Genetic variants influencing circulating lipid levels and risk of coronary artery disease

Dawn M. Waterworth, Sally L. Ricketts, Kijoung Song, Li Chen, Jing Hua Zhao, Samuli Ripatti, Yurii S. Aulchenko, Weihua Zhang, Xin Yuan, Noha Lim, Jian'An Luan, Sofie Ashford, Eleanor Wheeler, Elizabeth H. Young, David Hadley, John R. Thompson, Peter S. Braund, Toby Johnson, Maksim Struchalin, Ida SurakkaRobert Luben, Kay Tee Khaw, Sheila A. Rodwell, Ruth J F Loos, S. Matthijs Boekholdt, Michael Inouye, Panagiotis Deloukas, Paul Elliott, David Schlessinger, Serena Sanna, Angelo Scuteri, Anne Jackson, Karen L. Mohlke, Jaako Tuomilehto, Robert Roberts, Alexandre Stewart, Y. Antero Kesäniemi, Robert W. Mahley, Scott M Grundy, Wendy McArdle, Lon Cardon, Gérard Waeber, Peter Vollenweider, John C. Chambers, Michael Boehnke, Gonçalo R. Abecasis, Veikko Salomaa, Marjo Riitta Järvelin, Aimo Ruokonen, Inês Barroso, Stephen E. Epstein, Hakon H. Hakonarson, Daniel J. Rader, Muredach P. Reilly, Jacqueline C M Witteman, Alistair S. Hall, Nilesh J. Samani, David P. Strachan, Philip Barter, Cornelia M. Van Duijn, Jaspal S. Kooner, Leena Peltonen, Nicholas J. Wareham, Ruth McPherson, Vincent Mooser, Manjinder S. Sandhu

Research output: Contribution to journalArticlepeer-review

289 Scopus citations

Abstract

OBJECTIVE-: 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. METHODS AND RESULTS-: 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). CONCLUSION-: 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.

Original languageEnglish (US)
Pages (from-to)2264-2276
Number of pages13
JournalArteriosclerosis, thrombosis, and vascular biology
Volume30
Issue number11
DOIs
StatePublished - Nov 2010

Keywords

  • coronary artery disease
  • epidemiology
  • genetics
  • lipids

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine

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