Journal
ARTERIOSCLEROSIS THROMBOSIS AND VASCULAR BIOLOGY
Volume 30, Issue 11, Pages 2264-U566Publisher
LIPPINCOTT WILLIAMS & WILKINS
DOI: 10.1161/ATVBAHA.109.201020
Keywords
coronary artery disease; epidemiology; lipids; genetics
Categories
Funding
- United Kingdom Medical Research Council
- Wellcome Trust (WT) [068545/Z/02, 077016/Z/05/Z, 079895]
- British Heart Foundation
- European Commission
- GlaxoSmithKline
- Medical Research Council [G0000934, G0801566, G0500539]
- European Union [LSHM-CT-2003-503041]
- British Heart Foundation [PG/08/094]
- HSFO [NA6001]
- CIHR
- Swiss National Science Foundation [33CSCO-122661]
- Faculty of Biology and Medicine of Lausanne
- National Institute of Diabetes and Digestive and Kidney Diseases
- National Institute of Allergy and Infectious Diseases
- National Human Genome Research Institute
- National Institute of Child Health and Human Development
- Juvenile Diabetes Research Foundation International (JDRF) [U01 DK062418]
- National Institute of Diabetes and Digestive and Kidney Diseases [T1DGC]
- JDRF
- JDRF International
- National Institute for Health Research Cambridge Biomedical Research Center
- Cardiovascular Institute of the University of Pennsylvania
- Netherlands Organisation for Scientific Research (NWO) [175.010.2005.011, 911.03.012]
- Research Institute for Diseases in the Elderly [RIDE2, 01493015]
- Netherlands Genomic Initiative (NGI/NWO) [050-060-810]
- Academy of Finland, Center of Excellence in Complex Disease Genetics [104781, 120315, 1114194]
- University Hospital Oulu, Biocenter
- University of Oulu, Oulu, Finland
- National Heart, Lung, and Blood Institute [5R01HL087679-02, 1RL1MH083268-01]
- ENGAGE project [HEALTH-F4-2007-201413]
- Wellcome Trust, United Kingdom [GR069224]
- Academy of Finland and Biocentrum Helsinki
- MRC [MC_U106188470, G0601966, G0700931, MC_U105630924, G0000934, G0701863, G0801566, MC_qA137934] Funding Source: UKRI
- British Heart Foundation [PG/08/094/26019] Funding Source: researchfish
- Medical Research Council [MC_U105630924, MC_qA137934, MC_U106179471, MC_U106188470, G0000934, G0801056B, G0401527, G0801566, G0701863, G0601966, G0700931] Funding Source: researchfish
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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, 1.6X10(-8) to 3.1X10(-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, 1.1X10(-3) to 1.2X10(-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. (Arterioscler Thromb Vasc Biol. 2010;30:2264-2276.)
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