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Olle Melander

Principal investigator

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

Author

  • Philippa J. Talmud
  • Fotios Drenos
  • Sonia Shah
  • Tina Shah
  • Jutta Palmen
  • Claudio Verzilli
  • Tom R. Gaunt
  • Jacky Pallas
  • Ruth Lovering
  • Kawah Li
  • Juan Pablo Casas
  • Reecha Sofat
  • Meena Kumari
  • Santiago Rodriguez
  • Toby Johnson
  • Stephen J. Newhouse
  • Anna Dominiczak
  • Nilesh J. Samani
  • Mark Caulfield
  • Peter Sever
  • Alice Stanton
  • Denis C. Shields
  • Sandosh Padmanabhan
  • Olle Melander
  • Claire Hastie
  • Christian Delles
  • Shah Ebrahim
  • Michael G. Marmot
  • George Davey Smith
  • Debbie A. Lawlor
  • Patricia B. Munroe
  • Ian N. Day
  • Mika Kivimaki
  • John Whittaker
  • Steve E. Humphries
  • Aroon D. Hingorani

Summary, in English

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.

Department/s

  • Cardiovascular Research - Hypertension

Publishing year

2009

Language

English

Pages

628-642

Publication/Series

American Journal of Human Genetics

Volume

85

Issue

5

Document type

Journal article

Publisher

Cell Press

Topic

  • Medical Genetics

Status

Published

Research group

  • Cardiovascular Research - Hypertension

ISBN/ISSN/Other

  • ISSN: 0002-9297