Genome-Wide Association Study Pinpoints a New Functional ApoB Variant Influencing Oxidized LDL Levels but Not Cardiovascular Events: AtheroRemo Consortium

Background —Oxidized low-density lipoprotein (oxLDL) may be a key factor in the development of atherosclerosis. We performed a genome-wide association study (GWAS) on oxLDL and tested the impact of the associated single-nucleotide polymorphisms (SNPs) on the risk factors of atherosclerosis, and cardiovascular events. Methods and Results —A discovery GWAS was performed on a population of young healthy Caucasian individuals (N=2,080), and the SNPs associated with a p value -8 were replicated in two independent samples (A: N=2,912; and B: N=1,326). Associations with cardiovascular endpoints were also assessed with two additional clinical cohorts (C: N=1,118; and D: N=808). We found 328 SNPs associated with oxLDL. The genetic variant rs676210 (Pro2739Leu) in apolipoprotein B (apoB) was the proxy SNP behind all associations (p=4.3 x 10 -136 , effect size = 13.2 U/l per allele). This association was replicated in the two independent samples (A and B, p values = 2.5 x 10 -47 and 1.1 x 10 -11 , effect sizes = 10.3 U/l and 7.8 U/l, respectively). In the meta-analyses of cohorts A, C, and D (excluding cohort B without angiographic data), the top SNP did not associate significantly with the age of onset of angiographically verified coronary artery disease (CAD, hazard ratio [HR]=1.00 [0.94-1.06] per allele), three vessel CAD (HR=1.03 [0.94-1.13]) or myocardial infarction (HR=1.04 [0.96-1.12]). Conclusions —This novel genetic marker is an important factor regulating oxLDL levels but not a major genetic factor for the studied cardiovascular end-points.