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Large-Scale Gene-Centric Analysis Identifies Novel Variants for Coronary Artery Disease
Open accessAbstract
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 ∼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<5×10(-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 ∼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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“Since 2007, genomewide association analyses have identified more than 50 independent loci associated with the risk of coronary artery disease.7–15”
From Genetic Risk, Adherence to a Healthy Lifestyle, and Coronary Disease (2016) · cites this paper as [13]
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Metadata
- Authors
- The IBC 50K CAD Consortium
- Affiliations
- QIMR Berghofer Medical Research Institute (AU)
- Corresponding author
- The IBC 50K CAD Consortium
- Venue
- PLoS Genetics
- Publisher
- Public Library of Science (PLoS)
- Published
- 2011-09-22
- Volume
- 7
- Issue
- 9
- Pages
- e1002260
- ISSN
- 1553-7390 (ISSN-L)
- 1553-7404
- PMC
- PMC3178591
- OpenAlex
- W1590005134
- Cited by
- 237
- References
- 36
- Citations by year
- 2026: 8 · 2025: 7 · 2024: 2 · 2023: 7 · 2022: 12 · 2021: 11 · 2020: 7 · 2019: 9 · 2018: 17 · 2017: 18 · 2016: 22 · 2015: 25 · 2014: 36 · 2013: 28 · 2012: 26
- FWCI
- 18.36
- Type
- journal article
- Language
- en
- Update notices
- correction (2012-08-14)
- Open access
- gold
- doi.org
- Locations
- PLoS Genetics (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Research Publications (Maastricht University) (publishedVersion, cc-by)
- Pure Amsterdam UMC (publishedVersion)
- EUR Research Repository (Erasmus University Rotterdam) (publishedVersion, other-oa)
- ENLIGHTEN (Jurnal Bimbingan dan Konseling Islam) (acceptedVersion)
- Archivio Istituzionale della Ricerca (Universita Degli Studi Di Milano) (submittedVersion, other-oa)
- Surrey Research Insight Open Access (The University of Surrey) (submittedVersion)
- Data Archiving and Networked Services (DANS) (submittedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Utrecht University Repository (Utrecht University) (submittedVersion, other-oa)
- UCL Discovery (University College London) (submittedVersion)
- Figshare (submittedVersion, cc-by)
- Leicester Research Archive (University of Leicester) (submittedVersion, other-oa)
- Site cant be reached (submittedVersion, cc-by)
- Research Explorer (The University of Manchester) (submittedVersion)
- SERVAL (Université de Lausanne) (submittedVersion)
- Spiral (Imperial College London) (submittedVersion, other-oa)
- Hirsla (Landspítali University Hospital) (submittedVersion)
- Radboud Repository (Radboud University) (submittedVersion, other-oa)
- Research Publications (Maastricht University) (submittedVersion, other-oa)
- Funders
- AstraZeneca
- GlaxoSmithKline
- University of Pennsylvania
- Wellcome Trust (090532)
- National Institute for Health and Care Research (RP-PG-0310-1002, CL-2010-11-001, PG-0310-1002)
- British Heart Foundation (LSHM-CT-2007-037273, RG/09/12/28096, RP-PG-0310-1002, PG-0310-1002, RG/08/014/24067)
- University of Cambridge
- European Commission (201668, LSHM-CT-2007–037273, LSHM-CT 2006–037593, 28,29, LSHM-CT-2004-503485, 57,58)
- Fondation Leducq (05-CVD)
- ZonMw
- Bundesministerium für Bildung und Forschung (01GS0834)
- College ter Beoordeling van Geneesmiddelen
- Nederlandse Organisatie voor Wetenschappelijk Onderzoek (2001.064)
- Hjärt-Lungfonden
- Karolinska Institutet
- Knut och Alice Wallenbergs Stiftelse
- Novo Nordisk
- Stockholms Läns Landsting (560283)
- Top Institute Pharma
- KWF Kankerbestrijding
- Center for Translational Molecular Medicine
- Universität Ulm
- Medical Research Council (09/12)
- World Cancer Research Fund
- Agentschap NL
- Münchner Zentrum für Gesundheitswissenschaften
- National Heart, Lung, and Blood Institute
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic Associations and Epidemiology
- Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Cardiovascular Health and Risk Factors
- Life Sciences › Immunology and Microbiology › Immunology › Atherosclerosis and Cardiovascular Diseases
- Keywords
- coronary artery disease, genetic susceptibility, candidate gene association, novel genetic variants, 9p21.3, LPA, LIPA, TRIB1, ABCG5/ABCG8, CYP17A1, low-frequency variants, functional variants, South Asian populations, European populations, replication, gene expression, serum lipids
- MeSH terms
- Adult, Aged, Alleles, Coronary Artery Disease, Female, Humans, Male, Middle Aged, Risk, Genetic Variation, Case-Control Studies, Genetic Predisposition to Disease, Polymorphism, Single Nucleotide, White People, Asian People, Genome-Wide Association Study
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