mdo.chr11.30, and Mdo.chr11.34), was estimated to be 250 Kb in the ‘Golden Delicious’ apple genome and 107 Kb in the ‘Dangshansuli’ Chinese pear genome. Our results will help to identify the candidate gene for susceptibility to black spot disease in Japanese pear. PMID:27162498

  20. Intronic deletions of tva receptor gene decrease the susceptibility to infection by avian sarcoma and leukosis virus subgroup A

    PubMed Central

    Chen, Weiguo; Liu, Yang; Li, Hongxing; Chang, Shuang; Shu, Dingming; Zhang, Huanmin; Chen, Feng; Xie, Qingmei

    2015-01-01

    The group of avian sarcoma and leukosis virus (ASLV) in chickens contains six highly related subgroups, A to E and J. Four genetic loci, tva, tvb, tvc and tvj, encode for corresponding receptors that determine the susceptibility to the ASLV subgroups. The prevalence of ASLV in hosts may have imposed strong selection pressure toward resistance to ASLV infection, and the resistant alleles in all four receptor genes have been identified. In this study, two new alleles of the tva receptor gene, tvar5 and tvar6, with similar intronic deletions were identified in Chinese commercial broilers. These natural mutations delete the deduced branch point signal within the first intron, disrupting mRNA splicing of the tva receptor gene and leading to the retention of intron 1 and introduction of premature TGA stop codons in both the longer and shorter tva isoforms. As a result, decreased susceptibility to subgroup A ASLV in vitro and in vivo was observed in the subsequent analysis. In addition, we identified two groups of heterozygous allele pairs which exhibited quantitative differences in host susceptibility to ASLV-A. This study demonstrated that defective splicing of the tva receptor gene can confer genetic resistance to ASLV subgroup A in the host. PMID:25873518

  1. Fine mapping of the gene for susceptibility to black spot disease in Japanese pear (Pyrus pyrifolia Nakai).

    PubMed

    Terakami, Shingo; Moriya, Shigeki; Adachi, Yoshihiko; Kunihisa, Miyuki; Nishitani, Chikako; Saito, Toshihiro; Abe, Kazuyuki; Yamamoto, Toshiya

    2016-03-01

    Black spot disease, which is caused by the Japanese pear pathotype of the filamentous fungus Alternaria alternata (Fries) Keissler, is one of the most harmful diseases in Japanese pear cultivation. We mapped a gene for susceptibility to black spot disease in the Japanese pear (Pyrus pyrifolia Nakai) cultivar 'Kinchaku' (Aki gene) at the top of linkage group 11, similar to the positions of the susceptibility genes Ani in 'Osa Nijisseiki' and Ana in 'Nansui'. Using synteny-based marker enrichment, we developed novel apple SSR markers in the target region. We constructed a fine map of linkage group 11 of 'Kinchaku' and localized the Aki locus within a 1.5-cM genome region between SSR markers Mdo.chr11.28 and Mdo.chr11.34. Marker Mdo.chr11.30 co-segregated with Aki in all 621 F1 plantlets of a 'Housui' × 'Kinchaku' cross. The physical size of the Aki region, which includes three markers (Mdo.chr11.28, Mdo.chr11.30, and Mdo.chr11.34), was estimated to be 250 Kb in the 'Golden Delicious' apple genome and 107 Kb in the 'Dangshansuli' Chinese pear genome. Our results will help to identify the candidate gene for susceptibility to black spot disease in Japanese pear.

  2. Fine mapping of the gene for susceptibility to black spot disease in Japanese pear (Pyrus pyrifolia Nakai).

    PubMed

    Terakami, Shingo; Moriya, Shigeki; Adachi, Yoshihiko; Kunihisa, Miyuki; Nishitani, Chikako; Saito, Toshihiro; Abe, Kazuyuki; Yamamoto, Toshiya

    2016-03-01

    Black spot disease, which is caused by the Japanese pear pathotype of the filamentous fungus Alternaria alternata (Fries) Keissler, is one of the most harmful diseases in Japanese pear cultivation. We mapped a gene for susceptibility to black spot disease in the Japanese pear (Pyrus pyrifolia Nakai) cultivar 'Kinchaku' (Aki gene) at the top of linkage group 11, similar to the positions of the susceptibility genes Ani in 'Osa Nijisseiki' and Ana in 'Nansui'. Using synteny-based marker enrichment, we developed novel apple SSR markers in the target region. We constructed a fine map of linkage group 11 of 'Kinchaku' and localized the Aki locus within a 1.5-cM genome region between SSR markers Mdo.chr11.28 and Mdo.chr11.34. Marker Mdo.chr11.30 co-segregated with Aki in all 621 F1 plantlets of a 'Housui' × 'Kinchaku' cross. The physical size of the Aki region, which includes three markers (Mdo.chr11.28, Mdo.chr11.30, and Mdo.chr11.34), was estimated to be 250 Kb in the 'Golden Delicious' apple genome and 107 Kb in the 'Dangshansuli' Chinese pear genome. Our results will help to identify the candidate gene for susceptibility to black spot disease in Japanese pear. PMID:27162498

  3. Susceptibility loci for lung cancer are associated with mRNA levels of nearby genes in the lung.

    PubMed

    Nguyen, Justin Dang Uy; Lamontagne, Maxime; Couture, Christian; Conti, Massimo; Paré, Peter D; Sin, Don D; Hogg, James C; Nickle, David; Postma, Dirkje S; Timens, Wim; Laviolette, Michel; Bossé, Yohan

    2014-12-01

    Recent studies identified three genetic loci reproducibly associated with lung cancer in populations of European ancestry, namely 15q25, 5p15 and 6p21. The goals of this study are first to confirm whether these loci are associated with lung cancer in a French Canadian population and second to identify disease-associated single nucleotide polymorphisms (SNPs) influencing messenger RNA (mRNA) expression levels of genes in the lung, that is expression quantitative trait loci (eQTLs). SNPs were genotyped in 420 patients undergoing lung cancer surgery and compared with 3151 controls of European ancestry. Genome-wide gene expression levels in non-tumor lung tissues of the same 420 patients were also measured to identify eQTLs. Significant eQTLs were then followed-up in two replication sets (n = 339 and 363). SNPs found in the three susceptibility loci were associated with lung cancer in the French Canadian population. Strong eQTLs were found on chromosome 15q25 with the expression levels of CHRNA5 (P = 2.23 × 10(-) (22) with rs12907966). The CHRNA5-rs12907966 eQTL was convincingly validated in the two replication sets (P = 3.46 × 10(-) (16) and 2.01 × 10(-) (15)). On 6p21, a trend was observed for rs3131379 to be associated with the expression of APOM (P = 3.58 × 10(-) (4)) and validated in the replication sets (P = 1.11 × 10(-) (8) and 6.84 × 10(-) (4)). On 5p15, no significant eQTLs were found. This study confirmed that chromosomes 15q25, 5p15 and 6p21 harbored susceptibility loci for lung cancer in French Canadians. Most importantly, this study suggests that the risk alleles at 15q25 and 6p21 may mediate their effect by regulating the mRNA expression levels of CHRNA5 and APOM in the lung.

  4. Susceptibility loci for lung cancer are associated with mRNA levels of nearby genes in the lung

    PubMed Central

    Nguyen, Justin Dang Uy; Lamontagne, Maxime; Couture, Christian; Conti, Massimo; Paré, Peter D.; Sin, Don D.; Hogg, James C.; Nickle, David; Postma, Dirkje S.; Timens, Wim; Laviolette, Michel; Bossé, Yohan

    2014-01-01

    Recent studies identified three genetic loci reproducibly associated with lung cancer in populations of European ancestry, namely 15q25, 5p15 and 6p21. The goals of this study are first to confirm whether these loci are associated with lung cancer in a French Canadian population and second to identify disease-associated single nucleotide polymorphisms (SNPs) influencing messenger RNA (mRNA) expression levels of genes in the lung, that is expression quantitative trait loci (eQTLs). SNPs were genotyped in 420 patients undergoing lung cancer surgery and compared with 3151 controls of European ancestry. Genome-wide gene expression levels in non-tumor lung tissues of the same 420 patients were also measured to identify eQTLs. Significant eQTLs were then followed-up in two replication sets (n = 339 and 363). SNPs found in the three susceptibility loci were associated with lung cancer in the French Canadian population. Strong eQTLs were found on chromosome 15q25 with the expression levels of CHRNA5 (P = 2.23 × 10− 22 with rs12907966). The CHRNA5-rs12907966 eQTL was convincingly validated in the two replication sets (P = 3.46 × 10− 16 and 2.01 × 10− 15). On 6p21, a trend was observed for rs3131379 to be associated with the expression of APOM (P = 3.58 × 10− 4) and validated in the replication sets (P = 1.11 × 10− 8 and 6.84 × 10− 4). On 5p15, no significant eQTLs were found. This study confirmed that chromosomes 15q25, 5p15 and 6p21 harbored susceptibility loci for lung cancer in French Canadians. Most importantly, this study suggests that the risk alleles at 15q25 and 6p21 may mediate their effect by regulating the mRNA expression levels of CHRNA5 and APOM in the lung. PMID:25187487

  5. Antimicrobial Susceptibilities and Distribution of Resistance Genes for β-Lactams in Streptococcus pneumoniae Isolated in Hamadan

    PubMed Central

    Najafi Mosleh, Mohammad; Gharibi, Marzieh; Alikhani, Mohammad Yousef; Saidijam, Massoud; Kalantarian, Giti

    2014-01-01

    Background: β-lactams resistant Streptococcus pneumoniae are an emerging problem throughout the world. Several resistance mechanisms have been reported, including expression of drug-destroying enzymes such as β-lactamases, altered drug targets such as conformational changes in PBPs, decreased bacterial permeability, and increased drug efflux. Objectives: The present study aimed to determine the relationship between the results of polymerase chain reaction identification of the Pbp1a, Pbp2b and Pbp2x genes (penicillin-binding proteins) and susceptibilities of β-lactam antibiotics against S. pneumoniae. Materials and Methods: Fifty five isolates of S. pneumoniae were obtained from clinical samples with antimicrobial tests. The susceptibilities of isolates to benzylpenicillin, imipenem, oxacillin, ceftazidime were determined. The resistance genotype was determined by the polymerase chain reaction with primers designed for the PBP genes. Results: The number of S. pneumoniae isolates resistant to benzylpenicillin, imipenem, oxacillin and ceftazidime were 94.5%, 100%, 100%, and 21.8%, respectively. Analysis of mutation in the genes for pbp showed that 85% of isolates had mutations in pbp2x, pbp2b and pbp1a. Susceptibility to benzylpenicillin was decreased once the number of mutated pbp genes in S. pneumonia increased. According to the results of this study, S. pneumoniae isolates showed reduced susceptibility due to accumulation of resistance genes. Conclusions: We suggest that studies should be performed to evaluate changes in Minimum Inhibitory Concentration (MIC) values as well as genetic mutations in order to determine prevalence of S. pneumoniae resistance against antimicrobial agents. PMID:25632328

  6. Do the mutations of C1GALT1C1 gene play important roles in the genetic susceptibility to Chinese IgA nephropathy?

    PubMed Central

    Li, Gui-Sen; Nie, Guang-Jun; Zhang, Hong; LV, Ji-Cheng; Shen, Yan; Wang, Hai-Yan

    2009-01-01

    Background The deficiency of β1,3 galactose in hinge region of IgA1 molecule played a pivotal role in pathogenesis of IgA nephropathy (IgAN). Cosmc, encoded by C1GALT1C1 gene, was indispensable to β1,3 galactosylation of IgA1. We designed a serial study to investigate the relationship between the mutations of C1GALT1C1 gene and the genetic susceptibility to IgAN. Methods Nine hundred and thirty-eight subjects, including 661 patients with IgAN and 277 healthy controls were enrolled in the study. Firstly, single nucleotide polymorphisms (SNPs) in the promoter region of C1GALT1C1 gene were screened. Then the c.-347-190G>A was analyzed by PCR-restriction fragment length polymorphism (PCR-RFLP) for further case-control association analysis. Secondly the somatic mutations of DNAs from peripheral blood B lymphocytes were detected in 15 patients and 7 normal controls. Results No significant association was observed between the different alleles or genotypes of c.-347-190G>A and IgAN. The patients with different genotypes of C1GALT1C1 gene did not significantly associate with clinical manifestations, including hematuria, proteinuria, and serum creatinine of patients with IgAN. There was no somatic mutation detected in total 202 clones of 22 individuals. Conclusion The c.-347-190G>A polymorphism and the somatic mutation of encoding region of C1GALT1C1 gene were not significantly related to the genetic susceptibility to IgAN in Northern Chinese population. PMID:19778426

  7. Genetic identification of multiple loci that control breast cancer susceptibility in the rat.

    PubMed Central

    Shepel, L A; Lan, H; Haag, J D; Brasic, G M; Gheen, M E; Simon, J S; Hoff, P; Newton, M A; Gould, M N

    1998-01-01

    We have used a rat model of induced mammary carcinomas in an effort to identify breast cancer susceptibility genes. Using genetic crosses between the carcinoma-resistant Copenhagen (COP) and carcinoma-sensitive Wistar-Furth rats, we have confirmed the identification of the Mcs1 locus that modulates tumor number. We have now also identified two additional loci, Mcs2 and Mcs3. These three loci map to chromosomes 2, 7, and 1, respectively, and interact additively to suppress mammary carcinoma development in the COP strain. They are responsible for a major portion of the tumor-resistant phenotype of the COP rat. No loss of heterozygosity was observed surrounding the three loci. A fourth COP locus, Mcs4, has also been identified on chromosome 8 and acts in contrast to increase the number of carcinomas. These results show that mammary carcinoma susceptibility in the COP rat is a polygenic trait. Interestingly, a polymorphism in the human genomic region homologous to the rat Mcs4 region is associated with an increased breast cancer risk in African-American women. The isolation of the Mcs genes may help elucidate novel mechanisms of carcinogenesis, provide information important for human breast cancer risk estimation, and also provide unique drug discovery targets for breast cancer prevention. PMID:9584103

  8. Association of genetic variants of cancer stem cell gene CD44 haplotypes with gallbladder cancer susceptibility in North Indian population.

    PubMed

    Sharma, Kiran Lata; Yadav, Anu; Gupta, Annapurna; Tulsayan, Sonam; Kumar, Vijay; Misra, Sanjeev; Kumar, Ashok; Mittal, Balraj

    2014-03-01

    CD44 is an important marker for cancer stem cells. Germline variants in CD44 gene have been associated with susceptibility to breast and nasopharyngeal carcinomas but no study in gallbladder cancer (GBC) has been done yet. The present study included 405 GBC patients and 200 healthy controls from North India. Tagger SNPs for CD44 were selected from the GIH population data. Genotyping was carried out by PCR-RFLP and Taqman probes. Statistical analysis was done by SPSS. Bonferroni correction was applied in subgroup analysis. Logistic regression analysis showed no individual association of CD44 polymorphisms with GBC risk. However, [CCAT] haplotype was associated with overall reduced risk of GBC [P = 0.04, odds ratios (OR) = 0.47]. Gender stratification revealed that [CCAT] and [TAGT] haplotypes were significantly associated with decreased risk in female GBC patients [P = 0.022, OR = 0.38; P = 0.011, OR = 0.17, respectively]. The CAAT haplotype was marginally associated with low GBC risk in patients with co-existing gallstones [P = 0.026, OR = 0.53]. The cancer risk was not further modified with tobacco usage or age of onset. In silico analysis showed change in transcriptional regulation of selected SNPs. This study reports an important role of CD44 haplotypes with reduced risk of GBC.

  9. Insecticide susceptibility of Phlebotomus argentipes & assessment of vector control in two districts of West Bengal, India

    PubMed Central

    Kumar, Vijay; Shankar, Lokesh; Kesari, Shreekant; Bhunia, Gouri Shankar; Dinesh, Diwakar Singh; Mandal, Rakesh; Das, Pradeep

    2015-01-01

    Background & objectives: Kala-azar or visceral leishmanisis (VL) is known to be endemic in several States of India including West Bengal (WB). Only meager information is available on the vector dynamics of its vector species, Phlebotomus argentipes particularly in relation to control measure from this State. Hence, a pilot study was undertaken to assess the control strategy and its impact on vector in two endemic districts of WB, India. Methods: Two villages each from the two districts, Maldah and Burdwan, were selected for the study. Seasonal variation of sandflies was observed during pre-monsoon, post-monsoon and winter seasons. Susceptibility test of P. argentipes against DDT and bioassay on DDT sprayed wall and on long lasting insecticide nets (LN) Perma Net® 2.0 were conducted as per the WHO standard methods. Results: P. argentipes density was high during March to October. Susceptibility status of P. argentipes ranged from 40 to 61.54 per cent. Bioassay test showed 57.89 per cent mortality against LN PermaNet®-2.0. and 50 per cent against DDT on wall within 30 min of exposure. Interpretation & conclusions: Despite the integrated vector management approach, the sandfly population was high in the study area. The reason could be development of resistance in P. argentipes against DDT and low effectiveness of LN PermaNet®-2.0. The more pragmatic step will be to conduct large studies to monitor the susceptibility level in P. argentipes against DDT. PMID:26354219

  10. Antimicrobial Susceptibility of Klebsiella pneumoniae and Escherichia coli with Extended-Spectrum β-lactamase associated Genes in Hospital Tengku Ampuan Afzan, Kuantan, Pahang

    PubMed Central

    Mahdi Yahya Mohsen, Saleh; Hamzah, Hairul Aini; Muhammad Imad Al-Deen, Mustafa; Baharudin, Roesnita

    2016-01-01

    Background To assess antimicrobial susceptibility of extended-spectrum β-lactamase- (ESBL-) producing Klebsiella pneumoniae and Escherichia coli isolates from Hospital Tengku Ampuan Afzan (HTAA), as well as to identify ESBL genes. Methods Non-duplicate K. pneumoniae and E. coli isolates were recovered from various clinical samples. Isolates were screened for antimicrobial resistance by disc diffusion method. Isolates resistant to oxyimino-cephalosporins were subjected to phenotypic ESBL production. Detection of resistance genes was then performed using primers specific for ESBL genes (blaCTX-M, blaSHV and blaTEM). Results Piperacillin/tazobactam and carbapenems remained the active β-lactam antibiotic against K. pneumoniae and E. coli. ESBLs were detected among 35.5% (39/110) of K. pneumoniae and 18.8% (28/149) of E. coli isolates. CTX-M β-lactamase was detected in 90% of all ESBL-positive isolates, whereas blaSHV and blaTEM genes were found among 56% and 52% of them, respectively. Twenty-eight percent (28%) of the total ESBL-positive isolates harboured the three ESBL genes, while 50% carried two of the tested ESBL genes. Conclusion ESBLs encoded by at least one ESBL genes are frequently isolated among K. pneumoniae and E. coli in HTAA. The significant proportion rate of these resistant determinants is alarming, thus monitoring their transmission and dissemination is essential to control it at an early phase. PMID:27547110

  11. Transcription profiling of immune genes during parasite infection in susceptible and resistant strains of the flour beetles (Tribolium castaneum).

    PubMed

    Zhong, Daibin; Wang, Mei-Hui; Pai, Aditi; Yan, Guiyun

    2013-05-01

    The flour beetle, Tribolium castaneum, is an intermediate host for the tapeworm Hymenolepis diminuta and has become an important genetic model to explore immune responses to parasite infection in insect hosts. The present study examined the immune responses to tapeworm infection in resistant (TIW1) and susceptible (cSM) strains of the red flour beetle, T. castaneum, using real-time quantitative reverse transcription PCR on 29 immunity-related genes that exhibit antimicrobial properties. Thirteen of the 29 genes showed constitutive differences in expression between the two strains. Fourteen to fifteen of the 29 genes exhibited significant differences in transcription levels when beetles were challenged with tapeworm parasite in the resistant and susceptible strains. Nine genes (GNBP3, cSPH2, lysozyme4, defensin1, PGRP-SA, defensin2, coleoptericin1, attacin2 and serpin29) in cSM and 13 genes (lysozyme2, proPO1, GNBP3, cSPH2, lysozyme4, defensin1, PGRP-SA, defensin2, coleoptericin1, attacin2, proPO2/3, PGRP-LE and PGRP-SB) in TIW1 were up-regulated by infections or showed parasite infection-induced expression. Seven genes (attacin2, coleoptericin1, defensin1, defensin2, lysozyme2, PGRP-SA and PGRP-SB) were more than 10 folds higher in the resistant TIW1 strain than in the susceptible cSM strain after exposure to tapeworm parasites. This study demonstrated the effects of genetic background, the transcription profile to parasite infection, and identified the immunity-related genes that were significantly regulated by the infection of tapeworms in Tribolium beetles.

  12. Genes controlling root development in rice.

    PubMed

    Mai, Chung D; Phung, Nhung Tp; To, Huong Tm; Gonin, Mathieu; Hoang, Giang T; Nguyen, Khanh L; Do, Vinh N; Courtois, Brigitte; Gantet, Pascal

    2014-12-01

    In this review, we report on the recent developments made using both genetics and functional genomics approaches in the discovery of genes controlling root development in rice. QTL detection in classical biparental mapping populations initially enabled the identification of a very large number of large chromosomal segments carrying root genes. Two segments with large effects have been positionally cloned, allowing the identification of two major genes. One of these genes conferred a tolerance to low phosphate content in soil, while the other conferred a tolerance to drought by controlling root gravitropism, resulting in root system expansion deep in the soil. Findings based on the higher-resolution QTL detection offered by the development of association mapping are discussed. In parallel with genetics approaches, efforts have been made to screen mutant libraries for lines presenting alterations in root development, allowing for the identification of several genes that control different steps of root development, such as crown root and lateral root initiation and emergence, meristem patterning, and the control of root growth. Some of these genes are closely phylogenetically related to Arabidopsis genes involved in the control of lateral root initiation. This close relationship stresses the conservation among plant species of an auxin responsive core gene regulatory network involved in the control of post-embryonic root initiation. In addition, we report on several genetic regulatory pathways that have been described only in rice. The complementarities and the expected convergence of the direct and reverse genetic approaches used to decipher the genetic determinants of root development in rice are discussed in regards to the high diversity characterizing this species and to the adaptations of rice root system architecture to different edaphic environments.

  13. Penicillin-resistant, ampicillin-susceptible Enterococcus faecalis of hospital origin: pbp4 gene polymorphism and genetic diversity.

    PubMed

    Conceição, Natália; da Silva, Lucas Emanuel Pinheiro; Darini, Ana Lúcia da Costa; Pitondo-Silva, André; de Oliveira, Adriana Gonçalves

    2014-12-01

    Despite the spread of penicillin-resistant, ampicillin-susceptible Enterococcus faecalis (PRASEF) isolates in diverse countries, the mechanisms leading to this unusual resistance phenotype have not yet been investigated. The aim of this study was to evaluate whether polymorphism in the pbp4 gene is associated with penicillin resistance in PRASEF isolates and to determine their genetic diversity. E. faecalis isolates were recovered from different clinical specimens of hospitalized patients from February 2006 to June 2010. The β-lactam minimal inhibitory concentrations (MICs) were determined by E-test®. The PCR-amplified pbp4 gene was sequenced with an automated sequencer. The genetic diversities of the isolates were established by PFGE (pulsed-field gel electrophoresis) and MLST (multilocus sequencing typing). Seventeen non-producing β-lactamase PRASEF and 10 penicillin-susceptible, ampicillin-susceptible E. faecalis (PSASEF) strains were analyzed. A single-amino-acid substitution (Asp-573→Glu) in the penicillin-binding domain was significantly found in all PRASEF isolates by sequencing of the pbp4 gene but not in the penicillin-susceptible isolates. In contrast to the PSASEF isolates, a majority of the PRASEFs had similar PFGE profiles. Six representative PRASEF isolates were resolved by MLST into ST9 and ST524 and belong to the globally dispersed clonal complex 9 (CC9). In conclusion, it appears quite likely that the amino acid alteration (Asp-573→Glu) found in the PBP4 of the Brazilian PRASEF isolates may account for their reduced susceptibility to penicillin, although other resistance mechanisms remain to be investigated.

  14. Exome sequencing followed by genotyping suggests SYPL2 as a susceptibility gene for morbid obesity

    PubMed Central

    Jiao, Hong; Arner, Peter; Gerdhem, Paul; Strawbridge, Rona J; Näslund, Erik; Thorell, Anders; Hamsten, Anders; Kere, Juha; Dahlman, Ingrid

    2015-01-01

    Recently developed high-throughput sequencing technology shows power to detect low-frequency disease-causing variants by deep sequencing of all known exons. We used exome sequencing to identify variants associated with morbid obesity. DNA from 100 morbidly obese adult subjects and 100 controls were pooled (n=10/pool), subjected to exome capture, and subsequent sequencing. At least 100 million sequencing reads were obtained from each pool. After several filtering steps and comparisons of observed frequencies of variants between obese and non-obese control pools, we systematically selected 144 obesity-enriched non-synonymous, splicing site or 5′ upstream single-nucleotide variants for validation. We first genotyped 494 adult subjects with morbid obesity and 496 controls. Five obesity-associated variants (nominal P-value<0.05) were subsequently genotyped in 1425 morbidly obese and 782 controls. Out of the five variants, only rs62623713:A>G (NM_001040709:c.A296G:p.E99G) was confirmed. rs62623713 showed strong association with body mass index (beta=2.13 (1.09, 3.18), P=6.28 × 10−5) in a joint analysis of all 3197 genotyped subjects and had an odds ratio of 1.32 for obesity association. rs62623713 is a low-frequency (2.9% minor allele frequency) non-synonymous variant (E99G) in exon 4 of the synaptophysin-like 2 (SYPL2) gene. rs62623713 was not covered by Illumina or Affymetrix genotyping arrays used in previous genome-wide association studies. Mice lacking Sypl2 has been reported to display reduced body weight. In conclusion, using exome sequencing we identified a low-frequency coding variant in the SYPL2 gene that was associated with morbid obesity. This gene may be involved in the development of excess body fat. PMID:25406998

  15. Exome sequencing followed by genotyping suggests SYPL2 as a susceptibility gene for morbid obesity.

    PubMed

    Jiao, Hong; Arner, Peter; Gerdhem, Paul; Strawbridge, Rona J; Näslund, Erik; Thorell, Anders; Hamsten, Anders; Kere, Juha; Dahlman, Ingrid

    2015-09-01

    Recently developed high-throughput sequencing technology shows power to detect low-frequency disease-causing variants by deep sequencing of all known exons. We used exome sequencing to identify variants associated with morbid obesity. DNA from 100 morbidly obese adult subjects and 100 controls were pooled (n=10/pool), subjected to exome capture, and subsequent sequencing. At least 100 million sequencing reads were obtained from each pool. After several filtering steps and comparisons of observed frequencies of variants between obese and non-obese control pools, we systematically selected 144 obesity-enriched non-synonymous, splicing site or 5' upstream single-nucleotide variants for validation. We first genotyped 494 adult subjects with morbid obesity and 496 controls. Five obesity-associated variants (nominal P-value<0.05) were subsequently genotyped in 1425 morbidly obese and 782 controls. Out of the five variants, only rs62623713:A>G (NM_001040709:c.A296G:p.E99G) was confirmed. rs62623713 showed strong association with body mass index (beta=2.13 (1.09, 3.18), P=6.28 × 10(-5)) in a joint analysis of all 3197 genotyped subjects and had an odds ratio of 1.32 for obesity association. rs62623713 is a low-frequency (2.9% minor allele frequency) non-synonymous variant (E99G) in exon 4 of the synaptophysin-like 2 (SYPL2) gene. rs62623713 was not covered by Illumina or Affymetrix genotyping arrays used in previous genome-wide association studies. Mice lacking Sypl2 has been reported to display reduced body weight. In conclusion, using exome sequencing we identified a low-frequency coding variant in the SYPL2 gene that was associated with morbid obesity. This gene may be involved in the development of excess body fat. PMID:25406998

  16. Evaluation of Adenosine Triphosphate-Binding Cassette Transporter A1 (ABCA1) R219K and C-Reactive Protein Gene (CRP) +1059G/C Gene Polymorphisms in Susceptibility to Coronary Heart Disease.

    PubMed

    Li, Jing-Fang; Peng, Dian-Ying; Ling, Mei; Yin, Yong

    2016-01-01

    BACKGROUND This meta-analysis investigated the correlation of ABCA1 R219K and C-Reactive Protein Gene (CRP) +1059G/C gene polymorphisms with susceptibility to coronary heart disease (CHD). MATERIAL AND METHODS We searched PubMed, Springer link, Wiley, EBSCO, Ovid, Wanfang database, VIP database, and China National Knowledge Infrastructure (CNKI) databases to retrieve published studies by keyword. Searches were filtered using our stringent inclusion and exclusion criteria. Resultant high-quality data collected from the final selected studies were analyzed using Comprehensive Meta-analysis 2.0 software. Eleven case-control studies involving 3053 CHD patients and 3403 healthy controls met our inclusion criteria. Seven studies were conducted in Asian populations, 3 studies were done in Caucasian populations, and 1 was in an African population. RESULTS Our major finding was that ABCA1 R219K polymorphism increased susceptibility to CHD in allele model (OR=0.729, 95% CI=0.559~0.949, P=0.019) and dominant model (OR=0.698, 95% CI=0.507~0.961, P=0.027). By contrast, we were unable to find any significant association between the CRP +1059G/C polymorphism and susceptibility to CHD (allele model: OR=1.170, 95% CI=0.782~1.751, P=0.444; dominant model: OR=1.175, 95% CI=0.768~1.797, P=0.457). CONCLUSIONS This meta-analysis provides convincing evidence that polymorphism of ABCA1 R219K is associated with susceptibility to CHD while the CRP +1059G/C polymorphism appears to have no correlation with susceptibility to CHD. PMID:27560308

  17. Evaluation of Adenosine Triphosphate-Binding Cassette Transporter A1 (ABCA1) R219K and C-Reactive Protein Gene (CRP) +1059G/C Gene Polymorphisms in Susceptibility to Coronary Heart Disease.

    PubMed

    Li, Jing-Fang; Peng, Dian-Ying; Ling, Mei; Yin, Yong

    2016-08-25

    BACKGROUND This meta-analysis investigated the correlation of ABCA1 R219K and C-Reactive Protein Gene (CRP) +1059G/C gene polymorphisms with susceptibility to coronary heart disease (CHD). MATERIAL AND METHODS We searched PubMed, Springer link, Wiley, EBSCO, Ovid, Wanfang database, VIP database, and China National Knowledge Infrastructure (CNKI) databases to retrieve published studies by keyword. Searches were filtered using our stringent inclusion and exclusion criteria. Resultant high-quality data collected from the final selected studies were analyzed using Comprehensive Meta-analysis 2.0 software. Eleven case-control studies involving 3053 CHD patients and 3403 healthy controls met our inclusion criteria. Seven studies were conducted in Asian populations, 3 studies were done in Caucasian populations, and 1 was in an African population. RESULTS Our major finding was that ABCA1 R219K polymorphism increased susceptibility to CHD in allele model (OR=0.729, 95% CI=0.559~0.949, P=0.019) and dominant model (OR=0.698, 95% CI=0.507~0.961, P=0.027). By contrast, we were unable to find any significant association between the CRP +1059G/C polymorphism and susceptibility to CHD (allele model: OR=1.170, 95% CI=0.782~1.751, P=0.444; dominant model: OR=1.175, 95% CI=0.768~1.797, P=0.457). CONCLUSIONS This meta-analysis provides convincing evidence that polymorphism of ABCA1 R219K is associated with susceptibility to CHD while the CRP +1059G/C polymorphism appears to have no correlation with susceptibility to CHD.

  18. Meta-Analysis of Apolipoprotein E Gene Polymorphism and Susceptibility of Myocardial Infarction

    PubMed Central

    Xu, Hong; Li, Haiqing; Liu, Jun; Zhu, Dan; Wang, Zhe; Chen, Anqing; Zhao, Qiang

    2014-01-01

    A number of case-control studies have been conducted to clarify the association between ApoE polymorphisms and myocardial infarction (MI); however, the results are inconsistent. This meta-analysis was performed to clarify this issue using all the available evidence. Searching in PubMed retrieved all eligible articles. A total of 33 studies were included in this meta-analysis, including 18752 MI cases and 18963 controls. The pooled analysis based on all included studies showed that the MI patients had a decreased frequency of the ε2 allele (OR = 0.78, 95% CI = 0.70–0.87) and an increased frequency of the ε4 allele (OR = 1.15, 95% CI = 1.10–1.20); The results also showed a decreased susceptibility of MI in the ε2ε3 vs. ε3ε3 analysis (OR = 0.79, 95% CI = 0.68–0.90) and in the ε2 vs. ε3 analysis (OR = 0.78, 95% CI = 0.69–0.89), an increased susceptibility of MI in the ε3ε4 vs. ε3ε3 analysis (OR = 1.26, 95% CI = 1.12–1.41), in the ε4 vs. ε3 analysis (OR = 1.22, 95% CI = 1.12–1.32) and in the ε4ε4 vs. ε3ε3 analysis (OR = 1.59, 95% CI = 1.15–2.19). However, there were no significant associations among polymorphisms and MI for the following genetic models: frequency of the ε3 allele (OR = 0.99, 95% CI = 0.96–1.02); ε2ε2 vs. ε3ε3 analysis (OR = 0.73, 95% CI = 0.40–1.32); or ε2ε4 vs. ε3ε3 analysis (OR = 1.10, 95% CI = 0.99–1.21). Our results suggested that the ε4 allele of ApoE is a risk factor for the development of MI and the ε2 allele of ApoE is a protective factor in the development of MI. PMID:25111308

  19. Differential distribution of plasmid-mediated quinolone resistance genes in clinical enterobacteria with unusual phenotypes of quinolone susceptibility from Argentina.

    PubMed

    Andres, Patricia; Lucero, Celeste; Soler-Bistué, Alfonso; Guerriero, Leonor; Albornoz, Ezequiel; Tran, Tung; Zorreguieta, Angeles; Galas, Marcelo; Corso, Alejandra; Tolmasky, Marcelo E; Petroni, Alejandro

    2013-06-01

    We studied a collection of 105 clinical enterobacteria with unusual phenotypes of quinolone susceptibility to analyze the occurrence of plasmid-mediated quinolone resistance (PMQR) and oqx genes and their implications for quinolone susceptibility. The oqxA and oqxB genes were found in 31/34 (91%) Klebsiella pneumoniae and 1/3 Klebsiella oxytoca isolates. However, the oqxA- and oqxB-harboring isolates lacking other known quinolone resistance determinants showed wide ranges of susceptibility to nalidixic acid and ciprofloxacin. Sixty of the 105 isolates (57%) harbored at least one PMQR gene [qnrB19, qnrB10, qnrB2, qnrB1, qnrS1, or aac(6')-Ib-cr)], belong to 8 enterobacterial species, and were disseminated throughout the country, and most of them were categorized as susceptible by the current clinical quinolone susceptibility breakpoints. We developed a disk diffusion-based method to improve the phenotypic detection of aac(6')-Ib-cr. The most common PMQR genes in our collection [qnrB19, qnrB10, and aac(6')-Ib-cr] were differentially distributed among enterobacterial species, and two different epidemiological settings were evident. First, the species associated with community-acquired infections (Salmonella spp. and Escherichia coli) mainly harbored qnrB19 (a unique PMQR gene) located in small ColE1-type plasmids that might constitute its natural reservoirs. qnrB19 was not associated with an extended-spectrum β-lactamase phenotype. Second, the species associated with hospital-acquired infections (Enterobacter spp., Klebsiella spp., and Serratia marcescens) mainly harbored qnrB10 in ISCR1-containing class 1 integrons that may also have aac(6')-Ib-cr as a cassette within the variable region. These two PMQR genes were strongly associated with an extended-spectrum β-lactamase phenotype. Therefore, this differential distribution of PMQR genes is strongly influenced by their linkage or lack of linkage to integrons.

  20. Differentially regulated genes in the salivary glands of brown planthopper after feeding in resistant versus susceptible rice varieties.

    PubMed

    Wang, Xiaolan; Zhang, Mei; Feng, Fei; He, Ruifeng

    2015-06-01

    Brown planthopper (BPH) is a damaging insect pest of rice. We used suppression subtractive hybridization (SSH) and mirror orientation selection to identify differentially regulated genes in salivary glands of BPH after feeding on resistant and susceptible varieties. The forward SSH library included 768 clones with insertions ranging from 250 to 1000 bp. After differential screening, a total of 112 transcripts were identified, which included 27 upregulated genes and seven downregulated genes. Several of these transcripts showed sequence homology to known proteins such as trehalase, mucin-like protein, vitellogenin, calcium ion binding protein, and eukaryotic initiation factor-like protein. About half of the transcripts, however, did not match to any sequences in the protein databases currently available. Functional annotation of the transcripts showed gene ontology association with metabolism, signal transduction, and regulatory responses. Notably, many known functional genes were predicted to be secreted proteins. Also, gene expression profiles of the salivary glands of BPH feeding on resistant rice (B5) and susceptible rice (TN1) varieties were compared. Our data provide a molecular resource for future functional studies on salivary glands and will be useful for elucidating the molecular mechanisms between BPH feeding and rice varieties with BPH resistance differences.

  1. Antimicrobial susceptibility, virulence gene profiles and molecular subtypes of Salmonella Newport isolated from humans and other sources.

    PubMed

    Kuang, Dai; Xu, Xuebin; Meng, Jianghong; Yang, Xiaowei; Jin, Huiming; Shi, Weimin; Pan, Haijian; Liao, Ming; Su, Xudong; Shi, Xianmin; Zhang, Jianmin

    2015-12-01

    Salmonella Newport (S. Newport) is a major serotype associated with human salmonellosis. A total of 79 S. Newport recovered from humans and other sources in China were characterized for antimicrobial susceptibility, virulence gene profiles and molecular subtypes using pulsed field gel electrophoresis (PFGE). Approximately 63.3% of the isolates were susceptible to all of 16 antimicrobials tested. Nearly one third of the isolates (31.6%) were resistant to sulfisoxazole, 20.3% to tetracycline and 13.9% to nalidixic acid. Twelve isolates (15.2%) were resistant to three or more antimicrobials. Among 10 virulence genes detected, Salmonella pathogenicity island genes avrA, ssaQ, mgtC, siiD, and sopB and fimbrial gene bcfC were present in most of the isolates (93.7% to 100%). Overall, we observed nine distinct virulence gene profiles, three of which (VP1, VP2 and VP3) were most common (86.1%). A total of 56 PFGE patterns were identified and mainly grouped into seven clusters (A to G) with 80% pattern similarity. Isolates from aquatic product shared a high similarity with those from humans in several clusters, highlighting a potential risk of aquatic product as a source of S. Newport that infect humans. Furthermore, there was a strong association between certain PFGE clusters and virulence gene profiles, suggesting virulence subtyping can be a useful epidemiological tool to discriminate S. Newport isolates.

  2. Host genetic variations in glutathione-S-transferases, superoxide dismutases and catalase genes influence susceptibility to malaria infection in an Indian population.

    PubMed

    Fernandes, Rayzel C; Hasan, Marriyah; Gupta, Himanshu; Geetha, K; Rai, Padmalatha S; Hande, Manjunath H; D'Souza, Sydney C; Adhikari, Prabha; Brand, Angela; Satyamoorthy, Kapaettu

    2015-06-01

    Antioxidant enzymes can contribute to disease susceptibility or determine response to therapy in individuals with malaria. Genetic variations due to polymorphisms in host genes encoding antioxidant enzymes such as glutathione S-transferases-theta, mu, pi (GSTT, GSTM, GSTP), superoxide dismutases (SOD) and catalase (CAT), may therefore, influence inter-individual response to malaria pathology and propensity of infection caused by Plasmodium vivax (Pv) and Plasmodium falciparum (Pf). Therefore, using polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) and DNA sequencing, we investigated the association of deletions of GSTT1 and GSTM1, single nucleotide polymorphisms (SNPs) of GSTP1 (rs1695), SOD1 (rs2234694), SOD2 (rs4880, rs1141718), SOD3 (rs2536512) and CAT (rs1001179) in individuals infected with Pf (n = 100) and Pv (n = 100) against healthy controls (n = 150). Our data suggest a significant role for GSTM1 deletions in complicated Pv (p = 0.0007) malaria with ODDs ratio 3.8 [with 95 % confidence interval (CI) 1.9-7.4]. The results also indicated that polymorphisms present in GSTP1, SOD1 and CAT genes may be associated with malaria susceptibility (p < 0.05), whereas SOD3 polymorphism may play a role in malarial resistance (p < 0.05). In addition, we observed significant SNP-SNP interactions with synergistic genetic effects in SOD2, SOD3 and CAT genes for Pv and in SOD2 and SOD3 genes for Pf. In conclusion, our results provide convincing evidence for a relationship between polymorphisms in host antioxidant enzymes and susceptibility to malaria infection.

  3. Polymorphism of CYP1A1 gene and susceptibility to childhood acute lymphoblastic leukemia in Egypt.

    PubMed

    Agha, Adel; Shabaan, Howyda; Abdel-Gawad, Eman; El-Ghannam, Doaa

    2014-03-01

    The origin of acute lymphoblastic leukemia (ALL) may be explained by a combination of genetic susceptibility and environmental exposure. We aimed to study the frequency of CYP1A1 allelic variants in Egyptian patients with ALL, to evaluate their role in the development of ALL and to correlate these allelic variants with clinical and biological characteristics of the patients. Polymorphism of CYP1A1*2A, *2B and *4 alleles was examined in 186 Egyptian children with ALL and 200 normal individuals using polymerase chain reaction-single stranded conformation polymorphism (PCR-SSCP). A higher prevalence of the CYP1A1*4 allele was found in patients with ALL than in the normal population (19.4%vs. 10.0%, odds ratio [OR] = 2.160, 95% confidence interval [CI] = 1.200-3.89, p = 0.01), especially in the homozygous variant (OR = 6.6, 95% CI = 2.23-19.58, p = 0.001) and in male patients (p = 0.005), particularly those aged 2-10 years (OR = 5.214, 95% CI = 1.535-17.706, p = 0.008). CYP1A1*2A showed a significant difference between age groups (p = 0.046), with a higher incidence in the 10-17-year-old group (21.1%). Multivariate analysis showed that only the CYP1A1*4 allele remained as a probable independent risk factor for ALL development (OR = 2.250, 95% CI = 1.244-4.069; p = 0.007). Our results suggest that polymorphic variants in the CYP1A1*4 gene may increase the risk of childhood ALL, particularly in male patients aged 2-10 years.

  4. The schizophrenia susceptibility gene neuregulin 1 modulates tolerance to the effects of cannabinoids.

    PubMed

    Boucher, Aurélie A; Hunt, Glenn E; Micheau, Jacques; Huang, Xufeng; McGregor, Iain S; Karl, Tim; Arnold, Jonathon C

    2011-06-01

    Cannabis increases the risk of schizophrenia in genetically vulnerable individuals. In this study we aim to show that the schizophrenia susceptibility gene neuregulin 1 (Nrg1) modulates the development of tolerance to cannabinoids in mice. Nrg1 heterozygous (HET) and wild-type (WT) mice were treated daily for 15 d with the synthetic analogue of Δ9-tetrahydrocannabinol, CP55,940 (0.4 mg/kg). We measured the impact of this exposure on locomotor activity, anxiety, prepulse inhibition (PPI), body temperature and FosB/ΔFosB immunohistochemistry. Tolerance to CP55,940-induced hypothermia and locomotor suppression developed more rapidly in Nrg1 HET mice than WT mice. Conversely in the light-dark test, while tolerance to the anxiogenic effect of CP55,940 developed in WT mice over days of testing, Nrg1 hypomorphs maintained marked anxiety even after 15 d of treatment. Repeated cannabinoid exposure selectively increased FosB/ΔFosB expression in the lateral septum, ventral part (LSV) of Nrg1 HET but not WT mice. On day 1 of exposure opposite effects of CP55,940 treatment were observed on PPI, i.e. it was facilitated in Nrg1 hypomorphs and impaired in WT mice, despite the drug significantly impairing the acoustic startle reflex equally in both genotypes. These effects of CP55,940 on PPI were not maintained as both genotypes became tolerant to cannabinoid action with repeated exposure. Our results highlight that Nrg1 modulates the development of cannabinoid tolerance dependent on the parameter being measured. Furthermore, these data reinforce the notion that the VLS is an important brain region involved in Nrg1-cannabinoid interactions.

  5. Quantitative trait locus analysis, pathway analysis, and consomic mapping show genetic variants of Tnni3k, Fpgt, or H28 control susceptibility to viral myocarditis.

    PubMed

    Wiltshire, Sean A; Leiva-Torres, Gabriel André; Vidal, Silvia M

    2011-06-01

    Coxsackievirus B3 (CVB3) infection is the most common cause of viral myocarditis. The pathogenesis of viral myocarditis is strongly controlled by host genetic factors. Although certain indispensable components of immunity have been identified, the genes and pathways underlying natural variation between individuals remain unclear. Previously, we isolated the viral myocarditis susceptibility 1 (Vms1) locus on chromosome 3, which influences pathogenesis. We hypothesized that confirmation and further study of Vms1 controlling CVB3-mediated pathology, combined with pathway analysis and consomic mapping approaches, would elucidate both pathological and protective mechanisms accounting for natural variation in response to CVB3 infection. Vms1 was originally mapped to chromosome 3 using a segregating cross between susceptible A/J and resistant B10.A mice. To validate Vms1, C57BL/6J-Chr 3(A)/NaJ (a chromosome substitution strain that carries a diploid A/J chromosome 3) were used to replicate susceptibility compared with resistant C57BL/6J (B6). A second segregating F2 cross was generated between these, confirming both the localization and effects of Vms1. Microarray analysis of the four strains (A/J, B10.A, C57BL/6J, and C57BL/6J-Chr 3(A)/NaJ) illuminated a core program of response to CVB3 in all strains that is comprised mainly of IFN-stimulated genes. Microarray analysis also revealed strain-specific differential expression programs and genes that may be prognostic or diagnostic of susceptibility to CVB3 infection. A combination of analyses revealed very strong evidence for the existence and location of Vms1. Differentially expressed pathways were identified by microarray, and candidate gene analysis revealed Fpgt, H28, and Tnni3k as likely candidates for Vms1.

  6. Integrating genetic association, genetics of gene expression, and single nucleotide polymorphism set analysis to identify susceptibility Loci for type 2 diabetes mellitus.

    PubMed

    Greenawalt, Danielle M; Sieberts, Solveig K; Cornelis, Marilyn C; Girman, Cynthia J; Zhong, Hua; Yang, Xia; Guinney, Justin; Qi, Lu; Hu, Frank B

    2012-09-01

    Large-scale genome-wide association studies (GWAS) have identified over 40 genomic regions significantly associated with type 2 diabetes mellitus. However, GWAS results are not always straightforward to interpret, and linking these loci to meaningful disease etiology is often difficult without extensive follow-up studies. The authors expanded on previously reported type 2 diabetes mellitus GWAS from the nested case-control studies of 2 prospective US cohorts by incorporating expression single nucleotide polymorphism (SNP) information and applying SNP set enrichment analysis to identify sets of SNPs associated with genes that could provide further biologic insight to traditional genome-wide analysis. Using data collected between 1989 and 1994 in these previous studies to form a nested case-control study, the authors found that 3 of the most significantly associated SNPs to type 2 diabetes mellitus in their study are expression SNPs to the lymphocyte antigen 75 gene (LY75), the ubiquitin-specific peptidase 36 gene (USP36), and the phosphatidylinositol transfer protein, cytoplasmic 1 gene (PITPNC1). SNP set enrichment analysis of the GWAS results identified enrichment for expression SNPs to the macrophage-enriched module and the Gene Ontology (GO) biologic process fat cell differentiation human, which includes the transcription factor 7-like 2 gene (TCF7L2), as well as other type 2 diabetes mellitus-associated genes. Integrating genome-wide association, gene expression, and gene set analysis may provide valuable biologic support for potential type 2 diabetes mellitus susceptibility loci and may be useful in identifying new targets or pathways of interest for the treatment and prevention of type 2 diabetes mellitus.

  7. Susceptibility to type 2 diabetes mellitus--from genes to prevention.

    PubMed

    Hivert, Marie-France; Vassy, Jason L; Meigs, James B

    2014-04-01

    Knowledge of the genetics of type 2 diabetes mellitus (T2DM) has evolved tremendously over the past few years. Following advances in technology and analytical approaches, collaborative case-control genome-wide association studies have revealed up to 65 loci credibly associated with T2DM. Prospective population studies have demonstrated that aggregated genetic risk scores, so-called because they sum the genetic risk attributed to each locus, can predict incident T2DM among individuals of various age ranges and diverse ethnic backgrounds. With each set of T2DM loci discovered, increasing the number of loci in these scores has improved their predictive ability, although a prediction plateau may already have been reached. The current literature shows that intensive lifestyle interventions are effective for preventing T2DM at any level of genetic risk and might be particularly efficacious among individuals with high genetic susceptibility. By contrast, counselling to inform patients about their personal T2DM genetic risk profiles does not seem to improve motivation or attitudes that lead to positive lifestyle behaviour changes. Future studies should investigate the role of genetics for both T2DM prediction and prevention in young populations in the hope of reducing disease burden for future generations.

  8. Fire Severity Controlled Susceptibility to a 1940s Spruce Beetle Outbreak in Colorado, USA.

    PubMed

    Kulakowski, Dominik; Veblen, Thomas T; Bebi, Peter

    2016-01-01

    killed in the 1940s outbreak. No young post-fire trees (< ca. 128 years) were susceptible to the 1940s outbreak, implying that under the relatively cool and wet conditions of the mid-20th century, susceptibility to and spatial patterns of spruce beetle outbreak were most likely controlled by variations in severity of prior disturbance by fire. This study provides a baseline for comparing linked disturbances under the relatively warmer and drier conditions of recent (e.g. post-1990) outbreaks in order to assess how climate mitigates the degree to which pre-disturbance history and structure affect susceptibility to disturbances.

  9. Fire Severity Controlled Susceptibility to a 1940s Spruce Beetle Outbreak in Colorado, USA

    PubMed Central

    Kulakowski, Dominik; Veblen, Thomas T.; Bebi, Peter

    2016-01-01

    killed in the 1940s outbreak. No young post-fire trees (< ca. 128 years) were susceptible to the 1940s outbreak, implying that under the relatively cool and wet conditions of the mid-20th century, susceptibility to and spatial patterns of spruce beetle outbreak were most likely controlled by variations in severity of prior disturbance by fire. This study provides a baseline for comparing linked disturbances under the relatively warmer and drier conditions of recent (e.g. post-1990) outbreaks in order to assess how climate mitigates the degree to which pre-disturbance history and structure affect susceptibility to disturbances. PMID:27438289

  10. Fire Severity Controlled Susceptibility to a 1940s Spruce Beetle Outbreak in Colorado, USA.

    PubMed

    Kulakowski, Dominik; Veblen, Thomas T; Bebi, Peter

    2016-01-01

    killed in the 1940s outbreak. No young post-fire trees (< ca. 128 years) were susceptible to the 1940s outbreak, implying that under the relatively cool and wet conditions of the mid-20th century, susceptibility to and spatial patterns of spruce beetle outbreak were most likely controlled by variations in severity of prior disturbance by fire. This study provides a baseline for comparing linked disturbances under the relatively warmer and drier conditions of recent (e.g. post-1990) outbreaks in order to assess how climate mitigates the degree to which pre-disturbance history and structure affect susceptibility to disturbances. PMID:27438289

  11. Gene expression responses to Rice tungro spherical virus in susceptible and resistant near-isogenic rice plants.

    PubMed

    Satoh, Kouji; Kondoh, Hiroaki; De Leon, Teresa B; Macalalad, Reena Jesusa A; Cabunagan, Rogelio C; Cabauatan, Pepito Q; Mauleon, Ramil; Kikuchi, Shoshi; Choi, Il-Ryong

    2013-01-01

    Rice cultivar Taichung Native 1 (TN1) is susceptible to Rice tungro spherical virus (RTSV). TW16 is a backcross line developed between TN1 and RTSV-resistant cultivar Utri Merah. RTSV accumulation in TW16 was significantly lower than in TN1, although both TN1 and TW16 remained asymptomatic. We compared the gene expression profiles of TN1 and TW16 infected by RTSV to identify the gene expression patterns accompanying the accumulation and suppression of RTSV. About 11% and 12% of the genes in the entire genome were found differentially expressed by RTSV in TN1 and TW16, respectively. About 30% of the differentially expressed genes (DEGs) were detected commonly in both TN1 and TW16. DEGs related to development and stress response processes were significantly overrepresented in both TN1 and TW16. Evident differences in gene expression between TN1 and TW16 instigated by RTSV included (1) suppression of more genes for development-related transcription factors in TW16; (2) activation of more genes for development-related peptide hormone RALF in TN1; (3) TN1- and TW16-specific regulation of genes for jasmonate synthesis and pathway, and genes for stress-related transcription factors such as WRKY, SNAC, and AP2-EREBP; (4) activation of more genes for glutathione S-transferase in TW16; (5) activation of more heat shock protein genes in TN1; and (6) suppression of more genes for Golden2-like transcription factors involved in plastid development in TN1. The results suggest that a significant number of defense and development-related genes are still regulated in asymptomatic plants even with a very low level of RTSV, and that the TN1- and TW16-specific gene regulations might be associated with regulation of RTSV accumulation in the plants.

  12. The environmental risk factors in multiple sclerosis susceptibility: A case-control study

    PubMed Central

    Shaygannejad, Vahid; Rezaie, Nooshin; Paknahad, Zamzam; Ashtari, Freshteh; Maghzi, Helia

    2016-01-01

    Background: Multiple sclerosis (MS) is a demyelinating and degenerating disease which involves central nervous system. Environmental risk factors have a key role in MS susceptibility. Here we aim to investigate different risk factors effect on MS susceptibility in a large population of MS patients in Isfahan, Iran. Materials and Methods: This study is a cross-sectional hospital-based study, which was conducted on a large group of MS patients registered in Kashani hospital and a control group from normal healthy population. Demographic data, age at onset of the disease, history of viral infections, vaccination, history of trauma to head, recent stressful events, alimentation, familial history, method of delivery (caesarean section, normal vaginal delivery), disability score and history of smoking were gathered using a designed questionnaire. Results: Totally 536 MS patient with the mean age of 34.37 ± 9.22 and 399 individuals from healthy population with the mean age of 32.53 ± 9.91 were recruited. Significant difference in history of measles infection (control = 15.5%, case = 22.4%, P = 0.009), consumption of dairy products (case = 56.6%, control = 67.5%, P = 0.01) and major stressful life events (case = 62.2%, control = 52.7%, P < 0.05) between these two groups were demonstrated. Conclusion: A significant relation between stress, history of infection and milk consumption was reached that highlights the importance of environmental risk factors in MS pathogenesis. PMID:27376037

  13. Characteristics of carboxylesterase genes and their expression-level between acaricide-susceptible and resistant Tetranychus cinnabarinus (Boisduval).

    PubMed

    Wei, Peng; Shi, Li; Shen, Guangmao; Xu, Zhifeng; Liu, Jialu; Pan, Yu; He, Lin

    2016-07-01

    Carboxylesterases (CarEs) play important roles in metabolism and detoxification of dietary and environmental xenobiotics in insects and mites. On the basis of the Tetranychuscinnabarinus transcriptome dataset, 23 CarE genes (6 genes are full sequence and 17 genes are partial sequence) were identified. Synergist bioassay showed that CarEs were involved in acaricide detoxification and resistance in fenpropathrin- (FeR) and cyflumetofen-resistant (CyR) strains. In order to further reveal the relationship between CarE gene's expression and acaricide-resistance in T. cinnabarinus, we profiled their expression in susceptible (SS) and resistant strains (FeR, and CyR). There were 8 and 4 over-expressed carboxylesterase genes in FeR and CyR, respectively, from which the over-expressions were detected at mRNA level, but not DNA level. Pesticide induction experiment elucidated that 4 of 8 and 2 of 4 up-regulated genes were inducible with significance in FeR and CyR strains, respectively, but they could not be induced in SS strain, which indicated that these genes became more enhanced and effective to withstand the pesticides' stress in resistant T. cinnabarinus. Most expression-changed and all inducible genes possess the Abhydrolase_3 motif, which is a catalytic domain for hydrolyzing. As a whole, these findings in current study provide clues for further elucidating the function and regulation mechanism of these carboxylesterase genes in T. cinnabarinus' resistance formation. PMID:27265830

  14. The Flavin-Containing Monooxygenase 3 Gene and Essential Hypertension: The Joint Effect of Polymorphism E158K and Cigarette Smoking on Disease Susceptibility.

    PubMed

    Bushueva, Olga; Solodilova, Maria; Churnosov, Mikhail; Ivanov, Vladimir; Polonikov, Alexey

    2014-01-01

    Gene encoding flavin-containing monooxygenase 3 (FMO3), a microsomal antioxidant defense enzyme, has been suggested to contribute to essential hypertension (EH). The present study was designed to investigate whether common functional polymorphism E158K (rs2266782) of the FMO3 gene is associated with EH susceptibility in a Russian population. A total of 2 995 unrelated subjects from Kursk (1 362 EH patients and 843 healthy controls) and Belgorod (357 EH patients and 422 population controls) regions of Central Russia were recruited for this study. DNA samples from all study participants were genotyped for the FMO3 gene polymorphism through PCR followed by RFLP analysis. We found that the polymorphism E158K is associated with increased risk of essential hypertension in both discovery population from Kursk region (OR 1.36 95% CI 1.09-1.69, P = 0.01) and replication population from Belgorod region (OR 1.54 95% CI 1.07-1.89, P = 0.02) after adjustment for gender and age using logistic regression analysis. Further analysis showed that the increased hypertension risk in carriers of genotype 158KK gene occurred in cigarette smokers, whereas nonsmoker carriers of this genotype did not show the disease risk. This is the first study reporting the association of the FMO3 gene polymorphism and the risk of essential hypertension. PMID:25243081

  15. The Flavin-Containing Monooxygenase 3 Gene and Essential Hypertension: The Joint Effect of Polymorphism E158K and Cigarette Smoking on Disease Susceptibility

    PubMed Central

    Bushueva, Olga; Solodilova, Maria; Churnosov, Mikhail; Ivanov, Vladimir; Polonikov, Alexey

    2014-01-01

    Gene encoding flavin-containing monooxygenase 3 (FMO3), a microsomal antioxidant defense enzyme, has been suggested to contribute to essential hypertension (EH). The present study was designed to investigate whether common functional polymorphism E158K (rs2266782) of the FMO3 gene is associated with EH susceptibility in a Russian population. A total of 2 995 unrelated subjects from Kursk (1 362 EH patients and 843 healthy controls) and Belgorod (357 EH patients and 422 population controls) regions of Central Russia were recruited for this study. DNA samples from all study participants were genotyped for the FMO3 gene polymorphism through PCR followed by RFLP analysis. We found that the polymorphism E158K is associated with increased risk of essential hypertension in both discovery population from Kursk region (OR 1.36 95% CI 1.09–1.69, P = 0.01) and replication population from Belgorod region (OR 1.54 95% CI 1.07–1.89, P = 0.02) after adjustment for gender and age using logistic regression analysis. Further analysis showed that the increased hypertension risk in carriers of genotype 158KK gene occurred in cigarette smokers, whereas nonsmoker carriers of this genotype did not show the disease risk. This is the first study reporting the association of the FMO3 gene polymorphism and the risk of essential hypertension. PMID:25243081

  16. Scan statistic-based analysis of exome sequencing data identifies FAN1 at 15q13.3 as a susceptibility gene for schizophrenia and autism.

    PubMed

    Ionita-Laza, Iuliana; Xu, Bin; Makarov, Vlad; Buxbaum, Joseph D; Roos, J Louw; Gogos, Joseph A; Karayiorgou, Maria

    2014-01-01

    We used a family-based cluster detection approach designed to localize significant rare disease-risk variants clusters within a region of interest to systematically search for schizophrenia (SCZ) susceptibility genes within 49 genomic loci previously implicated by de novo copy number variants. Using two independent whole-exome sequencing family datasets and a follow-up autism spectrum disorder (ASD) case/control whole-exome sequencing dataset, we identified variants in one gene, Fanconi-associated nuclease 1 (FAN1), as being associated with both SCZ and ASD. FAN1 is located in a region on chromosome 15q13.3 implicated by a recurrent copy number variant, which predisposes to an array of psychiatric and neurodevelopmental phenotypes. In both SCZ and ASD datasets, rare nonsynonymous risk variants cluster significantly in affected individuals within a 20-kb window that spans several key functional domains of the gene. Our finding suggests that FAN1 is a key driver in the 15q13.3 locus for the associated psychiatric and neurodevelopmental phenotypes. FAN1 encodes a DNA repair enzyme, thus implicating abnormalities in DNA repair in the susceptibility to SCZ or ASD. PMID:24344280

  17. Methylation and expression analyses of the 7q autism susceptibility locus genes MEST , COPG2, and TSGA14 in human and anthropoid primate cortices.

    PubMed

    Schneider, E; Mayer, S; El Hajj, N; Jensen, L R; Kuss, A W; Zischler, H; Kondova, I; Bontrop, R E; Navarro, B; Fuchs, E; Zechner, U; Haaf, T

    2012-01-01

    The autism susceptibility locus on human chromosome 7q32 contains the maternally imprinted MEST and the non-imprinted COPG2 and TSGA14 genes. Autism is a disorder of the 'social brain' that has been proposed to be due to an overbalance of paternally expressed genes. To study regulation of the 7q32 locus during anthropoid primate evolution, we analyzed the methylation and expression patterns of MEST, COPG2, and TSGA14 in human, chimpanzee, Old World monkey (baboon and rhesus macaque), and New World monkey (marmoset) cortices. In all human and anthropoid primate cortices, the MEST promoter was hemimethylated, as expected for a differentially methylated imprinting control region, whereas the COPG2 and TSGA14 promoters were completely demethylated, typical for transcriptionally active non-imprinted genes. The MEST gene also showed comparable mRNA expression levels in all analyzed species. In contrast, COPG2 expression was downregulated in the human cortex compared to chimpanzee, Old and New World monkeys. TSGA14 either showed no differential regulation in the human brain compared to chimpanzee and marmoset or a slight upregulation compared to baboon. The human-specific downregulation supports a role for COPG2 in the development of a 'social brain'. Promoter methylation patterns appear to be more stable during evolution than gene expression patterns, suggesting that other mechanisms may be more important for inter-primate differences in gene expression.

  18. Association of TFAP2A gene polymorphism with susceptibility to non-syndromic cleft lip with or without palate risk in south Indian population.

    PubMed

    Babu Gurramkonda, Venkatesh; Syed, Altaf Hussain; Murthy, Jyotsna; V K S Lakkakula, Bhaskar

    2016-09-01

    The aetiology of non-syndromic cleft lip with or without cleft palate (NSCL/P) is complex involving multiple interacting genes and environmental factors. The primary objective of the present study was to investigate the role of TFAP2A gene single nucleotide polymorphisms (SNPs) in the pathogenesis of NSCL/P. In this study, 173 unrelated NSCL/P patients and 176 controls without clefts were genotyped with TFAP2A rs1675414 (Exon 1), rs3798691 (Intron 1), and rs303050 (Intron 4) variants by allele-specific amplification using the KASPar SNP genotyping system. The method of multifactor dimensionality reduction (MDR) was used to analyze gene-gene interactions. TFAP2A polymorphisms are not found to be associated with non-syndromic cleft lip with or without cleft palate (NSCL/P) at either the genotype or allele levels. No linkage disequilibrium (LD) was found between TFAP2A variants. MDR analysis did not show a significant effect of the TFAP2A gene polymorphisms on susceptibility to NSCL/P (p > 0.05). These results suggest that the analyzed variations in TFAP2A gene might not be associated with NSCL/P pathogenesis in south Indian population. PMID:27617216

  19. Haplotype-tagging single nucleotide polymorphisms in the GSTP1 gene promoter and susceptibility to lung cancer☆

    PubMed Central

    Tan, Xiang-Lin; Moslehi, Roxana; Han, WeiGuo; Spivack, Simon D.

    2013-01-01

    Background Glutathione S-transferase (GST) P1 is a major phase II xenobiotic-metabolizing enzyme in the human lung. Our laboratory had previously identified nine single nucleotide polymorphisms (SNPs) in the GSTP1 gene promoter, which were then grouped into three main haplotypes (Hap1, Hap2, and Hap3) based on statistical inference. Hap3 was found to display a high expression phenotype. The main objective of the current study was to test the association between GSTP1 promoter haplotypes with the risk of lung cancer after determining the promoter haplotypes experimentally through cloning and sequencing. Methods We conducted a case–control analysis of 150 subjects with lung cancer and 329 controls with no personal history of the disease. The three statistically inferred GSTP1 promoter haplotypes were confirmed experimentally through cloning and sequencing. Haplotype-tagging SNPs were selected and GSTP1 haplotypes were tested for genetic association to lung cancer using unconditional logistic regression after adjusting for confounders. Statistical interaction between GSTP1 promoter haplotypes with either cigarette smoking or dietary fruit and vegetable intake were tested using the likelihood ratio test. Results We did not find protective effects of Hap3 against lung cancer, despite an adequately powered design for this main effect. Homozygous variants of tagSNPs –1738 T >A and –354 G > T, which tag Hap2, showed an increased (but statistically non-significant) risk of lung cancer among all subjects as well as among individuals with low fruit and vegetable intake, compared to homozygous wildtypes for these SNPs. We did not find significant interactions between Hap2 and dietary intake of fruits and vegetables. Conclusions Our results do not support significant main and modifying effects for GSTP1 promoter haplotypes on susceptibility to lung cancer in this population, but reinforce the protective effects of dietary intake of fruits and vegetables. PMID:19282111

  20. Significance of a common variant in the CDKAL1 gene with susceptibility to type 2 diabetes mellitus in Iranian population

    PubMed Central

    Mansoori, Yaser; Daraei, Abdolreza; Naghizadeh, Mohammad Mehdi; Salehi, Rasoul

    2015-01-01

    Background: Type 2 diabetes mellitus (T2DM) is a worldwide problem that threatens the public health and economies of all countries. A multifactorial etiology and interaction between environmental factors and genetic components are responsible for triggering and progression of T2DM. Recently, rs7754840 single nucleotide polymorphism (SNP) in the CDKAL1 gene was reported to be associated with T2DM in various populations. However, due to inconsistent results in various populations about the association of rs7754840 with T2DM, and lack of information in the Iranian population, we have evaluated its association with T2DM in a subset of the Iranian population from Isfahan province, central part of Iran. Materials and Methods: The study included 140 patients and 140 controls selected based on the World Health Organization guidelines. Genomic DNA was extracted from blood samples and the rs7754840 SNP was genotyped using a polymerase chain reaction-restriction fragment length polymorphism assay with specific primers and restriction enzyme (Ac1I). Results: The frequency of the C allele in the cases was higher than that in the controls (72.9% vs. 65%; P = 0.045). Using logistic regression analysis, we found a significant risk association of CC genotype with T2DM susceptibility (OR = 2.319, 95% CI = 1.436-3.744, P = 0.001). Furthermore, compared with the CC genotype, individuals with the GC genotype had a lower risk (protective association) of developing T2DM (OR = 0.332, 95% CI = 0.202-0.547, P < 0.001). Conclusions: We confirmed that there is a significant risk association between rs7754840 polymorphism and development of T2DM in a subset of the Iranian population from Isfahan province. PMID:25789271

  1. Genetic control of susceptibility to Candida albicans in SM/J mice.

    PubMed

    Radovanovic, Irena; Leung, Vicki; Iliescu, Alexandra; Bongfen, Silayuv E; Mullick, Alaka; Langlais, David; Gros, Philippe

    2014-08-01

    In the immunocompromised host, invasive infection with the fungal pathogen Candida albicans is associated with high morbidity and mortality. Sporadic cases in otherwise normal individuals are rare, and they are thought to be associated with genetic predisposition. Using a mouse model of systemic infection with C. albicans, we identified the SM/J mouse strain as unusually susceptible to infection. Genetic linkage studies in informative [C57BL/6JxSM/J]F2 mice identified a major locus on distal chromosome 15, given the appellation Carg5, that regulates C. albicans replication in SM/J mice. Cellular and molecular immunophenotyping experiments, as well as functional studies in purified cell populations from SM/J and C57BL/6J, and in [C57BL/6JxSM/J]F2 mice fixed for homozygous or heterozygous Carg5 alleles, indicate that Carg5-regulated susceptibility in SM/J is associated with a complex defect in the myeloid compartment of these mice. SM/J neutrophils express lower levels of Ly6G, and importantly, they show significantly reduced production of reactive oxygen species in response to stimulation with fMLF and PMA. Likewise, CD11b(+)Ly6G(-)Ly6C(hi) inflammatory monocytes were present at lower levels in the blood of infected SM/J, recruited less efficiently at the site of infection, and displayed blunted oxidative burst. Studies in F2 mice establish strong correlations between Carg5 alleles, Ly6G expression, production of serum CCL2 (MCP-1), and susceptibility to C. albicans. Genomic DNA sequencing of chromatin immunoprecipitated for myeloid proinflammatory transcription factors IRF1, IRF8, STAT1 and NF-κB, as well as RNA sequencing, were used to develop a "myeloid inflammatory score" and systematically analyze and prioritize potential candidate genes in the Carg5 interval.

  2. Exome sequencing reveals frequent deleterious germline variants in cancer susceptibility genes in women with invasive breast cancer undergoing neoadjuvant chemotherapy.

    PubMed

    Ellingson, Marissa S; Hart, Steven N; Kalari, Krishna R; Suman, Vera; Schahl, Kimberly A; Dockter, Travis J; Felten, Sara J; Sinnwell, Jason P; Thompson, Kevin J; Tang, Xiaojia; Vedell, Peter T; Barman, Poulami; Sicotte, Hugues; Eckel-Passow, Jeanette E; Northfelt, Donald W; Gray, Richard J; McLaughlin, Sarah A; Moreno-Aspitia, Alvaro; Ingle, James N; Moyer, Ann M; Visscher, Daniel W; Jones, Katie; Conners, Amy; McDonough, Michelle; Wieben, Eric D; Wang, Liewei; Weinshilboum, Richard; Boughey, Judy C; Goetz, Matthew P

    2015-09-01

    When sequencing blood and tumor samples to identify targetable somatic variants for cancer therapy, clinically relevant germline variants may be uncovered. We evaluated the prevalence of deleterious germline variants in cancer susceptibility genes in women with breast cancer referred for neoadjuvant chemotherapy and returned clinically actionable results to patients. Exome sequencing was performed on blood samples from women with invasive breast cancer referred for neoadjuvant chemotherapy. Germline variants within 142 hereditary cancer susceptibility genes were filtered and reviewed for pathogenicity. Return of results was offered to patients with deleterious variants in actionable genes if they were not aware of their result through clinical testing. 124 patients were enrolled (median age 51) with the following subtypes: triple negative (n = 43, 34.7%), HER2+ (n = 37, 29.8%), luminal B (n = 31, 25%), and luminal A (n = 13, 10.5%). Twenty-eight deleterious variants were identified in 26/124 (21.0%) patients in the following genes: ATM (n = 3), BLM (n = 1), BRCA1 (n = 4), BRCA2 (n = 8), CHEK2 (n = 2), FANCA (n = 1), FANCI (n = 1), FANCL (n = 1), FANCM (n = 1), FH (n = 1), MLH3 (n = 1), MUTYH (n = 2), PALB2 (n = 1), and WRN (n = 1). 121/124 (97.6%) patients consented to return of research results. Thirteen (10.5%) had actionable variants, including four that were returned to patients and led to changes in medical management. Deleterious variants in cancer susceptibility genes are highly prevalent in patients with invasive breast cancer referred for neoadjuvant chemotherapy undergoing exome sequencing. Detection of these variants impacts medical management. PMID:26296701

  3. Differential Gene Expression Profile in the Rat Caudal Vestibular Nucleus is Associated with Individual Differences in Motion Sickness Susceptibility

    PubMed Central

    Zhou, Wei; Tang, Yi-Fan; Pan, Lei-Lei; Cai, Yi-Ling

    2015-01-01

    Objective To identify differentially expressed genes associated with motion sickness (MS) susceptibility in the rat caudal vestibular nucleus. Methods We identified MS susceptible (MSS) and insusceptible (inMSS) rats by quantifying rotation-induced MS symptoms: defecation and spontaneous locomotion activity. Microarray analysis was used to screen differentially expressed genes in the caudal vestibular nucleus (CVN) after rotation. Plasma stress hormones were identified by radioimmunoassay. Candidate genes were selected by bioinformatics analysis and the microarray results were verified by real-time quantitative-PCR (RT-qPCR) methods. By using Elvax implantation, receptor antagonists or recombinant adenovirus targeting the candidate genes were applied to the CVN to evaluate their contribution to MS susceptibility variability. Validity of gene expression manipulation was verified by RT-qPCR and western blot analysis. Results A total of 304 transcripts were differentially expressed in the MSS group compared with the inMSS group. RT-qPCR analysis verified the expression pattern of candidate genes, including nicotinic cholinergic receptor (nAchR) α3 subunit, 5-hydroxytryptamine receptor 4 (5-HT4R), tachykinin neurokinin-1 (NK1R), γ-aminobutyric acid A receptor (GABAAR) α6 subunit, olfactory receptor 81 (Olr81) and homology 2 domain-containing transforming protein 1 (Shc1). In MSS animals, the nAchR antagonist mecamylamine significantly alleviated rotation-induced MS symptoms and the plasma β-endorphin response. The NK1R antagonist CP99994 and Olr81 knock-down were effective for the defecation response, while the 5-HT4R antagonist RS39604 and Shc1 over-expression showed no therapeutic effect. In inMSS animals, rotation-induced changes in spontaneous locomotion activity and the plasma β-endorphin level occurred in the presence of the GABAAR antagonist gabazine. Conclusion Our findings suggested that the variability of the CVN gene expression profile after motion

  4. NPR-C gene polymorphism is associated with increased susceptibility to coronary artery disease in Chinese Han population: a multicenter study

    PubMed Central

    Hu, Qin; Liu, Qiji; Wang, Shasha; Zhen, Xi; Zhang, Zhimian; Lv, Ruijuan; Jiang, Guihua; Ma, Zhiyong; He, Hong; Li, Daqing; Liu, Xiaoling; Gao, Fei; Li, Jifu; Li, Li; Zhang, Mei; Ji, Xiaoping; Chen, Yuguo; Wang, Daowen; Huang, Dejia; Ma, Aiqun; Huang, Wei; Zhao, Yuxia; Gong, Yaoqin; Zhang, Cheng; Zhang, Yun

    2016-01-01

    To find a new locus that confers significant susceptibility to CAD in Chinese Han population, a genome-wide association study in 200 “extreme individuals” from a Shandong cohort and a pathway-based candidate gene study from a Shanghai cohort (293 CAD/293 controls) were simultaneously performed. Amongst them, 13 SNPs associated with CAD were selected to conduct validation and replication studies in additional 3363 CAD patients and 3148 controls. A novel locus rs700926 in natriuretic peptide receptor C (NPR-C) was identified in Shandong and Hubei cohorts. Then rs700926 and other nine tag SNPs were genotyped in four geographically different populations (Shandong, Shaanxi, Hubei and Sichuan cohorts), and 6 SNPs (rs700926, rs1833529, rs2270915, rs17541471, rs3792758 and rs696831) showed stronger association with CAD, regardless of single or combined analysis. We further genotyped rs2270915 and 10 additional tag SNPs in a central China cohort and identified rs12697273 and rs10066436 as the loci associated with CAD. All these positive associations remained significant after adjustment for traditional risk factors of CAD. NPR-C gene SNPs significantly contribute to CAD susceptibility in the Chinese Han population. PMID:27191271

  5. Contribution of Target Gene Mutations and Efflux to Decreased Susceptibility of Salmonella enterica Serovar Typhimurium to Fluoroquinolones and Other Antimicrobials▿

    PubMed Central

    Chen, Sheng; Cui, Shenghui; McDermott, Patrick F.; Zhao, Shaohua; White, David G.; Paulsen, Ian; Meng, Jianghong

    2007-01-01

    The mechanisms involved in fluoroquinolone resistance in Salmonella enterica include target alterations and overexpression of efflux pumps. The present study evaluated the role of known and putative multidrug resistance efflux pumps and mutations in topoisomerase genes among laboratory-selected and naturally occurring fluoroquinolone-resistant Salmonella enterica serovar Typhimurium strains. Strains with ciprofloxacin MICs of 0.25, 4, 32, and 256 μg/ml were derived in vitro using serovar Typhimurium S21. These mutants also showed decreased susceptibility or resistance to many nonfluoroquinolone antimicrobials, including tetracycline, chloramphenicol, and several β-lactams. The expression of efflux pump genes acrA, acrB, acrE, acrF, emrB, emrD, and mdlB were substantially increased (≥2-fold) among the fluoroquinolone-resistant mutants. Increased expression was also observed, but to a lesser extent, with three other putative efflux pumps: mdtB (yegN), mdtC (yegO), and emrA among mutants with ciprofloxacin MICs of ≥32 μg/ml. Deletion of acrAB or tolC in S21 and its fluoroquinolone-resistant mutants resulted in increased susceptibility to fluoroquinolones and other tested antimicrobials. In naturally occurring fluoroquinolone-resistant serovar Typhimurium strains, deletion of acrAB or tolC increased fluoroquinolone susceptibility 4-fold, whereas replacement of gyrA double mutations (S83F D87N) with wild-type gyrA increased susceptibility >500-fold. These results indicate that a combination of topoisomerase gene mutations, as well as enhanced antimicrobial efflux, plays a critical role in the development of fluoroquinolone resistance in both laboratory-derived and naturally occurring quinolone-resistant serovar Typhimurium strains. PMID:17043131

  6. Association Between Gene Polymorphisms on Chromosome 1 and Susceptibility to Pre-Eclampsia: An Updated Meta-Analysis

    PubMed Central

    Zhang, Guixin; Zhao, Jinheng; Yi, Jianping; Luan, Yuanyuan; Wang, Qian

    2016-01-01

    Background This meta-analysis enabled us to obtain a precise estimation of the association between gene polymorphisms on chromosome 1 (MTHFR, AGT, F5, IL-10, LEPR) and the susceptibility to pre-eclampsia (PE) in order to reach a uniform conclusion. Material/Methods Web of Science, PubMed, EMBASE, Cochran Library (CENTRAL), and Chinese databases (Chinese National Knowledge Infrastructure-CNKI and Wan Fang) were electronically searched to select relevant studies for this meta-analysis. We selected 95 case-control studies investigating 5 genes (MTHFR, AGT, F5, IL-10, and LEPR) with 8 SNPs. Odds ratios (OR) with their 95% confidence intervals (CI) were used for estimating the association. Results A total of 16 646 PE patients and 28 901 normal-pregnancy patients were included in this meta-analysis. The overall results suggested that rs1801133 of MTHFR (OR=1.17, 95% CI: 1.05–1.13) and rs6025 of F5 (OR=1.53, 95%CI: 1.07–2.20) are significantly associated with PE, whereas rs1801131 of MTHFR, rs699 and rs4762 of AGT, rs1800896 and rs1800871 of IL-10, and rs1137101 of LEPR have no significant association with PE. Subgroup analysis by ethnicity revealed that, except for MTHFR rs1801133 and F5 rs6025 in Caucasians, which were significantly associated with an increased risk of PE, none of these SNPs were significantly associated with PE. As suggested by a symmetric funnel plot in conjunction with the Egger’s test, there was no significant publication bias in MTHFR rs1801133 (P=0.318) and rs1801131 (P=0.204), F5 rs6025 (P=0.511), LEPR rs1137101 (P=0.511), AGT rs4762 (P=0.215) and rs699 (P=0.482), IL-10 rs1800871 (P=0.955), and rs1800896 (P=0.144). Conclusions This meta-analysis provides evidence that MTHFR rs1801133 and F5 rs6025 are associated with an increased risk of PE, especially in Caucasians. However, we do not have sufficient evidence to conclude there is a significant association between other gene polymorphisms and PE. PMID:27348238

  7. Meta-analysis of the urokinase gene 3′-UTR T/C polymorphism and susceptibility to urolithiasis

    PubMed Central

    LI, DAWEI; LIU, JIKAI; REN, JUCHAO; YAN, LEI; LIU, HAINAN; XU, ZHONGHUA

    2013-01-01

    Urokinase is involved in the processes of initiating urinary stones. Several published case-control studies have examined the relationship of urokinase gene 3′-untranslated region (3′-UTR) T/C polymorphism and urolithiasis, but yielded inconsistent findings. In this study, a comprehensive meta-analysis was conducted by pooling relevant studies to obtain reliable conclusions. Studies focusing on the association between urokinase gene 3′-UTR T/C polymorphism and urolithiasis were retrieved through PubMed, Medline, Web of Science and the China National Knowledge Infrastructure platform without any limit on language, until October 2012. Four independent articles were eventually identified as eligible for the final meta-analysis, involving 1,195 subjects. Crude odds ratios (ORs), as well as 95% confidence intervals (CIs), were assessed for the association by either fixed- or random-effects models using RevMan 5.0 software. Significant associations were noted in the ‘TC vs. CC’ codominant model for total population (OR=2.53; 95% CI, 1.43–4.46; P=0.001), Asian population (OR=2.46; 95% CI, 1.38–4.40; P=0.002), male (OR=2.98; 95% CI, 1.43–6.21; P=0.004), Hardy-Weinberg equilibrium (HWE) (OR=2.46; 95% CI, 1.38–4.40; P=0.002) and recurrence (OR=2.66; 95% CI, 1.51–4.67; P=0.00). Statistically significant associations were also observed in the ‘TT+TC vs. CC’ dominant model for the Asian, male, HWE and recurrence population (P<0.05). Additionally, a significant difference was detected in the ‘T vs. C’ allele model for HWE. However, there were no associations in either the ‘TT vs. CC’ codominant model or ‘TT vs. TC+CC’ recessive model. In conclusion, the present meta-analysis suggests that urokinase gene T allele may increase the susceptibility of urolithiasis. PMID:24648951

  8. Gene Expression-Genotype Analysis Implicates GSDMA, GSDMB, and LRRC3C as Contributors to Inflammatory Bowel Disease Susceptibility

    PubMed Central

    Söderman, Jan; Berglind, Linda; Almer, Sven

    2015-01-01

    To investigate the biological foundation of the inflammatory bowel disease (IBD), ulcerative colitis and Crohn's disease, susceptibility locus rs2872507, we have investigated the expression of 13 genes using ileal and colonic biopsies from patients with IBD (inflamed and noninflamed mucosa) or from individuals without IBD (noninflamed mucosa). The susceptibility allele was consistently associated with reduced expression of GSDMB (P = 4.1 × 10−3–7.2 × 10−10). The susceptibility allele was also associated with the increased expression of GSDMA (P = 1.6 × 10−4) and LRRC3C (P = 7.8 × 10−6) in colon tissue from individuals without IBD and with the reduced expression of PGAP3 (IBD; P = 2.0 × 10−3) and ZPBP2 (Crohn's disease; P = 7.7 × 10−4) in noninflamed ileum. Inflammation resulted in the reduced colonic expression of ERBB2, GRB7, MIEN1, and PGAP3 (P = 1.0 × 10−4–1.0 × 10−9) and the increased colonic expression of IKZF3 and CSF3 (P = 2.4 × 10−7–3.5 × 10−8). Based on our results and published findings on GSDMA, GSDMB, LRRC3C, and related proteins, we propose that this locus in part affects IBD susceptibility via effects on apoptosis and cell proliferation and believe this hypothesis warrants further experimental investigation. PMID:26484354

  9. The application of nonsense-mediated mRNA decay inhibition to the identification of breast cancer susceptibility genes

    PubMed Central

    2012-01-01

    Background Identification of novel, highly penetrant, breast cancer susceptibility genes will require the application of additional strategies beyond that of traditional linkage and candidate gene approaches. Approximately one-third of inherited genetic diseases, including breast cancer susceptibility, are caused by frameshift or nonsense mutations that truncate the protein product [1]. Transcripts harbouring premature termination codons are selectively and rapidly degraded by the nonsense-mediated mRNA decay (NMD) pathway. Blocking the NMD pathway in any given cell will stabilise these mutant transcripts, which can then be detected using gene expression microarrays. This technique, known as gene identification by nonsense-mediated mRNA decay inhibition (GINI), has proved successful in identifying sporadic nonsense mutations involved in many different cancer types. However, the approach has not yet been applied to identify germline mutations involved in breast cancer. We therefore attempted to use GINI on lymphoblastoid cell lines (LCLs) from multiple-case, non- BRCA1/2 breast cancer families in order to identify additional high-risk breast cancer susceptibility genes. Methods We applied GINI to a total of 24 LCLs, established from breast-cancer affected and unaffected women from three multiple-case non-BRCA1/2 breast cancer families. We then used Illumina gene expression microarrays to identify transcripts stabilised by the NMD inhibition. Results The expression profiling identified a total of eight candidate genes from these three families. One gene, PPARGC1A, was a candidate in two separate families. We performed semi-quantitative real-time reverse transcriptase PCR of all candidate genes but only PPARGC1A showed successful validation by being stabilised in individuals with breast cancer but not in many unaffected members of the same family. Sanger sequencing of all coding and splice site regions of PPARGC1A did not reveal any protein truncating mutations

  10. Mapping of Mcs30, a New Mammary Carcinoma Susceptibility Quantitative Trait Locus (QTL30) on Rat Chromosome 12: Identification of Fry as a Candidate Mcs Gene

    PubMed Central

    Ren, Xuefeng; Graham, Jessica C.; Jing, Lichen; Mikheev, Andrei M.; Gao, Yuan; Lew, Jenny Pan; Xie, Hong; Kim, Andrea S.; Shang, Xiuling; Friedman, Cynthia; Vail, Graham; Fang, Ming Zhu; Bromberg, Yana; Zarbl, Helmut

    2013-01-01

    Rat strains differ dramatically in their susceptibility to mammary carcinogenesis. On the assumption that susceptibility genes are conserved across mammalian species and hence inform human carcinogenesis, numerous investigators have used genetic linkage studies in rats to identify genes responsible for differential susceptibility to carcinogenesis. Using a genetic backcross between the resistant Copenhagen (Cop) and susceptible Fischer 344 (F344) strains, we mapped a novel mammary carcinoma susceptibility (Mcs30) locus to the centromeric region on chromosome 12 (LOD score of ∼8.6 at the D12Rat59 marker). The Mcs30 locus comprises approximately 12 Mbp on the long arm of rat RNO12 whose synteny is conserved on human chromosome 13q12 to 13q13. After analyzing numerous genes comprising this locus, we identified Fry, the rat ortholog of the furry gene of Drosophila melanogaster, as a candidate Mcs gene. We cloned and determined the complete nucleotide sequence of the 13 kbp Fry mRNA. Sequence analysis indicated that the Fry gene was highly conserved across evolution, with 90% similarity of the predicted amino acid sequence among eutherian mammals. Comparison of the Fry sequence in the Cop and F344 strains identified two non-synonymous single nucleotide polymorphisms (SNPs), one of which creates a putative, de novo phosphorylation site. Further analysis showed that the expression of the Fry gene is reduced in a majority of rat mammary tumors. Our results also suggested that FRY activity was reduced in human breast carcinoma cell lines as a result of reduced levels or mutation. This study is the first to identify the Fry gene as a candidate Mcs gene. Our data suggest that the SNPs within the Fry gene contribute to the genetic susceptibility of the F344 rat strain to mammary carcinogenesis. These results provide the foundation for analyzing the role of the human FRY gene in cancer susceptibility and progression. PMID:24023717

  11. The efficiency of silencing expression of the gene coding STAT3 transcriptional factor and susceptibility of bladder cancer cells to apoptosis

    PubMed Central

    Bednarek, Ilona; Sypniewski, Daniel; Gawlik, Natalia; Goraus, Karol

    2012-01-01

    Aim of the study Abnormalities in signaling as well as altered gene expression have been identified in numerous diseases, including cancer. The biological functions of signal transducer and activator of transcription 3 (STAT3) are very broad. It is thought that STAT3 can also contribute to oncogenesis. RNA interference (RNAi) is one of the most efficient tools for silencing gene expression within cells. The main goal of the study was to verify the effectiveness of STAT3 gene silencing and its influence on cell proliferation and activation of apoptosis in bladder cancer cells. Material and methods The study was conducted on cellular material, which was the stable human bladder cancer cell line T24. The synthesis of shRNA (short hairpin RNA) interfering with the STAT3 gene was based on pSUPER. neo expression vector. The gene expression at the mRNA level was determined by the real-time PCR method. The influence of STAT3 gene silencing on apoptosis induced in cells with modulated STAT3 expression was evaluated using parallel quantification of mono- and oligonucleosomal DNA degradation of genomic DNA. Results In transfected T24 cells, the STAT3 mRNA expression decreased to the level of 68.3% compared to the scrambled (SCR) control. Silencing the STAT3 gene induced changes in the phenotype of T24 cells. Statistically significant differences in cell proliferation (p = 0.0318) and apoptosis induction (p = 0.0376) were observed. Conclusions Application of the designed shRNA for the STAT3 gene contributed to a decrease of expression of the examined gene. It also decreased the proliferation and increased the susceptibility to apoptosis in T24 bladder cancer cells. PMID:23788901

  12. The TLR4 gene polymorphisms and susceptibility to cancer: a systematic review and meta-analysis.

    PubMed

    Zhang, Kui; Zhou, Bin; Wang, Yanyun; Rao, Li; Zhang, Lin

    2013-03-01

    Growing studies revealed the association between polymorphisms in Toll-like receptor 4 (TLR4) and susceptibility to cancer, however, the results remained inconsistent. To assess the effect of six selected SNPs (rs1927914, rs4986790, rs4986791, rs11536889, rs1927911 and rs2149356) in TLR4 on cancer, we conducted a meta-analysis, up to February 2012, 22 case-control studies were available. Summary odds ratios (OR) and corresponding 95% confidence intervals (CIs) for polymorphisms in TLR4 and cancer risk were estimated. Our meta-analysis identified that two SNPs (rs4986790 and rs4986791) in TLR4 were associated with increased cancer risk (for rs4986790: OR=1.24, 95% CI=1.01-1.52 in dominant model; OR=1.24, 95% CI=1.02-1.52 in overdominant model; for rs4986791: OR=1.81, 95% CI=1.18-2.77 in allele comparison; OR=1.79, 95% CI=1.15-2.80 in dominant model; OR=1.70, 95% CI=1.09-2.67 in overdominant model) and one SNP (rs1927911) in TLR4 was associated with decreased cancer risk (for rs1927911: OR=0.63, 95% CI=0.41-0.99 in allele comparison; OR=0.57, 95% CI=0.35-0.95 in dominant model; OR=0.67, 95% CI=0.46-0.97 in codominant model). Moreover, in terms of stratified analyses by cancer type for SNP rs4986790, significantly elevated risk was observed to be associated with G allele in gastric cancer and 'other cancers'. These findings indicate that polymorphisms in TLR4 may play a role, although modest, in cancer development.

  13. Methylenetetrahydrofolate reductase gene and susceptibility to breast cancer: a meta-analysis.

    PubMed

    Zintzaras, E

    2006-04-01

    The methylenetetrahydrofolate reductase (MTHFR) gene polymorphisms have been linked to the risk of developing breast cancer. A meta-analysis of 18 case-control studies investigating the association between the C677T and the A1298C polymorphisms of the MTHFR gene and breast cancer (BC) was carried out. The meta-analysis included genotype data on 5467/7336 and 3768/5276 cases/controls for C677T and A1298C, respectively. In the meta-analysis, the consistency of genetic effects across different ethnicities and the effect of menopausal status for various genetic contrasts were investigated. The overall analysis for investigating the association between the C677T allele T and the risk of developing BC showed significant heterogeneity (p = 0.08, I2 = 34%) and non-significant association [odds ratio (OR) 1.02; 95% confidence interval (0.95-1.10)]. The allele contrast was not significant in Caucasians (nine studies) and in East Asians (four studies) [OR 1.03 (0.93-1.14) and OR 0.96 (0.81-1.15), respectively] or in pre-menopausal (five studies) and post-menopausal (four studies) groups [OR 1.10 (0.94-1.29) and OR 1.06 (0.95-1.18), respectively]. The genotype contrast of the homozygotes (TT vs CC) produced significant results only for pre-menopausal cases [OR 1.46 (1.05-2.03)]. The recessive model for allele T produced significant association only in pre-menopausal cases [OR 1.49 (1.09-2.03)]. The dominant model for the effect of allele T produced no significant results, overall and in each subgroup. For the A1298C polymorphism, all genotype contrasts showed lack of association, overall and in Caucasians. In summary, the accumulated evidence supports an association in pre-menopausal women. BC is a complex disease with multifactorial etiology, and therefore, case-control studies that investigate gene-environment interaction might elucidate further the genetics of the disease.

  14. Cis-eQTL analysis and functional validation of candidate susceptibility genes for high-grade serous ovarian cancer

    PubMed Central

    Lawrenson, Kate; Li, Qiyuan; Kar, Siddhartha; Seo, Ji-Heui; Tyrer, Jonathan; Spindler, Tassja J.; Lee, Janet; Chen, Yibu; Karst, Alison; Drapkin, Ronny; Aben, Katja K. H.; Anton-Culver, Hoda; Antonenkova, Natalia; Bowtell, David; Webb, Penelope M.; deFazio, Anna; Baker, Helen; Bandera, Elisa V.; Bean, Yukie; Beckmann, Matthias W.; Berchuck, Andrew; Bisogna, Maria; Bjorge, Line; Bogdanova, Natalia; Brinton, Louise A.; Brooks-Wilson, Angela; Bruinsma, Fiona; Butzow, Ralf; Campbell, Ian G.; Carty, Karen; Chang-Claude, Jenny; Chenevix-Trench, Georgia; Chen, Anne; Chen, Zhihua; Cook, Linda S.; Cramer, Daniel W.; Cunningham, Julie M.; Cybulski, Cezary; Dansonka-Mieszkowska, Agnieszka; Dennis, Joe; Dicks, Ed; Doherty, Jennifer A.; Dörk, Thilo; du Bois, Andreas; Dürst, Matthias; Eccles, Diana; Easton, Douglas T.; Edwards, Robert P.; Eilber, Ursula; Ekici, Arif B.; Fasching, Peter A.; Fridley, Brooke L.; Gao, Yu-Tang; Gentry-Maharaj, Aleksandra; Giles, Graham G.; Glasspool, Rosalind; Goode, Ellen L.; Goodman, Marc T.; Grownwald, Jacek; Harrington, Patricia; Harter, Philipp; Hasmad, Hanis Nazihah; Hein, Alexander; Heitz, Florian; Hildebrandt, Michelle A. T.; Hillemanns, Peter; Hogdall, Estrid; Hogdall, Claus; Hosono, Satoyo; Iversen, Edwin S.; Jakubowska, Anna; James, Paul; Jensen, Allan; Ji, Bu-Tian; Karlan, Beth Y.; Kruger Kjaer, Susanne; Kelemen, Linda E.; Kellar, Melissa; Kelley, Joseph L.; Kiemeney, Lambertus A.; Krakstad, Camilla; Kupryjanczyk, Jolanta; Lambrechts, Diether; Lambrechts, Sandrina; Le, Nhu D.; Lee, Alice W.; Lele, Shashi; Leminen, Arto; Lester, Jenny; Levine, Douglas A.; Liang, Dong; Lissowska, Jolanta; Lu, Karen; Lubinski, Jan; Lundvall, Lene; Massuger, Leon F. A. G.; Matsuo, Keitaro; McGuire, Valerie; McLaughlin, John R.; Nevanlinna, Heli; McNeish, Ian; Menon, Usha; Modugno, Francesmary; Moysich, Kirsten B.; Narod, Steven A.; Nedergaard, Lotte; Ness, Roberta B.; Azmi, Mat Adenan Noor; Odunsi, Kunle; Olson, Sara H.; Orlow, Irene; Orsulic, Sandra; Weber, Rachel Palmieri; Pearce, Celeste L.; Pejovic, Tanja; Pelttari, Liisa M.; Permuth-Wey, Jennifer; Phelan, Catherine M.; Pike, Malcolm C.; Poole, Elizabeth M.; Ramus, Susan J.; Risch, Harvey A.; Rosen, Barry; Rossing, Mary Anne; Rothstein, Joseph H.; Rudolph, Anja; Runnebaum, Ingo B.; Rzepecka, Iwona K.; Salvesen, Helga B.; Schildkraut, Joellen M.; Schwaab, Ira; Sellers, Thomas A.; Shu, Xiao-Ou; Shvetsov, Yurii B.; Siddiqui, Nadeem; Sieh, Weiva; Song, Honglin; Southey, Melissa C.; Sucheston, Lara; Tangen, Ingvild L.; Teo, Soo-Hwang; Terry, Kathryn L.; Thompson, Pamela J.; Timorek, Agnieszka; Tsai, Ya-Yu; Tworoger, Shelley S.; van Altena, Anne M.; Van Nieuwenhuysen, Els; Vergote, Ignace; Vierkant, Robert A.; Wang-Gohrke, Shan; Walsh, Christine; Wentzensen, Nicolas; Whittemore, Alice S.; Wicklund, Kristine G.; Wilkens, Lynne R.; Woo, Yin-Ling; Wu, Xifeng; Wu, Anna H.; Yang, Hannah; Zheng, Wei; Ziogas, Argyrios; Monteiro, Alvaro; Pharoah, Paul D.; Gayther, Simon A.; Freedman, Matthew L.

    2015-01-01

    Genome-wide association studies have reported 11 regions conferring risk of high-grade serous epithelial ovarian cancer (HGSOC). Expression quantitative trait locus (eQTL) analyses can identify candidate susceptibility genes at risk loci. Here we evaluate cis-eQTL associations at 47 regions associated with HGSOC risk (P≤10−5). For three cis-eQTL associations (P<1.4 × 10−3, FDR<0.05) at 1p36 (CDC42), 1p34 (CDCA8) and 2q31 (HOXD9), we evaluate the functional role of each candidate by perturbing expression of each gene in HGSOC precursor cells. Overexpression of HOXD9 increases anchorage-independent growth, shortens population-doubling time and reduces contact inhibition. Chromosome conformation capture identifies an interaction between rs2857532 and the HOXD9 promoter, suggesting this SNP is a leading causal variant. Transcriptomic profiling after HOXD9 overexpression reveals enrichment of HGSOC risk variants within HOXD9 target genes (P=6 × 10−10 for risk variants (P<10−4) within 10 kb of a HOXD9 target gene in ovarian cells), suggesting a broader role for this network in genetic susceptibility to HGSOC. PMID:26391404

  15. Overwintering Is Associated with Reduced Expression of Immune Genes and Higher Susceptibility to Virus Infection in Honey Bees.

    PubMed

    Steinmann, Nadja; Corona, Miguel; Neumann, Peter; Dainat, Benjamin

    2015-01-01

    The eusocial honey bee, Apis mellifera, has evolved remarkable abilities to survive extreme seasonal differences in temperature and availability of resources by dividing the worker caste into two groups that differ in physiology and lifespan: summer and winter bees. Most of the recent major losses of managed honey bee colonies occur during the winter, suggesting that winter bees may have compromised immune function and higher susceptibility to diseases. We tested this hypothesis by comparing the expression of eight immune genes and naturally occurring infection levels of deformed wing virus (DWV), one of the most widespread viruses in A. mellifera populations, between summer and winter bees. Possible interactions between immune response and physiological activity were tested by measuring the expression of vitellogenin and methyl farnesoate epoxidase, a gene coding for the last enzyme involved in juvenile hormone biosynthesis. Our data show that high DWV loads in winter bees correlate with reduced expression of genes involved in the cellular immune response and physiological activity and high expression of humoral immune genes involved in antibacterial defense compared with summer bees. This expression pattern could reflect evolutionary adaptations to resist bacterial pathogens and economize energy during the winter under a pathogen landscape with reduced risk of pathogenic viral infections. The outbreak of Varroa destructor infestation could have overcome these adaptations by promoting the transmission of viruses. Our results suggest that reduced cellular immune function during the winter may have increased honey bee's susceptibility to DWV. These results contribute to our understanding of honey bee colony losses in temperate regions.

  16. Transcriptomic analysis of colistin-susceptible and colistin-resistant isolates identifies genes associated with colistin resistance in Acinetobacter baumannii.

    PubMed

    Park, Y K; Lee, J-Y; Ko, K S

    2015-08-01

    The emergence of colistin-resistant Acinetobacter baumannii is concerning, as colistin is often regarded as the last option for treating multidrug-resistant (MDR) A. baumannii infections. Using mRNA sequencing, we compared whole transcriptomes of colistin-susceptible and colistin-resistant A. baumannii strains, with the aim of identifying genes involved in colistin resistance. A clinical colistin-susceptible strain (06AC-179) and a colistin-resistant strain (07AC-052) were analysed in this study. In addition, a colistin-resistant mutant (06AC-179-R1) derived from 06AC-179 was also included in this study. High throughput mRNA sequencing was performed with an Illumina HiSeq TM 2000. In total, six genes were identified as associated with colistin resistance in A. baumannii. These six genes encode PmrAB two-component regulatory enzymes, PmrC (a lipid A phosphoethanolamine transferase), a glycosyltransferase, a poly-β-1,6-N-acetylglucosamine deacetylase, and a putative membrane protein. Matrix-assisted laser desorption/ionization time of flight mass spectrometry revealed that all three colistin-resistant strains used in this study had modified lipid A structure by addition of phosphoethanolamine. As genes found in our results are all associated with either lipopolysaccharide biosynthesis or electrostatic changes in the bacterial cell membrane, lipopolysaccharide modification might be one of the principal modes of acquisition of colistin resistance in some A. baumannii strains.

  17. Antimicrobial susceptibility and antibiotic resistance gene transfer analysis of foodborne, clinical, and environmental Listeria spp. isolates including Listeria monocytogenes.

    PubMed

    Bertsch, David; Muelli, Mirjam; Weller, Monika; Uruty, Anaïs; Lacroix, Christophe; Meile, Leo

    2014-02-01

    The aims of this study were to assess antibiotic resistance pheno- and genotypes in foodborne, clinical, and environmental Listeria isolates, as well as to elucidate the horizontal gene transfer potential of detected resistance genes. A small fraction of in total 524 Listeria spp. isolates (3.1%) displayed acquired antibiotic resistance mainly to tetracycline (n = 11), but also to clindamycin (n = 4) and trimethoprim (n = 3), which was genotypically confirmed. In two cases, a tetracycline resistance phenotype was observed together with a trimethoprim resistance phenotype, namely in a clinical L. monocytogenes strain and in a foodborne L. innocua isolate. Depending on the applied guidelines, a differing number of isolates (n = 2 or n = 20) showed values for ampicillin that are on the edge between intermediate susceptibility and resistance. Transferability of the antibiotic resistance genes from the Listeria donors, elucidated in vitro by filter matings, was demonstrated for genes located on transposons of the Tn916 family and for an unknown clindamycin resistance determinant. Transfer rates of up to 10(-5) transconjugants per donor were obtained with a L. monocytogenes recipient and up to 10(-7) with an Enterococcus faecalis recipient, respectively. Although the prevalence of acquired antibiotic resistance in Listeria isolates from this study was rather low, the transferability of these resistances enables further spread in the future. This endorses the importance of surveillance of L. monocytogenes and other Listeria spp. in terms of antibiotic susceptibility.

  18. Confirmation of FWT1 as a Wilms' tumour susceptibility gene and phenotypic characteristics of Wilms' tumour attributable to FWT1.

    PubMed

    Rahman, N; Abidi, F; Ford, D; Arbour, L; Rapley, E; Tonin, P; Barton, D; Batcup, G; Berry, J; Cotter, F; Davison, V; Gerrard, M; Gray, E; Grundy, R; Hanafy, M; King, D; Lewis, I; Ridolfi Luethy, A; Madlensky, L; Mann, J; O'Meara, A; Oakhill, T; Skolnick, M; Strong, L; Stratton, M R

    1998-11-01

    A susceptibility gene for Wilms' tumour (WT), designated FWT1, was previously mapped to chromosome 17q12-q21 by linkage analysis of a single family. We now confirm the existence of this gene by analysis of additional cases in the original family (3-point LOD score=5.69), and by detecting strong evidence of linkage to this region in an unrelated pedigree with seven cases of WT (3-point LOD score=2.56). Analysis of 11 smaller WT families confirms that there is genetic heterogeneity in familial WT, as three families exhibit strong evidence against linkage to FWT1. One of these was subsequently found to have a predisposing WT1 mutation. However, the other two families show evidence against both FWT1 and WT1, suggesting that at least one further familial WT gene exists. Analysis of the phenotype of 16 WT cases from the families linked to FWT1 demonstrates that they present at a significantly older age and a significantly later stage than both sporadic WT and the six cases from two families unlinked to either FWT1 or WT1. The results confirm the role of FWT1 in susceptibility to WT, provide strong evidence for genetic heterogeneity in familial WT and suggest there are phenotypic differences between familial WT due to FWT1, familial WT due to other genes and non-familial WT. PMID:9860296

  19. Cis-eQTL analysis and functional validation of candidate susceptibility genes for high-grade serous ovarian cancer.

    PubMed

    Lawrenson, Kate; Li, Qiyuan; Kar, Siddhartha; Seo, Ji-Heui; Tyrer, Jonathan; Spindler, Tassja J; Lee, Janet; Chen, Yibu; Karst, Alison; Drapkin, Ronny; Aben, Katja K H; Anton-Culver, Hoda; Antonenkova, Natalia; Baker, Helen; Bandera, Elisa V; Bean, Yukie; Beckmann, Matthias W; Berchuck, Andrew; Bisogna, Maria; Bjorge, Line; Bogdanova, Natalia; Brinton, Louise A; Brooks-Wilson, Angela; Bruinsma, Fiona; Butzow, Ralf; Campbell, Ian G; Carty, Karen; Chang-Claude, Jenny; Chenevix-Trench, Georgia; Chen, Anne; Chen, Zhihua; Cook, Linda S; Cramer, Daniel W; Cunningham, Julie M; Cybulski, Cezary; Dansonka-Mieszkowska, Agnieszka; Dennis, Joe; Dicks, Ed; Doherty, Jennifer A; Dörk, Thilo; du Bois, Andreas; Dürst, Matthias; Eccles, Diana; Easton, Douglas T; Edwards, Robert P; Eilber, Ursula; Ekici, Arif B; Fasching, Peter A; Fridley, Brooke L; Gao, Yu-Tang; Gentry-Maharaj, Aleksandra; Giles, Graham G; Glasspool, Rosalind; Goode, Ellen L; Goodman, Marc T; Grownwald, Jacek; Harrington, Patricia; Harter, Philipp; Hasmad, Hanis Nazihah; Hein, Alexander; Heitz, Florian; Hildebrandt, Michelle A T; Hillemanns, Peter; Hogdall, Estrid; Hogdall, Claus; Hosono, Satoyo; Iversen, Edwin S; Jakubowska, Anna; James, Paul; Jensen, Allan; Ji, Bu-Tian; Karlan, Beth Y; Kruger Kjaer, Susanne; Kelemen, Linda E; Kellar, Melissa; Kelley, Joseph L; Kiemeney, Lambertus A; Krakstad, Camilla; Kupryjanczyk, Jolanta; Lambrechts, Diether; Lambrechts, Sandrina; Le, Nhu D; Lee, Alice W; Lele, Shashi; Leminen, Arto; Lester, Jenny; Levine, Douglas A; Liang, Dong; Lissowska, Jolanta; Lu, Karen; Lubinski, Jan; Lundvall, Lene; Massuger, Leon F A G; Matsuo, Keitaro; McGuire, Valerie; McLaughlin, John R; Nevanlinna, Heli; McNeish, Ian; Menon, Usha; Modugno, Francesmary; Moysich, Kirsten B; Narod, Steven A; Nedergaard, Lotte; Ness, Roberta B; Azmi, Mat Adenan Noor; Odunsi, Kunle; Olson, Sara H; Orlow, Irene; Orsulic, Sandra; Weber, Rachel Palmieri; Pearce, Celeste L; Pejovic, Tanja; Pelttari, Liisa M; Permuth-Wey, Jennifer; Phelan, Catherine M; Pike, Malcolm C; Poole, Elizabeth M; Ramus, Susan J; Risch, Harvey A; Rosen, Barry; Rossing, Mary Anne; Rothstein, Joseph H; Rudolph, Anja; Runnebaum, Ingo B; Rzepecka, Iwona K; Salvesen, Helga B; Schildkraut, Joellen M; Schwaab, Ira; Sellers, Thomas A; Shu, Xiao-Ou; Shvetsov, Yurii B; Siddiqui, Nadeem; Sieh, Weiva; Song, Honglin; Southey, Melissa C; Sucheston, Lara; Tangen, Ingvild L; Teo, Soo-Hwang; Terry, Kathryn L; Thompson, Pamela J; Timorek, Agnieszka; Tsai, Ya-Yu; Tworoger, Shelley S; van Altena, Anne M; Van Nieuwenhuysen, Els; Vergote, Ignace; Vierkant, Robert A; Wang-Gohrke, Shan; Walsh, Christine; Wentzensen, Nicolas; Whittemore, Alice S; Wicklund, Kristine G; Wilkens, Lynne R; Woo, Yin-Ling; Wu, Xifeng; Wu, Anna H; Yang, Hannah; Zheng, Wei; Ziogas, Argyrios; Monteiro, Alvaro; Pharoah, Paul D; Gayther, Simon A; Freedman, Matthew L

    2015-01-01

    Genome-wide association studies have reported 11 regions conferring risk of high-grade serous epithelial ovarian cancer (HGSOC). Expression quantitative trait locus (eQTL) analyses can identify candidate susceptibility genes at risk loci. Here we evaluate cis-eQTL associations at 47 regions associated with HGSOC risk (P≤10(-5)). For three cis-eQTL associations (P<1.4 × 10(-3), FDR<0.05) at 1p36 (CDC42), 1p34 (CDCA8) and 2q31 (HOXD9), we evaluate the functional role of each candidate by perturbing expression of each gene in HGSOC precursor cells. Overexpression of HOXD9 increases anchorage-independent growth, shortens population-doubling time and reduces contact inhibition. Chromosome conformation capture identifies an interaction between rs2857532 and the HOXD9 promoter, suggesting this SNP is a leading causal variant. Transcriptomic profiling after HOXD9 overexpression reveals enrichment of HGSOC risk variants within HOXD9 target genes (P=6 × 10(-10) for risk variants (P<10(-4)) within 10 kb of a HOXD9 target gene in ovarian cells), suggesting a broader role for this network in genetic susceptibility to HGSOC.

  20. Cis-eQTL analysis and functional validation of candidate susceptibility genes for high-grade serous ovarian cancer.

    PubMed

    Lawrenson, Kate; Li, Qiyuan; Kar, Siddhartha; Seo, Ji-Heui; Tyrer, Jonathan; Spindler, Tassja J; Lee, Janet; Chen, Yibu; Karst, Alison; Drapkin, Ronny; Aben, Katja K H; Anton-Culver, Hoda; Antonenkova, Natalia; Baker, Helen; Bandera, Elisa V; Bean, Yukie; Beckmann, Matthias W; Berchuck, Andrew; Bisogna, Maria; Bjorge, Line; Bogdanova, Natalia; Brinton, Louise A; Brooks-Wilson, Angela; Bruinsma, Fiona; Butzow, Ralf; Campbell, Ian G; Carty, Karen; Chang-Claude, Jenny; Chenevix-Trench, Georgia; Chen, Anne; Chen, Zhihua; Cook, Linda S; Cramer, Daniel W; Cunningham, Julie M; Cybulski, Cezary; Dansonka-Mieszkowska, Agnieszka; Dennis, Joe; Dicks, Ed; Doherty, Jennifer A; Dörk, Thilo; du Bois, Andreas; Dürst, Matthias; Eccles, Diana; Easton, Douglas T; Edwards, Robert P; Eilber, Ursula; Ekici, Arif B; Fasching, Peter A; Fridley, Brooke L; Gao, Yu-Tang; Gentry-Maharaj, Aleksandra; Giles, Graham G; Glasspool, Rosalind; Goode, Ellen L; Goodman, Marc T; Grownwald, Jacek; Harrington, Patricia; Harter, Philipp; Hasmad, Hanis Nazihah; Hein, Alexander; Heitz, Florian; Hildebrandt, Michelle A T; Hillemanns, Peter; Hogdall, Estrid; Hogdall, Claus; Hosono, Satoyo; Iversen, Edwin S; Jakubowska, Anna; James, Paul; Jensen, Allan; Ji, Bu-Tian; Karlan, Beth Y; Kruger Kjaer, Susanne; Kelemen, Linda E; Kellar, Melissa; Kelley, Joseph L; Kiemeney, Lambertus A; Krakstad, Camilla; Kupryjanczyk, Jolanta; Lambrechts, Diether; Lambrechts, Sandrina; Le, Nhu D; Lee, Alice W; Lele, Shashi; Leminen, Arto; Lester, Jenny; Levine, Douglas A; Liang, Dong; Lissowska, Jolanta; Lu, Karen; Lubinski, Jan; Lundvall, Lene; Massuger, Leon F A G; Matsuo, Keitaro; McGuire, Valerie; McLaughlin, John R; Nevanlinna, Heli; McNeish, Ian; Menon, Usha; Modugno, Francesmary; Moysich, Kirsten B; Narod, Steven A; Nedergaard, Lotte; Ness, Roberta B; Azmi, Mat Adenan Noor; Odunsi, Kunle; Olson, Sara H; Orlow, Irene; Orsulic, Sandra; Weber, Rachel Palmieri; Pearce, Celeste L; Pejovic, Tanja; Pelttari, Liisa M; Permuth-Wey, Jennifer; Phelan, Catherine M; Pike, Malcolm C; Poole, Elizabeth M; Ramus, Susan J; Risch, Harvey A; Rosen, Barry; Rossing, Mary Anne; Rothstein, Joseph H; Rudolph, Anja; Runnebaum, Ingo B; Rzepecka, Iwona K; Salvesen, Helga B; Schildkraut, Joellen M; Schwaab, Ira; Sellers, Thomas A; Shu, Xiao-Ou; Shvetsov, Yurii B; Siddiqui, Nadeem; Sieh, Weiva; Song, Honglin; Southey, Melissa C; Sucheston, Lara; Tangen, Ingvild L; Teo, Soo-Hwang; Terry, Kathryn L; Thompson, Pamela J; Timorek, Agnieszka; Tsai, Ya-Yu; Tworoger, Shelley S; van Altena, Anne M; Van Nieuwenhuysen, Els; Vergote, Ignace; Vierkant, Robert A; Wang-Gohrke, Shan; Walsh, Christine; Wentzensen, Nicolas; Whittemore, Alice S; Wicklund, Kristine G; Wilkens, Lynne R; Woo, Yin-Ling; Wu, Xifeng; Wu, Anna H; Yang, Hannah; Zheng, Wei; Ziogas, Argyrios; Monteiro, Alvaro; Pharoah, Paul D; Gayther, Simon A; Freedman, Matthew L

    2015-01-01

    Genome-wide association studies have reported 11 regions conferring risk of high-grade serous epithelial ovarian cancer (HGSOC). Expression quantitative trait locus (eQTL) analyses can identify candidate susceptibility genes at risk loci. Here we evaluate cis-eQTL associations at 47 regions associated with HGSOC risk (P≤10(-5)). For three cis-eQTL associations (P<1.4 × 10(-3), FDR<0.05) at 1p36 (CDC42), 1p34 (CDCA8) and 2q31 (HOXD9), we evaluate the functional role of each candidate by perturbing expression of each gene in HGSOC precursor cells. Overexpression of HOXD9 increases anchorage-independent growth, shortens population-doubling time and reduces contact inhibition. Chromosome conformation capture identifies an interaction between rs2857532 and the HOXD9 promoter, suggesting this SNP is a leading causal variant. Transcriptomic profiling after HOXD9 overexpression reveals enrichment of HGSOC risk variants within HOXD9 target genes (P=6 × 10(-10) for risk variants (P<10(-4)) within 10 kb of a HOXD9 target gene in ovarian cells), suggesting a broader role for this network in genetic susceptibility to HGSOC. PMID:26391404

  1. Radiosensitivity of Human Fibroblasts is Associated With Amino Acid Substitution Variants in Susceptible Genes And Correlates With The Number of Risk Alleles

    SciTech Connect

    Alsbeih, Ghazi . E-mail: galsbeih@kfshrc.edu.sa; El-Sebaie, Medhat; Al-Harbi, Najla; Al-Buhairi, Muneera; Al-Hadyan, Khaled; Al-Rajhi, Nasser

    2007-05-01

    Purpose: Genetic predictive markers of radiosensitivity are being sought for stratifying radiotherapy for cancer patients and risk assessment of radiation exposure. We hypothesized that single nucleotide polymorphisms in susceptible genes are associated with, and the number of risk alleles has incremental effect on, individual radiosensitivity. Methods and Materials: Six amino acid substitution variants (ATM 1853 Asp/Asn G>A, p53 72 Arg/Pro G>C, p21 31 Ser/Arg C>A, XRCC1 399 Arg/Gln G>A, XRCC3 241 Thr/Met C>T, and TGF{beta}1 10 Leu/Pro T>C) were genotyped by direct sequencing in 54 fibroblast strains of different radiosensitivity. Results: The clonogenic survival fraction at 2 Gy range was 0.15-0.50 (mean, 0.34, standard deviation, 0.08). The mean survival fraction at 2 Gy divided the cell strains into radiosensitive (26 cases) and normal (28 controls). A significant association was observed between the survival fraction at 2 Gy and ATM 1853 Asn, XRCC3 241 Met, and TGF{beta}1 10 Leu alleles (p = 0.05, p = 0.02, and p = 0.02, respectively). The p53 72 Arg allele showed a borderline association (p = 0.07). The number of risk alleles increased with increasing radiosensitivity, and the group comparison showed a statistically significant difference between the radiosensitive and control groups (p {<=}0.001). Conclusion: The results of our study have shown that single nucleotide polymorphisms in susceptible genes influence cellular radiation response and that the number of risk alleles has a combined effect on radiosensitivity. Individuals with multiple risk alleles could be more susceptible to radiation effects than those with fewer risk alleles. These results may have implications in predicting normal tissue reactions to radiotherapy and risk assessment of radiation exposure.

  2. Control mechanisms of plastid gene expression

    SciTech Connect

    Gruissem, W.; Tonkyn, J.C.

    1993-12-31

    Plastid DNAs of higher plants contain approximately 150 genes that encode RNAs and proteins for genetic and photosynthetic functions of the organelle. Results published in the last few years illustrate that the spatial and temporal expression of these plastid genes is regulated, in part, at the transcriptional level, but that developmentally controlled changes in mRNA stability, translational activity, and protein phosphorylation also have an important role in the control of plastid functions. This comprehensive review summarizes and discusses the mechanisms by which regulation of gene expres