Genetic Variants Influencing Circulating Lipid Levels and Risk of Coronary Artery Disease

Genetics Division, GlaxoSmithKline R&D, King of Prussia, PA, USA.
Arteriosclerosis Thrombosis and Vascular Biology (Impact Factor: 6). 11/2010; 30(11):2264-76. DOI: 10.1161/ATVBAHA.109.201020
Source: PubMed


Genetic studies might provide new insights into the biological mechanisms underlying lipid metabolism and risk of CAD. We therefore conducted a genome-wide association study to identify novel genetic determinants of low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), and triglycerides.
We combined genome-wide association data from 8 studies, comprising up to 17 723 participants with information on circulating lipid concentrations. We did independent replication studies in up to 37 774 participants from 8 populations and also in a population of Indian Asian descent. We also assessed the association between single-nucleotide polymorphisms (SNPs) at lipid loci and risk of CAD in up to 9 633 cases and 38 684 controls. We identified 4 novel genetic loci that showed reproducible associations with lipids (probability values, 1.6×10(-8) to 3.1×10(-10)). These include a potentially functional SNP in the SLC39A8 gene for HDL-C, an SNP near the MYLIP/GMPR and PPP1R3B genes for LDL-C, and at the AFF1 gene for triglycerides. SNPs showing strong statistical association with 1 or more lipid traits at the CELSR2, APOB, APOE-C1-C4-C2 cluster, LPL, ZNF259-APOA5-A4-C3-A1 cluster and TRIB1 loci were also associated with CAD risk (probability values, 1.1×10(-3) to 1.2×10(-9)).
We have identified 4 novel loci associated with circulating lipids. We also show that in addition to those that are largely associated with LDL-C, genetic loci mainly associated with circulating triglycerides and HDL-C are also associated with risk of CAD. These findings potentially provide new insights into the biological mechanisms underlying lipid metabolism and CAD risk.

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Available from: Alexandre Stewart, Jan 05, 2016
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    • "level of statistical significance. The well-documented association of LDL-C levels with APOE on chromosome 19 (Waterworth et al., 2010), was also detected, with a p-value of 1.56 × 10 −12 . "
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    ABSTRACT: A variety of health-related data are commonly deposited into electronic health records (EHRs), including laboratory, diagnostic, and medication information. The digital nature of EHR data facilitates efficient extraction of these data for research studies, including genome-wide association studies (GWAS). Previous GWAS have identified numerous SNPs associated with variation in total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), and triglycerides (TG). These findings have led to the development of specialized genotyping platforms that can be used for fine-mapping and replication in other populations. We have combined the efficiency of EHR data and the economic advantages of the Illumina Metabochip, a custom designed SNP chip targeted to traits related to coronary artery disease, myocardial infarction, and type 2 diabetes, to conduct an array-wide analysis of lipid traits in a population with extreme obesity. Our analyses identified associations with 12 of 21 previously identified lipid-associated SNPs with effect sizes similar to prior results. Association analysis using several approaches to account for lipid-lowering medication use resulted in fewer and less strongly associated SNPs. The availability of phenotype data from the EHR and the economic efficiency of the specialized Metabochip can be exploited to conduct multi-faceted genetic association analyses.
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    • "The present study indicated that TG was associated with TRIB1 rs2954029 only in women, which was partially consistent with previous studies (Teslovich et al. 2010; Waterworth et al. 2010; Zhang et al. 2011) because TC, LDL-C, and HDL-C were not associated with TRIB1 rs2954029 in this study. This difference might be due to the relatively small sample size compared to previous studies. "
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    • "The association of the rs17248720 polymorphism with hypercholesterolemia confirms previous observations from GWAS suggesting that non-coding variants located at the LDLR locus are associated with blood lipid levels, including LDL-C [8,9,12,13]. While studies attempt to find new loci implicated in the hereditability of lipid levels, the strongest locus associated with LDL-C continues to be that containing the LDLR gene [10]. "
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