Coronary Artery Disease Risk Loci Research Articles

Abstract 3451: Risk for Coronary Artery Disease at the 9p21.3 Locus Is Abolished by a Protective Locus at 8p21.3 Identified by a Genome-Wide Association Study

Background : Coronary artery disease (CAD) is the leading cause of death in the western world. The only common genetic risk locus identified to date by us and others in genome wide association studies (GWAS) resides at 9p21.3. Methods: The Ottawa Heart Genomic Study compared genotypes of 1,542 early onset CAD patients (average 49y) and 1,455 elderly control Caucasians (average 75y). Results: Here, we report two protective haplotypes in the 3′ region of the lipoprotein lipase (LPL) gene at 8p21.3. LPL promotes lipolysis of circulating triglycerides (TG) and increases levels of atheroprotective high density lipoprotein (HDL) cholesterol. Since the 8p21.3 haplotypes are protective, we tested their interaction with the 9p21.3 risk allele. The rs10503669 haplotype associated with elevated TG and HDL levels but did not affect risk from 9p21.3. In contrast, the rs17411031 haplotype was not associated with TG or HDL levels and showed a significant interaction that abolished 9p21.3 risk independent of known risk factors. The interaction was confirmed using data of the Wellcome Trust Case Control Consortium. Excluding carriers of the interacting allele, accuracy of 9p21.3 to predict CAD risk is dramatically improved. Conclusion: Identification of the first modifier gene of the 9p21.3 risk locus for CAD improves CAD risk assessment and provides novel insight into coronary atherosclerosis. This protective 8p21.3 locus may provide a target for novel therapy.

Association Between the Coronary Artery Disease Risk Locus on Chromosome 9p21.3 and Abdominal Aortic Aneurysm

Recent genome-wide studies have shown a significant association of a locus on chromosome 9p21.3 and coronary artery disease. We performed a case-control study to investigate the association between this locus and abdominal aortic aneurysm (AAA). A total of 1714 patients (899 patients with AAA and 815 controls) were genotyped for the lead single-nucleotide polymorphism, rs1333049, on chromosome 9p21. The frequency of the C (risk) allele of rs1333049 in the control group was 0.471. There was a significant association between the C allele and AAA (odds ratio, 1.22; 95% confidence interval, 1.06 to 1.39; P=0.004). The genotypic-specific odds ratios (compared with the GG genotype) were 1.17 (95% confidence interval, 0.93 to 1.47; P=0.191) for the GC genotype and 1.50 (95% confidence interval, 1.14 to 1.97; P=0.004) for the CC genotype. In logistic regression modeling, the association of the CC genotype with AAA was independent of the presence of clinical coronary artery disease (odds ratio, 1.46; 95% confidence interval, 1.11 to 1.94; P=0.008). Our study shows that the recently identified chromosome 9 variant that increases risk of coronary artery disease is also associated with the presence of AAA. The findings suggest that the effect of this locus on risk of cardiovascular disease extends beyond the coronary circulation.