Gene-centric Association Signals for Lipids and Apolipoproteins Identified via the HumanCVD BeadChip


Talmud, PJ; Drenos, F; Shah, S; Shah, T; Palmen, J; Verzilli, C; Gaunt, TR; Pallas, J; Lovering, R; LI, K; Casas, JP; Sofat, R; Kumari, M; Rodriguez, S; Johnson, T; Newhouse, SJ; Dominiczak, A; Samani, NJ; Caulfield, M; Sever, P; Stanton, A; Shields, DC; Padmanabhan, S; Melander, O; Hastie, C; Delles, C; Ebrahim, S; Marmot, MG; Smith, GD; Lawlor, DA; Munroe, PB; Day, IN; Kivimaki, M; Whittaker, J; Humphries, SE; Hingorani, AD; Consortium, AINIB; (2009) Gene-centric Association Signals for Lipids and Apolipoproteins Identified via the HumanCVD BeadChip. American journal of human genetics, 85 (5). pp. 628-642. ISSN 0002-9297 DOI: https://doi.org/10.1016/j.ajhg.2009.10.014

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Abstract

Blood lipids are important cardiovascular disease (CVD) risk factors with both genetic and environmental determinants. The Whitehall II study (n = 5592) was genotyped with the gene-centric HumanCVD BeadChip (Illumina). We identified 195 SNPs in 16 genes/regions associated with 3 major lipid fractions and 2 apolipoprotein components at p < 10(-5), with the associations being broadly concordant with prior genome-wide analysis. SNPs associated with LDL cholesterol and apolipoprotein B were located in LDLR, PCSK9, APOB, CELSR2, HWGCR, CETP, the TOMM40-APOE-C1-C2-C4 cluster, and the APOA5-A4-C3-A1 cluster; SNPs associated with HDL cholesterol and apolipoprotein AI were in CETP, LPL, LIPC, APOA5-A4-C3-A1, and ABCA1; and SNPs associated with triglycerides in GCKR, BAZIB, MLXIPL, LPL, and APOA5-A4-C3-A1. For 48 SNPs in previously unreported loci that were significant at p < 10(-4) in Whitehall II, in silico analysis including the British Women's Heart and Health Study, BRIGHT, ASCOT, and NORDIL studies (total n > 12,500) revealed previously unreported associations of SH2B3 (p < 2.2 x 10(-6)), BMPR2 (p < 2.3 x 10(-7)), BCL3/PVRL2 (flanking APOE; p < 4.4 x 10(-8)), and SMARCA4 (flanking LDLR; p < 2.5 x 10(-7)) with LDL cholesterol. Common alleles in these genes explained 6.1%-14.7% of the variance in the five lipid-related traits, and individuals at opposite tails of the additive allele score exhibited substantial differences in trait levels (e.g., > 1 mmol/L in LDL cholesterol [similar to 1 SD of the trait distribution]). These data suggest that multiple common alleles of small effect can make important contributions to individual differences in blood lipids potentially relevant to the assessment of CVD risk. These genes provide further insights into lipid metabolism and the likely effects of modifying the encoded targets therapeutically.

Item Type: Article
Keywords: coronary-heart-disease, density-lipoprotein cholesterol, genome-wide, association, whitehall-ii, myocardial-infarction, statistical-model, risk, loci, population, cohort
Faculty and Department: Faculty of Epidemiology and Population Health > Dept of Non-Communicable Disease Epidemiology
Research Centre: Centre for Global Non-Communicable Diseases (NCDs)
PubMed ID: 19913121
Web of Science ID: 271916500010
URI: http://researchonline.lshtm.ac.uk/id/eprint/4418

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