Large-Scale Gene-Centric Analysis Identifies Novel Variants for Coronary Artery Disease
The IBC 50K CAD Consortium¶*Abstract
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.
Author Summary
Coronary artery disease (CAD) has a strong genetic basis that remains poorly characterised. Using a custom-designed array, we tested the association with CAD of almost 50,000 common and low frequency variants in ~2,000 genes of known or suspected cardiovascular relevance. We genotyped the 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) and attempted to replicate putative novel associations in an additional 17,121 CAD cases and 40,473 controls. We report the novel association of variants in or near four genes with CAD and in additional studies identify potential mechanisms by which some of these novel variants affect CAD risk. Interestingly, we found that these variants, as well as the majority of previously reported CAD variants, have similar associations in Europeans and South Asians. Contrary to prior expectations, many previously suggested candidate genes did not show evidence of any effect on CAD risk, and neither did we identify any novel low frequency alleles with strong effects amongst the genes tested. Discovery of novel genes associated with heart disease may help to further understand the aetiology of cardiovascular disease and identify new targets for therapeutic interventions.
Citation: The IBC 50K CAD Consortium (2011) Large-Scale Gene-Centric Analysis Identifies Novel Variants for Coronary Artery Disease. PLoS Genet 7(9): e1002260. doi:10.1371/journal.pgen.1002260
Editor: Peter M. Visscher, Queensland Institute of Medical Research, Australia
Received: March 3, 2011; Accepted: June 29, 2011; Published: September 22, 2011
Copyright: © 2011 Butterworth et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Funding: BHF-FHS: Recruitment of CAD cases for the BHF-FHS study was supported by the British Heart Foundation (BHF) and the UK Medical Research Council. Controls were provided by the Wellcome Trust Case Control Consortium. Genotyping of the IBC 50K array for the BHF-FHS study was funded by the BHF. NJS and SGB hold personal chairs supported by the BHF. The work described in this paper forms part of the portfolio of translational research supported by the Leicester NIHR Biomedical Research Unit in Cardiovascular Disease. BLOODOMICS: The Bloodomics partners from AMC (The Netherlands), LURIC (Germany), the University of Cambridge (UK), and the Wellcome Trust Sanger Institute (UK) received funding through the 6th Framework funded Integrated Project Bloodomics (grant LSHM-CT-2004-503485). The University of Cambridge group in the Department of Haematology also received programme grant funding from the British Heart Foundation (RG/09/12/28096) and the National Institute for Health Research (RP-PG-0310-1002). BLOODOMICS-Dutch: This study was supported by research grants from The Netherlands Heart Foundation (grants 2001D019, 2003T302 and 2007B202), the Leducq Foundation (grant 05-CVD), the Center for Translational Molecular Medicine (CTMM COHFAR), and the Interuniversity Cardiology Institute of The Netherlands (project 27). BLOODOMICS-German: LURIC has received funding through the 6th Framework Program (integrated project Bloodomics, grant LSHM-CT-2004-503485) and 7th Framework Program (integrated project Atheroremo, Grant Agreement number 201668) of the European Union. CARe Consortium: CARe was performed with the support of the National Heart, Lung, and Blood Institute and acknowledges the contributions of the research institutions, study investigators, and field staff in creating this resource for biomedical research. Full details of the studies in the CARe Consortium can be found in Text S1. LOLIPOP: Genotyping of the IBC 50K array for the LOLIPOP Study was funded by the British Heart Foundation. Paul Elliott is a National Institute for Health Research Senior Investigator. MONICA-KORA: The MONICA/KORA Augsburg studies were financed by the Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany, and supported by grants from the German Federal Ministry of Education and Research (BMBF). Part of this work was financed by the German National Genome Research Network (NGFNPlus, project number 01GS0834) and through additional funds from the University of Ulm. Furthermore, the research was supported within the Munich Center of Health Sciences (MC Health) as part of LMU innovative. PennCATH: Muredach P Reilly and Daniel J Rader have been supported by the Penn Cardiovascular Institute and GlaxoSmithKline. PROCARDIS: The PROCARDIS study has been supported by the British Heart Foundation, the European Community Sixth Framework Program (LSHM-CT-2007-037273), AstraZeneca, the Wellcome Trust, the United Kingdom Medical Research Council, the Swedish Heart–Lung Foundation, the Swedish Medical Research Council, the Knut and Alice Wallenberg Foundation, the Torsten and Ragnar Söderberg Foundation, the Strategic Cardiovascular Program of Karolinska Institutet and Stockholm County Council, the Foundation for Strategic Research and the Stockholm County Council (560283). PROMIS: Epidemiological field work in PROMIS was supported by unrestricted grants to investigators at the University of Cambridge and in Pakistan. Genotyping for this study was funded by the Wellcome Trust and the EU Framework 6–funded Bloodomics Integrated Project (LSHM-CT-2004-503485). The British Heart Foundation has supported some biochemical assays. The Yousef Jameel Foundation supported D Saleheen. The cardiovascular disease epidemiology group of J Danesh is underpinned by programme grants from the British Heart Foundation and the UK Medical Research Council. EPIC-NL: The EPIC-NL study was funded by “Europe against Cancer” Programme of the European Commission (SANCO); the Dutch Ministry of Health; the Dutch Cancer Society; ZonMW the Netherlands Organisation for Health Research and Development; World Cancer Research Fund (WCRF). We thank the institute PHARMO for follow-up data on diabetes. Genotyping was funded by IOP Genomics grant IGE 05012 from NL Agency. UCP: The project was funded by Veni grant Organization for Scientific Research (NWO), Grant no. 2001.064 Netherlands Heart Foundation (NHS), and TI Pharma Grant T6-101 Mondriaan. Cardiogenics: Cardiogenics was funded through the 6th Framework Programme (integrated project Cardiogenics, grant LSHM-CT-2006-037593) of the European Union. None of the sponsors had any role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; or preparation, review, or approval of the manuscript.
Competing interests: Muredach P Reilly and Daniel J Rader have a research grant from GlaxoSmithKline. The division of Pharmacoepidemiology and Clinical Pharmacology employing Bas Peters, Olaf Klungel, Anthonius de Boer, and Anke-Hilse Maitland-van der Zee has received unrestricted funding for pharmacoepidemiological research from GlaxoSmithKline, Novo Nordisk, the private-public funded Top Institute Pharma (http://www.tipharma.nl/, includes co-funding from universities, government, and industry), the Dutch Medicines Evaluation Board, and the Dutch Ministry of Health. Arthur AM Wilde is a consultant for Transgenomics (Familion test) and Sorin. No other disclosures were reported.
* E-mail: njs@leicester.ac.uk (Nilesh J Samani); jd292@medschl.cam.ac.uk (John Danesh); hugh.watkins@cardiov.ox.ac.uk (Hugh Watkins)
¶ A full list of the IBC 50K CAD Consortium authors, affiliations, and study collaborators is provided in the Acknowledgments.
Editor: Peter M. Visscher, Queensland Institute of Medical Research, Australia
Received: March 3, 2011; Accepted: June 29, 2011; Published: September 22, 2011
Copyright: © 2011 Butterworth et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Funding: BHF-FHS: Recruitment of CAD cases for the BHF-FHS study was supported by the British Heart Foundation (BHF) and the UK Medical Research Council. Controls were provided by the Wellcome Trust Case Control Consortium. Genotyping of the IBC 50K array for the BHF-FHS study was funded by the BHF. NJS and SGB hold personal chairs supported by the BHF. The work described in this paper forms part of the portfolio of translational research supported by the Leicester NIHR Biomedical Research Unit in Cardiovascular Disease. BLOODOMICS: The Bloodomics partners from AMC (The Netherlands), LURIC (Germany), the University of Cambridge (UK), and the Wellcome Trust Sanger Institute (UK) received funding through the 6th Framework funded Integrated Project Bloodomics (grant LSHM-CT-2004-503485). The University of Cambridge group in the Department of Haematology also received programme grant funding from the British Heart Foundation (RG/09/12/28096) and the National Institute for Health Research (RP-PG-0310-1002). BLOODOMICS-Dutch: This study was supported by research grants from The Netherlands Heart Foundation (grants 2001D019, 2003T302 and 2007B202), the Leducq Foundation (grant 05-CVD), the Center for Translational Molecular Medicine (CTMM COHFAR), and the Interuniversity Cardiology Institute of The Netherlands (project 27). BLOODOMICS-German: LURIC has received funding through the 6th Framework Program (integrated project Bloodomics, grant LSHM-CT-2004-503485) and 7th Framework Program (integrated project Atheroremo, Grant Agreement number 201668) of the European Union. CARe Consortium: CARe was performed with the support of the National Heart, Lung, and Blood Institute and acknowledges the contributions of the research institutions, study investigators, and field staff in creating this resource for biomedical research. Full details of the studies in the CARe Consortium can be found in Text S1. LOLIPOP: Genotyping of the IBC 50K array for the LOLIPOP Study was funded by the British Heart Foundation. Paul Elliott is a National Institute for Health Research Senior Investigator. MONICA-KORA: The MONICA/KORA Augsburg studies were financed by the Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany, and supported by grants from the German Federal Ministry of Education and Research (BMBF). Part of this work was financed by the German National Genome Research Network (NGFNPlus, project number 01GS0834) and through additional funds from the University of Ulm. Furthermore, the research was supported within the Munich Center of Health Sciences (MC Health) as part of LMU innovative. PennCATH: Muredach P Reilly and Daniel J Rader have been supported by the Penn Cardiovascular Institute and GlaxoSmithKline. PROCARDIS: The PROCARDIS study has been supported by the British Heart Foundation, the European Community Sixth Framework Program (LSHM-CT-2007-037273), AstraZeneca, the Wellcome Trust, the United Kingdom Medical Research Council, the Swedish Heart–Lung Foundation, the Swedish Medical Research Council, the Knut and Alice Wallenberg Foundation, the Torsten and Ragnar Söderberg Foundation, the Strategic Cardiovascular Program of Karolinska Institutet and Stockholm County Council, the Foundation for Strategic Research and the Stockholm County Council (560283). PROMIS: Epidemiological field work in PROMIS was supported by unrestricted grants to investigators at the University of Cambridge and in Pakistan. Genotyping for this study was funded by the Wellcome Trust and the EU Framework 6–funded Bloodomics Integrated Project (LSHM-CT-2004-503485). The British Heart Foundation has supported some biochemical assays. The Yousef Jameel Foundation supported D Saleheen. The cardiovascular disease epidemiology group of J Danesh is underpinned by programme grants from the British Heart Foundation and the UK Medical Research Council. EPIC-NL: The EPIC-NL study was funded by “Europe against Cancer” Programme of the European Commission (SANCO); the Dutch Ministry of Health; the Dutch Cancer Society; ZonMW the Netherlands Organisation for Health Research and Development; World Cancer Research Fund (WCRF). We thank the institute PHARMO for follow-up data on diabetes. Genotyping was funded by IOP Genomics grant IGE 05012 from NL Agency. UCP: The project was funded by Veni grant Organization for Scientific Research (NWO), Grant no. 2001.064 Netherlands Heart Foundation (NHS), and TI Pharma Grant T6-101 Mondriaan. Cardiogenics: Cardiogenics was funded through the 6th Framework Programme (integrated project Cardiogenics, grant LSHM-CT-2006-037593) of the European Union. None of the sponsors had any role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; or preparation, review, or approval of the manuscript.
Competing interests: Muredach P Reilly and Daniel J Rader have a research grant from GlaxoSmithKline. The division of Pharmacoepidemiology and Clinical Pharmacology employing Bas Peters, Olaf Klungel, Anthonius de Boer, and Anke-Hilse Maitland-van der Zee has received unrestricted funding for pharmacoepidemiological research from GlaxoSmithKline, Novo Nordisk, the private-public funded Top Institute Pharma (http://www.tipharma.nl/, includes co-funding from universities, government, and industry), the Dutch Medicines Evaluation Board, and the Dutch Ministry of Health. Arthur AM Wilde is a consultant for Transgenomics (Familion test) and Sorin. No other disclosures were reported.
* E-mail: njs@leicester.ac.uk (Nilesh J Samani); jd292@medschl.cam.ac.uk (John Danesh); hugh.watkins@cardiov.ox.ac.uk (Hugh Watkins)
¶ A full list of the IBC 50K CAD Consortium authors, affiliations, and study collaborators is provided in the Acknowledgments.
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PLoS Genetics: Large-Scale Gene-Centric Analysis Identifies Novel Variants for Coronary Artery Disease
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