Association Between Chromosome 9p21 Variants and the Ankle-Brachial Index Identified by a Meta-Analysis of 21 Genome-Wide Association Studies

Abstract

Background Genetic determinants of peripheral arterial disease (PAD) remain largely unknown. To identify genetic variants associated with the ankle-brachial index (ABI), a noninvasive measure of PAD, we conducted a meta-analysis of genome-wide association study data from 21 population-based cohorts. Methods and Results Continuous ABI and PAD (ABI≤0.9) phenotypes adjusted for age and sex were examined. Each study conducted genotyping and imputed data to the ~2.5 million SNPs in HapMap. Linear and logistic regression models were used to test each SNP for association with ABI and PAD using additive genetic models. Study-specific data were combined using fixed-effects inverse variance weighted meta-analyses. There were a total of 41,692 participants of European ancestry (~60% women, mean ABI 1.02 to 1.19), including 3,409 participants with PAD and with GWAS data available. In the discovery meta-analysis, rs10757269 on chromosome 9 near CDKN2B had the strongest association with ABI (β= −0.006, p=2.46x10−8). We sought replication of the 6 strongest SNP associations in 5 population-based studies and 3 clinical samples (n=16,717). The association for rs10757269 strengthened in the combined discovery and replication analysis (p=2.65x10−9). No other SNP associations for ABI or PAD achieved genome-wide significance. However, two previously reported candidate genes for PAD and one SNP associated with coronary artery disease (CAD) were associated with ABI : DAB21P (rs13290547, p=3.6x10−5); CYBA (rs3794624, p=6.3x10−5); and rs1122608 (LDLR, p=0.0026). Conclusions GWAS in more than 40,000 individuals identified one genome-wide significant association on chromosome 9p21 with ABI. Two candidate genes for PAD and 1 SNP for CAD are associated with ABI.

Epidemiology of Peripheral Artery Disease

“…96 One genomewide significant association on chromosome 9p21, rs10757269, was identified for ABI. Two candidate genes for PAD and 1 single nucleotide polymorphism for coronary artery disease were associated with ABI, DAB21P (rs13290547), CYBA (rs3794624), and rs1122608 (LDLR).…”

Association between Polymorphisms rs1333040 and rs7865618 of Chromosome 9p21 and Sporadic Brain Arteriovenous Malformations

“…In this study, we investigated the hypothesis that the 9p21 locus, which is the most replicated genetic marker for diseases such as CAD, peripheral artery disease, AAA, stroke, and intracranial aneurysms [4,5,6,7,8,9,10], is also associated with sporadic BAVMs. To test this hypothesis, we studied the distribution of two prototypical SNPs of chromosome 9p21 in two cohorts of BAVM cases and controls from Rome and Turin, Italy.…”

“…These studies have revealed that the 9p21 locus contains single nucleotide polymorphisms (SNPs) associated with myocardial infarction, coronary artery disease (CAD), peripheral artery disease, abdominal aortic aneurysms (AAA), intracranial aneurysms, and stroke [4,5,6,7,8,9,10]. …”

Common genetic variants do not associate with CAD in familial hypercholesterolemia

“…25,26 Martinelli et al 25 suggest that the effect they observed is due to the lipid effects of the variants. 25,26 The effect of common CAD-associated genetic variants on general population samples has also yielded conflicting results. In a study among B3000 cases and 3000 controls, a gene score comprising nine SNPs was associated with CAD risk.…”