We identify the SLC22A3-LPAL2-LPA gene cluster as a strong susceptibility locus for coronary artery disease (CAD) through a genome-wide haplotype association (GWHA) study. This locus was not identified from previous genome-wide association (GWA) studies focused on univariate analyses of SNPs. The proposed approach may have wide utility for analyzing GWA data for other complex traits.
BackgroundSerum 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 FindingsFirst, 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.ConclusionThus, 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.
OBJECTIVE-Lipin, a novel molecular protein expressed by adipocytes, has marked effects on adipose tissue mass, insulin sensitivity, and glucose homeostasis. Thus, we hypothesized that genetic variants within LPIN1 are associated with traits of the metabolic syndrome.RESEARCH DESIGN AND METHODS-A total of 15 single nucleotide polymorphisms (SNPs) covering the LPIN1 gene region were genotyped in an age-and sex-stratified sample of the general population (Monitoring Trends and Determinants on Cardiovascular Diseases Study Augsburg; DNA and phenotypes of 1,416 Caucasians). Ten SNPs were also genotyped for replication in an independent sample of 1,030 subjects recruited throughout Germany. The metabolic syndrome was defined via the sum of its core components and, additionally, by a factor score derived from factor analysis. Permutation-based methods were used to test the association between genetic LPIN1 variants and metabolic traits for empirical significance.RESULTS-Linkage disequilibrium (LD) analysis revealed three LD blocks encompassing LPIN1. We identified three associated three-marker haplotypes: one common haplotype (26.8% frequency) increases the risk for the metabolic syndrome (odds ratio 1.6 [95% CI 1.2-2.2]), while the other two, being less common (5.7 and 4.0%), are strongly associated with lower blood pressure levels (systolic blood pressure 127 Ϯ 18 vs. 135 Ϯ 20 mmHg; P ϭ 0.0001), a lower BMI (24.6 Ϯ 3.6 vs. 26.9 Ϯ 4.1 kg/m 2 ; P ϭ 3.7 ϫ 10 Ϫ7 ) and waist circumference (82 Ϯ 12 vs. 90 Ϯ 12 cm; P ϭ 3.2 ϫ 10 Ϫ8 ), lower A1C levels (5.1 Ϯ 0.7 vs. 5.3 Ϯ 0.9%; P ϭ 0.0002), as well as a lower metabolic syndrome factor score (Ϫ0.67 Ϯ 1.00 vs. 0.04 Ϯ 1.24; P ϭ 1.4 ϫ 10 Ϫ7 ). Furthermore, the frequencies of arterial hypertension (23.7 vs. 46.4%; P ϭ 0.00001), obesity (12.9 vs. 30.8%; P ϭ 0.0003), diabetes (2.2 vs. 8.2%; P ϭ 0.041), and the presence of three or more metabolic syndrome components (3.3 vs. 13.7%; P ϭ 0.002) were significantly lower than in subjects not carrying one of these protective haplotypes.Strong associations were also observed in the replication sample using the same haplotypes but with effects in the opposite direction.CONCLUSIONS-These data suggest that allelic variants of the LPIN1 gene have significant effects in human metabolic traits and thus implicate lipin in the pathophysiology of the metabolic syndrome.
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