Susceptibility locus for clinical and subclinical coronary artery disease at chromosome 9p21 in the multi-ethnic ADVANCE study

Abstract

A susceptibility locus for coronary artery disease (CAD) at chromosome 9p21 has recently been reported, which may influence the age of onset of CAD. We sought to replicate these findings among white subjects and to examine whether these results are consistent with other racial/ethnic groups by genotyping three single nucleotide polymorphisms (SNPs) in the risk interval in the Atherosclerotic Disease, Vascular Function, and Genetic Epidemiology (ADVANCE) study. One or more of these SNPs was associated with clinical CAD in whites, U.S. Hispanics and U.S. East Asians. None of the SNPs were associated with CAD in African Americans although the power to detect an odds ratio (OR) in this group equivalent to that seen in whites was only 24-30%. ORs were higher in Hispanics and East Asians and lower in African Americans, but in all groups the 95% confidence intervals overlapped with ORs observed in whites. High-risk alleles were also associated with increased coronary artery calcification in controls and the magnitude of these associations by racial/ethnic group closely mirrored the magnitude observed for clinical CAD. Unexpectedly, we noted significant genotype frequency differences between male and female cases (P = 0.003-0.05). Consequently, men tended towards a recessive and women tended towards a dominant mode of inheritance. Finally, an effect of genotype on the age of onset of CAD was detected but only in men carrying two versus one or no copy of the high-risk allele and presenting with CAD at age >50 years. Further investigations in other populations are needed to confirm or refute our findings.

Chromosome 9p21 polymorphism is associated with myocardial infarction but not with clinical outcome in Han Chinese

“…These observations were in line with the report by Anderson et al (12), and suggested that variants at the 9p21 locus may robustly predict the prevalence of angiographic CAD, but not angiographic CAD severity. Assimes et al revealed that chromosome 9p21 variation was associated with total coronary plaque burden as expressed by calcification scores (13). However, angiographic CAD severity defined as number of stenotic coronary arteries appeared to correlate weakly with atherosclerotic plaque burden of the coronary tree.…”

9p21 and the Genetic Revolution for Coronary Artery Disease

“…9p21 was confirmed as a risk factor in the Korean (28 ), Japanese (28 ), and Chinese populations (29 ). In a study involving a large number of Southeast Asians, Assimes et al (30 ) showed that 9p21 was a CAD risk factor with features similar to those shown in the Caucasian studies; however, African Americans did not exhibit 9p21 as a risk factor in this study (30 ). In a more recent study, the Coronary Artery Disease Genetics Consortium (31 ) performed a GWAS of a discovery population of 30 482 individuals that included 6996 cases of South Asian ancestry from Pakistan and India, with replication in a sample size of 40 593 individuals that included 6187 South Asians.…”

“…These groups appear not to have had the time to intermingle and break up the DNA haplotype that carries the risk. In contrast, in Africans, who have had a much longer history, the 9p21 risk region (haplotype) has been broken into smaller haplotypes that produce minimal or no risk for CAD (30 ).…”

Genetics of myocardial infarction in clinical practice. Is it ready for prime time?

“…[5][6][7][8] These data for the first time were replicated in several cohorts of different ethnic origin, confirming the robustness of the results. [9][10][11][12][13][14] Moreover, they have been validated in a meta-analysis, performed on 12,000 cases and 29,000 controls, which showed a relative risk of 1.27 (95% CI 1.23-1.31; p=1.62 10 -12 ) for ischemic heart disease in the presence of each risk allele. [15] All currently identified risk alleles are relatively frequent.…”

“…It has been hypothesized that aggregating the contributions of multiple SNPs into a single genetic risk score, combining the relatively small effect of individual genes, may help to identify the individual risk and increase the probability of predicting myocardial infarction beyond traditional risk factors. [13,14] However, the attempts made so far have led to mixed results and there are still few solid data supporting the clinical usefulness of such a scoring system. [19,[25][26][27][28] Kathiresan et al [25] tested the hypothesis that a combination of nine genetic variants associated with increased blood lipid levels into a genotype score contributes to the risk prediction of cardiovascular disease.…”