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Association of common polymorphisms in GLUT9 gene with gout but not with coronary artery disease in a large case-control study.

ABSTRACT: BACKGROUND: Serum uric acid (UA) levels have recently been shown to be genetically influenced by common polymorphisms in the GLUT9 gene in two genome-wide association analyses of Italian and British populations. Elevated serum UA levels are often found in conjunction with the metabolic syndrome. Hyperuricemia is the major risk factor for gout and has been associated with increased cardiovascular morbidity and mortality. The aim of the present study was to further elucidate the association of polymorphisms in GLUT9 with gout and coronary artery disease (CAD) or myocardial infarction (MI). To test our hypotheses, we performed two large case-control association analyses of individuals from the German MI Family Study. METHODS AND FINDINGS: First, 665 patients with gout and 665 healthy controls, which were carefully matched for age and gender, were genotyped for four single nucleotide polymorphisms (SNPs) within or near the GLUT9 gene. All four SNPs demonstrated highly significant association with gout. SNP rs6855911, located within intron 7 of GLUT9, showed the strongest signal with a protective effect of the minor allele with an allelic odds ratio of 0.62 (95% confidence interval 0.52-0.75; p = 3.2*10(-7)). Importantly, this finding was not influenced by adjustment for components of the metabolic syndrome or intake of diuretics. Secondly, 1,473 cases with severe CAD or MI and 1,241 healthy controls were tested for the same four GLUT9 SNPs. The analyses revealed, however, no significant association with CAD or with MI. Additional screening of genome-wide association data sets showed no signal for CAD or MI within the GLUT9 gene region. CONCLUSION: Thus, our results provide compelling evidence that common genetic variations within the GLUT9 gene strongly influence the risk for gout but are unlikely to have a major effect on CAD or MI in a German population.

SUBMITTER: Stark K

PROVIDER: S-EPMC2275796 | biostudies-literature | 2008

REPOSITORIES: biostudies-literature

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Association of common polymorphisms in GLUT9 gene with gout but not with coronary artery disease in a large case-control study.

Stark Klaus K Reinhard Wibke W Neureuther Katharina K Wiedmann Silke S Sedlacek Kamil K Baessler Andrea A Fischer Marcus M Weber Stefan S Kaess Bernhard B Erdmann Jeanette J Schunkert Heribert H Hengstenberg Christian C

PloS one 20080409 4

<h4>Background</h4>Serum uric acid (UA) levels have recently been shown to be genetically influenced by common polymorphisms in the GLUT9 gene in two genome-wide association analyses of Italian and British populations. Elevated serum UA levels are often found in conjunction with the metabolic syndrome. Hyperuricemia is the major risk factor for gout and has been associated with increased cardiovascular morbidity and mortality. The aim of the present study was to further elucidate the association ...[more]

PMID: 18398472

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Project description:Background Genome wide association studies (GWAS) have successfully revealed >40 genetic risk loci associated with coronary artery disease (CAD) in Europeans. Only five loci have been replicated in South Asians. Methods We assessed the association of 47 genome-wide significant single-nucleotide polymorphisms (SNPs) with CAD in a Pakistani sample comprising of 663 clinically ascertained and angiographically confirmed cases and controls. Genotypes were performed using Sequenom’s iPLEX assay. The association of selected SNPs with coronary stenosis was initially determined by chi-square and additive genetic model. We selected 12 SNPs based on additive model and their association was also analyzed by using dominant model. All statistical analyses were performed by R software. Linkage disequilibrium (LD) of significant SNPs was determined by SNAP web portal and functional annotation of SNPs was determined by RegulomeDB. Results We had five significant SNPs out of 47 variants (rs4252120; P=0.003, rs2505083; P=0.006, rs2048327; P=0.04, rs602633; P=0.02 & rs46522; P=0.02) under dominant model and two, PLG/rs4252120 (P=0.003) and KIAA1462/rs2505083 (P=0.006), showed significant association with CAD in our sample after correcting for multiple testing (q<0.05). The odds ratio (OR) in cases vs. controls for two significant SNPs were; [PLG/rs4252120 (OR =1.83; P=0.003, FDR =0.02)] and [KIAA1462/rs2505083 (OR =1.65, P=0.006, FDR =0.03)]. PLG/rs4252120 was in LD with two other functional PLG variants (rs4252126 and rs4252135) having RegulomeDB score of 1f. Likewise, KIAA1462/rs2505083 was in LD with a functional SNP KIAA1462/rs3739998 having RegulomeDB score of 2b (likely affects TF binding). Conclusions We have successfully replicated two previously reported genome-wide significant SNPs in our Pakistani sample. KIAA1462/rs2505083 appears to be functional by itself as well as proxy of a functional SNP (KIAA1462/rs3739998). PLG/rs4252120 is proxy of two functional SNPs. Further association studies in other non-European populations and future functional studies are warranted to assess the impact of these two variants on risk of CAD.

Project description:Lipoprotein(a) is a well-known independent risk factor for coronary artery disease (CAD) and primarily determined by variation in the LPA gene coding for the apolipoprotein(a) moiety. Our study purpose was to evaluate the association between the human LPA gene polymorphisms and CAD in Han and Uyghur populations in Xinjiang, China. A case-control study was conducted with 831 Han people (392 CAD patients and 439 control subjects) and 829 Uygur people (513 CAD patients and 316 control subjects). All participants were genotyped for the same 3 single nucleotide polymorphisms (rs1801693, rs6923877, and rs9364559) of the LPA gene by a Real-time PCR instrument. In CAD patients, the levels of lipoprotein(a) were significantly higher in the Han population with the C/C genotype at the rs1801693 (P = .018) and the A/A genotype at the rs9364559 (P = .029) than in the Uyghur population. The polymorphisms rs1801693, rs6923877, and rs9364559 were found to be associated with CAD in the Han population. For men, the distribution of rs1801693 in genotypes, alleles and recessive model (CC vs CT + TT) showed a significant difference (all P < .05), and the difference in recessive model was retained after adjustment for covariates (odds ratio [OR]: 0.557, 95% confidence interval [CI]: 0.355-0.874, P = .011). But the distribution of rs6923877 in genotypes and dominant model (GG vs AG + AA) showed a significant difference (both P < .05) in both men and women, and the difference was kept in dominant model after adjustment (OR: 1.473, 95% CI:1.009-2.148, P = .045). For women, a significant difference was found in the distribution of rs9364559 in the alleles and dominant model (AA vs AG + GG) (for alleles: P = .021, for dominant model: P = .025, OR: 0.560, 95% CI:0.350-0.898, P = .016) after adjustment. Polymorphisms rs1801693, rs6923877, and rs9364559 of the LPA gene are associated with CAD in the Han population in Xinjiang Uygur Autonomous Region of China.

Project description:Background: Coronary artery disease (CAD) is one of the main fatal diseases all over the world. CAD is a complex disease, which has multiple risk factors mechanisms. In recent years, genome-wide association study (GWAS) had revealed single nucleotide polymorphism genes (SNPs) which were closely related with CAD risks. The relationship between long non-coding RNA (lncRNA) MALAT1 (metastasis-associated lung adenocarcinoma transcript 1) and CAD risk is largely unknown. To our knowledge, this is the first study which demonstrated the interaction effects of SNP-SNP and SNP-environment with CAD risk. In general, our case-control study is to detect the association between MALAT1 (rs619586, rs4102217) SNPs and CAD risk. Methods: Three hundred and sixty-five CAD patients and three hundred and eighty-four matched control participants blood samples were collected in Liaoning province, China. Two polymorphisms (rs619586, rs4102217) in lncRNA MALAT1 were genotyped by KASP platform. Results: In a stratified analysis, we found that non-drinkers with GC genotype and the recessive model of rs4102217 had higher CAD risk (P=0.010, odds ratio (OR): 1.96, 95% confidence interval (CI) = 1.17-3.28; P=0.026, OR: 1.73, 95% CI = 1.07-2.79) and diabetes mellitus (DM) history group (P=0.010, OR: 4.07, 95% CI = 1.41-11.81; P=0.019, OR: 3.29, 95% CI = 1.22-8.88). In SNP-SNP interactions analysis between MALAT1 and CAD risk, we found rs4102217 had an increase in smokers (GG: OR: 2.04, 95% CI = 1.42-2.92; CC+GC: OR: 2.64, 95% CI = 1.64-4.26) and a decrease in drinkers (CC+GC: OR: 0.33, 95% CI = 0.20-0.55). Smokers with MALAT1 rs619586 AA genotype (OR: 2.20, 95% CI = 1.57-3.07) and GG+AG genotype (OR: 2.11, 95% CI = 1.17-3.81) had a higher risk of CAD. Moreover, drinkers with AA genotype (OR: 0.22, 95% CI = 0.10-0.48) and GG+AG genotype (OR: 0.38, 95% CI = 0.22-0.65) had a lower risk of CAD. According to the MDR software, MALAT1 rs4102217 polymorphism-smoking-drinking was the best interaction model, which has higher risk of CAD (Testing Bal.ACC. = 0.6979). Conclusion: Our study demonstrated that the GC genotype and the recessive model of rs4102217 potentially increased CAD risk in some specific group.

Dataset Information

Association of common polymorphisms in GLUT9 gene with gout but not with coronary artery disease in a large case-control study.

Publications

Association of common polymorphisms in GLUT9 gene with gout but not with coronary artery disease in a large case-control study.

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