Journal
PLOS GENETICS
Volume 7, Issue 9, Pages -Publisher
PUBLIC LIBRARY SCIENCE
DOI: 10.1371/journal.pgen.1002260
Keywords
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Categories
Funding
- British Heart Foundation (BHF)
- UK Medical Research Council
- Leicester NIHR Biomedical Research Unit in Cardiovascular Disease
- AMC (The Netherlands)
- LURIC (Germany)
- University of Cambridge (UK)
- Wellcome Trust Sanger Institute (UK)
- Bloodomics [LSHM-CT-2004-503485]
- British Heart Foundation [RG/09/12/28096]
- National Institute for Health Research [RP-PG-0310-1002]
- Netherlands Heart Foundation [2001D019, 2003T302, 2007B202]
- Leducq Foundation [05-CVD]
- Center for Translational Molecular Medicine (CTMM COHFAR)
- Interuniversity Cardiology Institute of The Netherlands
- LURIC [LSHM-CT-2004-503485]
- European Union [201668, LSHM-CT-2006-037593]
- National Heart, Lung, and Blood Institute
- Helmholtz Zentrum Munchen
- German Research Center for Environmental Health
- Neuherberg, Germany
- German Federal Ministry of Education and Research (BMBF)
- German National Genome Research Network [01GS0834]
- University of Ulm
- Munich Center of Health Sciences (MC Health)
- Penn Cardiovascular Institute
- GlaxoSmithKline
- British Heart Foundation
- European Community [LSHM-CT-2007-037273]
- AstraZeneca
- Wellcome Trust
- United Kingdom Medical Research Council
- Swedish Heart-Lung Foundation
- Swedish Medical Research Council
- Knut and Alice Wallenberg Foundation
- Torsten and Ragnar Soderberg Foundation
- Karolinska Institutet and Stockholm County Council
- Foundation for Strategic Research
- Stockholm County Council [560283]
- University of Cambridge and in Pakistan
- EU Framework 6-funded Bloodomics Integrated Project [LSHM-CT-2004-503485]
- Yousef Jameel Foundation
- European Commission (SANCO)
- Dutch Ministry of Health
- Dutch Cancer Society
- ZonMW
- Netherlands Organisation for Health Research and Development
- World Cancer Research Fund (WCRF)
- NL Agency [IGE 05012]
- Organization for Scientific Research (NWO)
- Netherlands Heart Foundation (NHS) [2001.064]
- TI Pharma [T6-101]
- Novo Nordisk
- Top Institute Pharma
- Dutch Medicines Evaluation Board
- MRC [G0700931, G0701863, MC_U105260792, MC_U137686857, G0801056, G0601966] Funding Source: UKRI
- British Heart Foundation [RG/08/014/24067] Funding Source: researchfish
- Medical Research Council [G0700931, G0801056, MC_U106179471, G0801056B, G0601966, G0701863, G0401527, MC_U105260792, MC_U137686857, G1000143] Funding Source: researchfish
- National Institute for Health Research [CL-2010-11-001, RP-PG-0310-1002] Funding Source: researchfish
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Coronary artery disease (CAD) has a significant genetic contribution that is incompletely characterized. To complement genome-wide association (GWA) studies, we conducted a large and systematic candidate gene study of CAD susceptibility, including analysis of many uncommon and functional variants. We examined 49,094 genetic variants in similar to 2,100 genes of cardiovascular relevance, using a customised gene array in 15,596 CAD cases and 34,992 controls (11,202 cases and 30,733 controls of European descent; 4,394 cases and 4,259 controls of South Asian origin). We attempted to replicate putative novel associations in an additional 17,121 CAD cases and 40,473 controls. Potential mechanisms through which the novel variants could affect CAD risk were explored through association tests with vascular risk factors and gene expression. We confirmed associations of several previously known CAD susceptibility loci (eg, 9p21.3:p<10(-33); LPA:p<10(-19); 1p13.3:p<10(-17)) as well as three recently discovered loci (COL4A1/COL4A2, ZC3HC1, CYP17A1:p<5x10(-7)). However, we found essentially null results for most previously suggested CAD candidate genes. In our replication study of 24 promising common variants, we identified novel associations of variants in or near LIPA, IL5, TRIB1, and ABCG5/ABCG8, with per-allele odds ratios for CAD risk with each of the novel variants ranging from 1.06-1.09. Associations with variants at LIPA, TRIB1, and ABCG5/ABCG8 were supported by gene expression data or effects on lipid levels. Apart from the previously reported variants in LPA, none of the other similar to 4,500 low frequency and functional variants showed a strong effect. Associations in South Asians did not differ appreciably from those in Europeans, except for 9p21.3 (per-allele odds ratio: 1.14 versus 1.27 respectively; P for heterogeneity = 0.003). This large-scale gene-centric analysis has identified several novel genes for CAD that relate to diverse biochemical and cellular functions and clarified the literature with regard to many previously suggested genes.
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