Association of single nucleotide polymorphisms in the LPA gene region with serum Lp(a) levels and myocardial infarction

Elevated serum Lp(a) levels are a risk factor for atherosclerosis and myocardial infarction. Lp(a) serum levels are highly heritable, and to a great extend determined by the LPA locus on chromosome 6q27. Polymorphisms influencing the Lp(a) levels have already been identified, but a proportion of the variance in Lp(a) levels remains to be explained. In this investigation different methods were used to explore the influence of SNP markers located in the LPA gene region on Lp(a) levels. The methods comprised a pooling strategy that made use of data from a previous linkage analysis, and served as a screening tool for probably relevant SNP markers. For several SNP markers an association with serum Lp(a) levels could be shown. The identified SNP markers were genotyped in individuals of a large family sample and findings were replicated for all investigated markers. In a third step, a sample of the general population was investigated to underline the robustness of findings. Furthermore, for SNP markers showning a strong association with Lp(a) levels, the association with myocardial infarction (MI) and coronary artery disease was investigated. Particularly one SNP marker in the LPA gene could be identified. This marker (rs11751605) showed a strong influence on Lp(a) levels in multiple populations and is significantly associated with both familial and incidental MI. Moreover, it contributes to the evidence of linkage to the Lp(a) locus on chromosome 6q27. Association with Lp(a) levels and with CAD could be replicated for a SNP marker (rs3798220) recently described in the literature. Furthermore data from a genome-wide association analysis using 500,000 SNP markers were analyzed. The results provide the basis for the identification of factors (apart from markers in LPA gene region) modulating Lp(a) levels

Association of Common Polymorphisms in GLUT9 Gene with Gout but Not with Coronary Artery Disease in a Large Case-Control Study

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

Association between PPARα gene polymorphisms and myocardial infarction

International audiencePeroxisome proliferator activated receptor alpha (PPAR{eta}) regulates the expression of genes that are involved in lipid metabolism, tissue homeostasis, and inflammation. Consistent rodent and human studies suggest a link between PPAR{eta} function and cardiovascular disease, qualifying PPAR {eta} as a candidate gene for coronary artery disease. We comprehensively evaluated common genetic variations within the PPAR {eta} gene and assessed their association with myocardial infarction. First, we characterized the linkage disequilibrium within the PPAR {eta} gene in an initial case-control sample of 806 individuals from the Regensburg Myocardial Infarction Family Study using a panel of densely spaced single nucleotide polymorphisms (SNPs) across the gene. Single SNP analysis showed significant association with the disease phenotype (OR=0.74, P=0.012, 95% CI=0.61-0.94 for rs135551). Moreover, we identified a protective 3-marker haplotype with an association trend for myocardial infarction (OR=0.76, P=0.067, 95% CI=0.56-1.92). Subsequently, we were able to confirm the single SNP and haplotype association results in an independent second case-control cohort with 667 cases from the Regensburg Myocardial Infarction Family Study and 862 control individuals from the WHO MONICA Augsburg project (OR=0.87, P=0.046, 95% CI=0.72-0.99 for rs135551; OR=0.80, P=0.034, 95% CI=0.65-0.98 for the 3-marker haplotype, respectively). From these cross-sectional association results, we provide evidence that common variations in the PPAR {eta} gene may influence the risk of myocardial infarction in a European population

Association analysis results in CAD case-control sample.

<p>MAF: minor allele frequency; numbers of genotypes (11, 12, 22) according to alleles from <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0001948#pone-0001948-t003" target="_blank">Table 3</a>.</p

Association analysis results in female gout case-control sample.

<p>MAF: minor allele frequency; numbers of genotypes (11, 12, 22) according to alleles from <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0001948#pone-0001948-t003" target="_blank">Table 3</a>.</p><p>n. a.: not applicable due to low counts of minor allele for χ².</p

Association analysis results in gout case-control sample.

<p>MAF: minor allele frequency; numbers of genotypes (11, 12, 22) according to alleles from <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0001948#pone-0001948-t003" target="_blank">Table 3</a>.</p

Characteristics of gout case and control study sample.

<p>Values denote means ± standard deviations unless indicated otherwise. n. s., not significant; CAD, coronary artery disease; MI, myocardial infarction; LDL-C, low-density lipoprotein cholesterol; HDL-C, high-density lipoprotein cholesterol; BMI, body mass index.</p>a<p>Matching parameter.</p>b<p>Defined as LDL-C ≥160 mg/dL or intake of lipid lowering medication.</p>c<p>Defined as blood pressure ≥140/90 mm Hg or ongoing antihypertensive therapy.</p>d<p>Defined as history of diabetes mellitus or intake of antidiabetic medication.</p>e<p>Former or current smoking habit.</p

Characteristics of CAD case and control study sample.

<p>Values denote means ± standard deviations unless indicated otherwise. CAD, coronary artery disease; MI, myocardial infarction; LDL-C, low-density lipoprotein cholesterol; HDL-C, high-density lipoprotein cholesterol; BMI, body mass index.</p>a<p>Defined as LDL-C ≥160 mg/dL or intake of lipid lowering medication.</p>b<p>Defined as blood pressure ≥140/90 mm Hg or ongoing antihypertensive therapy.</p>c<p>Defined as history of diabetes mellitus or intake of antidiabetic medication.</p>d<p>Former or current smoking habit.</p

Association analysis results in male gout case-control sample.

<p>MAF: minor allele frequency; numbers of genotypes (11, 12, 22) according to alleles from <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0001948#pone-0001948-t003" target="_blank">Table 3</a>.</p