Association of Genetic Variants Influencing Lipid Levels with Coronary Artery Disease in Japanese Individuals

Background/Objective: In Japanese populations, we performed a replication study of genetic loci previously identified in European-descent populations as being associated with lipid levels and risk of coronary artery disease (CAD). Methods: We genotyped 48 single nucleotide polymorphisms (SNPs) from 22 candidate loci that had previously been identified by genome-wide association (GWA) meta-analyses for low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), and/or triglycerides in Europeans. We selected 22 loci with 2 parallel tracks from 95 reported loci: 16 significant loci (p<1x10(-30) in Europeans) and 6 other loci including those with suggestive evidence of lipid associations in 1292 GWA-scanned Japanese samples. Genotyping was done in 4990 general population samples, and 1347 CAD cases and 1337 controls. For 9 SNPs, we further examined CAD associations in an additional panel of 3052 CAD cases and 6335 controls. Principal Findings: Significant lipid associations (one-tailed p<0.05) were replicated for 18 of 22 loci in Japanese samples, with significant inter-ethnic heterogeneity at 4 loci-APOB, APOE-C1, CETP, and APOA5-and allelic heterogeneity. The strongest association was detected at APOE rs7412 for LDL-C (p = 1.3x10(-41)), CETP rs3764261 for HDL-C (p = 5.2x10(-24)), and APOA5 rs662799 for triglycerides (p = 5.8x10(-54)). CAD association was replicated and/or verified for 4 loci: SORT1 rs611917 (p = 1.7x10(-8)), APOA5 rs662799 (p = 0.0014), LDLR rs1433099 (p = 2.1x10(-7)), and APOE rs7412 (p = 6.1x10(-13)). Conclusions: Our results confirm that most of the tested lipid loci are associated with lipid traits in the Japanese, further indicating that in genetic susceptibility to lipid levels and CAD, the related metabolic pathways are largely common across the populations, while causal variants at individual loci can be population-specific.