Journal
AMERICAN JOURNAL OF HUMAN GENETICS
Volume 85, Issue 5, Pages 628-642Publisher
CELL PRESS
DOI: 10.1016/j.ajhg.2009.10.014
Keywords
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Funding
- British Heart Foundation (BHF) [PG/07/133/24260, RG/08/008, SP/07/007/23671, FS/2005/125]
- National Heart Lung and Blood Institute (NHLBI) [HL36310]
- Medical Research Council
- British Heart Foundation
- Health and Safety Executive
- Department of Health
- National Institute on Aging, NIH, US [AG13196]
- Agency for Health Care Policy Research [HS06516]
- John D. and Catherine T. MacArthur Foundation Research Networks on Successful Midlife Development and Socio-economic Status and Health
- BHF
- UK Department of Health
- BHF [PG/07/131/24254, FS/05/065/19497, RG/07/005/23633, SP/08/005/25115]
- Medical Research Council of Great Britain [G9521010D]
- British Heart Foundation [PG/02/128]
- EU Ingenious HyperCare Consortium
- Integrated Genomics, Clinical Research, and Care in Hypertension [LSHM-C7-2006-037093]
- Pfizer, New York, NY, USA
- Servier Research Group, Paris, France
- Leo Laboratories, Copenhagen, Denmark
- MRC UK
- US NIH [NHLBI 33014]
- Du Pont Pharma, Wilmington, VA, USA
- British Heart Foundation [RG/07/008/23674, SP/07/007/23671, RG/08/008/25291] Funding Source: researchfish
- Economic and Social Research Council [ES/G007543/1] Funding Source: researchfish
- Medical Research Council [G0600705, G0100222, G9521010, G8802774, G19/35] Funding Source: researchfish
- ESRC [ES/G007543/1] Funding Source: UKRI
- MRC [G9521010, G0600705] Funding Source: UKRI
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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.
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