Genomewide association analysis of coronary artery disease

Background - Modern genotyping platforms permit a systematic search for inherited components of complex diseases. We performed a joint analysis of two genomewide association studies of coronary artery disease. Methods - We first identified chromosomal loci that were strongly associated with coronary artery disease in the Wellcome Trust Case Control Consortium (WTCCC) study (which involved 1926 case subjects with coronary artery disease and 2938 controls) and looked for replication in the German MI [Myocardial Infarction] Family Study (which involved 875 case subjects with myocardial infarction and 1644 controls). Data on other single-nucleotide polymorphisms (SNPs) that were significantly associated with coronary artery disease in either study (P<0.001) were then combined to identify additional loci with a high probability of true association. Genotyping in both studies was performed with the use of the GeneChip Human Mapping 500K Array Set (Affymetrix). Results - Of thousands of chromosomal loci studied, the same locus had the strongest association with coronary artery disease in both the WTCCC and the German studies: chromosome 9p21.3 (SNP, rs1333049) (P=1.80x10–14 and P=3.40x10–6, respectively). Overall, the WTCCC study revealed nine loci that were strongly associated with coronary artery disease (P80%) of a true association: chromosomes 1p13.3 (rs599839), 1q41 (rs17465637), 10q11.21 (rs501120), and 15q22.33 (rs17228212). Conclusions - We identified several genetic loci that, individually and in aggregate, substantially affect the risk of development of coronary artery disease

Association analysis results in CAD case-control sample.

<p>Numbers of genotypes (11, 12, 22) according to alleles from <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0007729#pone-0007729-t003" target="_blank">Table 3</a>.</p>a<p>Model including age at inclusion, gender, hypercholesterolemia, diabetes, hypertension, smoking, and BMI.</p>b<p>Power was calculated for the given OR using the respective MAF in controls and a two-tailed <i>p</i> = 0.05.</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 mmHg 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>Numbers of genotypes (11, 12, 22) according to alleles from <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0007729#pone-0007729-t003" target="_blank">Table 3</a>.</p>a<p>Model including medication with diuretics, lipid lowering and antihypertensive therapy, HDL-C, type 2 diabetes, smoking, and BMI.</p

Association analysis results in gout case-control sample.

<p>Numbers of genotypes (11, 12, 22) according to alleles from <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0007729#pone-0007729-t003" target="_blank">Table 3</a>.</p>a<p>Model including gender, medication with diuretics, lipid lowering and antihypertensive therapy, HDL-C, type 2 diabetes, smoking, and BMI.</p>b<p>Power was calculated for the given OR using the respective MAF in controls and a two-tailed <i>p</i> = 0.05.</p

Association analysis results in female gout case-control sample.

<p>Numbers of genotypes (11, 12, 22) according to alleles from <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0007729#pone-0007729-t003" target="_blank">Table 3</a>.</p>a<p>Model including medication with diuretics, lipid lowering and antihypertensive therapy, HDL-C, type 2 diabetes, smoking, and BMI.</p

SNP marker used in analysis.

a<p>on human genome build 18.</p>b<p>in total sample (<i>n</i> = 4,960).</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>At inclusion to study.</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 mmHg 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

Genetic determination of sPLA₂-IIa concentrations.

a<p>Based on non-parametric Kruskal-Wallis test on untransformed sPLA₂-IIa concentrations.</p>b<p>Percent change in geometric mean sPLA₂-IIa concentration in heterozygotes in reference to common homozygotes.</p>c<p>Percent change in geometric mean sPLA₂-IIa concentration in rare homozygotes in reference to common homozygotes.</p>d<p>Percent change in geometric mean sPLA₂-IIa concentration per minor allele present.</p><p>Genotype distributions, proportion of variance in <i>ln</i>-transformed sPLA₂-IIa serum concentration explained by the SNPs studied (R²; one-way ANOVA), and results from age- and sex-adjusted regression models predicting <i>ln</i>-transformed sPLA₂-IIa concentrations from genotypes.</p

Lipoprotein (a) plasma levels at baseline and change of lipoprotein (a) plasma levels over time between acute coronary syndrome and one to three months follow-up.

Plasma levels of lipoprotein(a) were measured at time of acute coronary syndrome (A). In a subgroup of 80 patients (B) lipoprotein (a) was measured at baseline (white boxes) and after one to three months of follow-up (grey boxes). Patients were stratified in four groups according baseline Lp(a) levels: ≤15mg/dL, >15-30mg/dL, >30-60mg/dL, and >60mg/dL; * p<0.05, # p<0.001 baseline vs. follow-up.</p