Genomewide Association Analysis of Coronary Artery Disease

Abstract

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=1.80×10−14 and P=3.40×10−6, respectively). Overall, the WTCCC study revealed nine loci that were strongly associated with coronary artery disease (P<1.2×10−5 and less than a 50% chance of being falsely positive). In addition to chromosome 9p21.3, two of these loci were successfully replicated (adjusted P<0.05) in the German study: chromosome 6q25.1 (rs6922269) and chromosome 2q36.3 (rs2943634). The combined analysis of the two studies identified four additional loci significantly associated with coronary artery disease (P<1.3×10−6) and a high probability (>80%) 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.

Lifestyle Cardiovascular Risk Score, Genetic Risk Score, and Myocardial Infarction in Hispanic/Latino Adults Living in Costa Rica

“…The association for the GRS and higher odds of MI was consistent with previous literature analyzing SNPs in the chromosome 9p21 and higher risk of CHD and mortality 6, 10, 12. Moreover, we observed that participants with the highest genetic risk in combination with the highest lifestyle risk factors (both all‐together as well as individually) had higher odds of MI.…”

“…Although the genetic variants used in the GRS have been associated with increased risk of CHD in European populations,6, 10, 12 they account for a modest portion of the variability in MI, and other genetic variants (for example, in genes of the inflammation response) could have a stronger effect in this population. A more comprehensive evaluation of gene–environment interactions with genetic markers in additional loci warrants future investigation.…”

“…In addition to lifestyle, compelling evidence indicates that genetic susceptibility alone is part of the etiology of CHD and heart‐related events 6, 7, 8, 9, 10, 11. Genome‐wide association studies have identified chromosomal regions and genetic variants associated with CHD 6, 10, 12.…”

“…Genome‐wide association studies have identified chromosomal regions and genetic variants associated with CHD 6, 10, 12. One of the most robust genetic associations for CHD is the chromosome 9p21 region.…”

The impact of genome‐wide association studies on the pathophysiology and therapy of cardiovascular disease

“…In 2007, the first GWAS were published for CAD, all of which identified a locus on chromosome 9p21 to be genome‐wide significantly associated with the disease (Helgadottir et al , 2007; McPherson et al , 2007; Samani et al , 2007). This locus became the first claim of what has later been called a gold rush of CAD genetics.…”