Gene-centric association signals for lipids and apolipoproteins identified via the humanCVD BeadChip

Talmud, P. et al. (2009) Gene-centric association signals for lipids and apolipoproteins identified via the humanCVD BeadChip. American Journal of Human Genetics, 85(5), pp. 628-642. (doi: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, HMGCR, 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, BAZ1B, 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 × 10−6), BMPR2 (p < 2.3 × 10−7), BCL3/PVRL2 (flanking APOE; p < 4.4 × 10−8), and SMARCA4 (flanking LDLR; p < 2.5 × 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 [not, vert, similar1 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:Articles
Status:Published
Refereed:Yes
Glasgow Author(s) Enlighten ID:Hastie, Dr Claire and Padmanabhan, Professor Sandosh and Dominiczak, Professor Anna and Delles, Professor Christian
Authors: Talmud, P., Drenos, F., Shah, S., Shah, T., Palmen, J., Verzilli, C., Gaunt, T., Pallas, J., Lovering, R., Li, K., Casas, J., Sofat, R., Kumari, M., Rodriguez, S., Johnson, T., Newhouse, S.J., Dominiczak, A., Samani, N.J., Caulfield, M., Sever, P., Stanton, A., Shields, D.C., Padmanabhan, S., Melander, O., Hastie, C., Delles, C., Ebrahim, S., Marmot, M.G., Smith, G.D., Lawlor, D.A., Munroe, P.B., Day, I.N., Kivimaki, M., Whittaker, J., Humphries, S.E., and Hingorani, A.D.
Subjects:R Medicine > R Medicine (General)
Q Science > QH Natural history > QH426 Genetics
College/School:College of Medical Veterinary and Life Sciences > Institute of Cardiovascular and Medical Sciences
College of Medical Veterinary and Life Sciences > Institute of Cardiovascular and Medical Sciences
College of Medical Veterinary and Life Sciences > Institute of Cardiovascular and Medical Sciences
College of Medical Veterinary and Life Sciences > Institute of Cardiovascular and Medical Sciences
College of Medical Veterinary and Life Sciences
Journal Name:American Journal of Human Genetics
ISSN:0002-9297
ISSN (Online):1537-6605
Published Online:12 November 2009

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