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. 2012;7(9):e46385.
doi: 10.1371/journal.pone.0046385. Epub 2012 Sep 26.

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

Free PMC article

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

Fumihiko Takeuchi et al. PLoS One. .
Free PMC article


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<1 × 10(-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=1.3 × 10(-41)), CETP rs3764261 for HDL-C (p=5.2 × 10(-24)), and APOA5 rs662799 for triglycerides (p=5.8 × 10(-54)). CAD association was replicated and/or verified for 4 loci: SORT1 rs611917 (p=1.7 × 10(-8)), APOA5 rs662799 (p=0.0014), LDLR rs1433099 (p=2.1 × 10(-7)), and APOE rs7412 (p=6.1 × 10(-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.

Conflict of interest statement

Competing Interests: The authors have declared that no competing interests exist.


Figure 1
Figure 1. Correlation of effect sizes for CAD risk and 3 lipid traits–LDL-C (a), HDL-C (b), and TG (c)–at SNPs tested for replication in the current study.
Genetic impacts on lipid level (β in x-axis) and CAD risk (OR in y-axis) are compared for the SNPs that were previously reported to associate with the corresponding (lead) lipid trait in Europeans: 18 SNPs for LDL-C (a), 20 SNPs for HDL-C (b), and 12 SNPs for TG (c), where 3 SNPs at LPL are included in both (b) and (c). The names of SNPs that were genotyped in the tier-2 CAD case-control study panel are denoted in the plots. For the purpose of readability, error bars are not shown at the individual SNP loci in the figure. See details about the individual SNP loci in Table S2.
Figure 2
Figure 2. Cross-population comparison of per-allele effect of SNPs associated with LDL-C (a), HDL-C (b), and TG (c) between the Japanese and European-descent populations.
Effect alleles are defined as those that increase LDL-C or TG or that decrease HDL-C. The effects of each variant on lipid traits are shown by squares, colored in red (Japanese) and blue (Europeans). The gray dotted lines between the red and blue squares represent an identical locus. See details about the individual SNP loci in Table S3.
Figure 3
Figure 3. Meta-analysis of CAD association with selected SNPs or variants, including the current and previously reported studies.
Effect sizes of SORT1 and APOE variants were heterogeneous between the current study and those previously reported , : p =  6.8×10−4 for SORT1, p = 1.7×10−3 for APOE (E2 carriers vs. E3/E3) and p = 0.041 for APOE (E4 carriers vs. E3/E3) by Woolf's test.

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Grant support

This work was supported by the Grant of National Center for Global Health and Medicine and the Ministry of Health Labour and Welfare. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.