Genome-Wide Association Study Pinpoints a New Functional Apolipoprotein B Variant Influencing Oxidized Low-Density Lipoprotein Levels But Not Cardiovascular Events

BACKGROUND: Oxidized low-density lipoprotein may be a key factor in the development of atherosclerosis. We performed a genome-wide association study on oxidized low-density lipoprotein and tested the impact of associated single-nucleotide polymorphisms (SNPs) on the risk factors of atherosclerosis and cardiovascular events. METHODS AND RESULTS: A discovery genome-wide association study was performed on a population of young healthy white individuals (N=2080), and the SNPs associated with a P<5×10(-8) were replicated in 2 independent samples (A: N=2912; B: N=1326). Associations with cardiovascular endpoints were also assessed with 2 additional clinical cohorts (C: N=1118; and D: N=808). We found 328 SNPs associated with oxidized low-density lipoprotein. The genetic variant rs676210 (Pro2739Leu) in apolipoprotein B was the proxy SNP behind all associations (P=4.3×10(-136), effect size=13.2 U/L per allele). This association was replicated in the 2 independent samples (A and B, P=2.5×10(-47) and 1.1×10(-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 (hazard ratio=1.00 [0.94-1.06] per allele), 3-vessel coronary artery disease (hazard ratio=1.03 [0.94-1.13]), or myocardial infarction (hazard ratio=1.04 [0.96-1.12]). CONCLUSIONS: This novel genetic marker is an important factor regulating oxidized low-density lipoprotein levels but not a major genetic factor for the studied cardiovascular endpoints.