Mendelian randomization of blood lipids for coronary heart disease

Michael V. Holmes, Folkert W. Asselbergs, Tom M. Palmer, Fotios Drenos, Matthew B. Lanktree, Christopher P. Nelson, Caroline E. Dale, Sandosh Padmanabhan, Chris Finan, Daniel I. Swerdlow, Vinicius Tragante, Erik P A Van Iperen, Suthesh Sivapalaratnam, Sonia Shah, Clara C. Elbers, Tina Shah, Jorgen Engmann, Claudia Giambartolomei, Jon White, Delilah ZabanehReecha Sofat, Stela McLachlan, Pieter A. Doevendans, Anthony J. Balmforth, Alistair S. Hall, Kari E. North, Berta Almoguera, Ron C. Hoogeveen, Mary Cushman, Myriam Fornage, Sanjay R. Patel, Susan Redline, David S. Siscovick, Michael Y. Tsai, Konrad J. Karczewski, Marten H. Hofker, W. Monique Verschuren, Michiel L. Bots, Yvonne T. Van Der Schouw, Olle Melander, Anna F. Dominiczak, Richard Morris, Yoav Ben-Shlomo, Jackie Price, Meena Kumari, Jens Baumert, Annette Peters, Barbara Thorand, Wolfgang Koenig, Tom R. Gaunt, Steve E. Humphries, Robert Clarke, Hugh Watkins, Martin Farrall, James G. Wilson, Stephen S. Rich, Paul I W De Bakker, Leslie A. Lange, George Davey Smith, Alex P. Reiner, Philippa J. Talmud, Mika Kivimäki, Debbie A. Lawlor, Frank Dudbridge, Nilesh J. Samani, Brendan J. Keating, Aroon D. Hingorani, Juan P. Casas

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421 Scopus citations


Aims To investigate the causal role of high-density lipoprotein cholesterol (HDL-C) and triglycerides in coronary heart disease (CHD) using multiple instrumental variables for Mendelian randomization. Methods and results We developed weighted allele scores based on single nucleotide polymorphisms (SNPs) with established associations with HDL-C, triglycerides, and low-density lipoprotein cholesterol (LDL-C). For each trait, we constructed two scores. The first was unrestricted, including all independent SNPs associated with the lipid trait identified from a prior meta-analysis (threshold P < 2 × 10-6); and the second a restricted score, filtered to remove any SNPs also associated with either of the other two lipid traits at P ≤ 0.01. Mendelian randomization meta-analyses were conducted in 17 studies including 62,199 participants and 12,099 CHD events. Both the unrestricted and restricted allele scores for LDL-C (42 and 19 SNPs, respectively) associated with CHD. For HDL-C, the unrestricted allele score (48 SNPs) was associated with CHD (OR: 0.53; 95% CI: 0.40, 0.70), per 1 mmol/L higher HDL-C, but neither the restricted allele score (19 SNPs; OR: 0.91; 95% CI: 0.42, 1.98) nor the unrestricted HDL-C allele score adjusted for triglycerides, LDL-C, or statin use (OR: 0.81; 95% CI: 0.44, 1.46) showed a robust association. For triglycerides, the unrestricted allele score (67 SNPs) and the restricted allele score (27 SNPs) were both associated with CHD (OR: 1.62; 95% CI: 1.24, 2.11 and 1.61; 95% CI: 1.00, 2.59, respectively) per 1-log unit increment. However, the unrestricted triglyceride score adjusted for HDL-C, LDL-C, and statin use gave an OR for CHD of 1.01 (95% CI: 0.59, 1.75). Conclusion The genetic findings support a causal effect of triglycerides on CHD risk, but a causal role for HDL-C, though possible, remains less certain.

Original languageEnglish (US)
Pages (from-to)539-550
Number of pages12
JournalEuropean heart journal
Issue number9
StatePublished - Mar 1 2015

Bibliographical note

Funding Information:
M.V.H.wasfundedbyaUKMedicalResearchCouncilPopulationHealthSci-entist Fellowship (G0802432). F.W.A. is supported by UCL Hospitals NIHR Biomedical Research Centre. D.I.S. is supported by a Medical Research Council Doctoral Training Award and a grant from the Rosetrees Foundation. ME.K. is supported by the National Institute of Aging and the National Heart, Lung and Blood Institute (HL36310). S.E.H. and P.J.T. are supported by the British Heart Foundation (BHF RG 08/008, PG/07/133/24260), UK Medical Research Council, the US National Institutes of Health (grant NHLBI 33014) and Du Pont Pharma, Wilmington, USA. N.J.S. holds a Chair funded by the British Heart Foundation and is an NIHR Senior Investigator. MI.K. is supported by the National Institute of Aging, the Medical Research Council, the British Heart Foundation, and the National Heart, Lung and Blood Institute and the Academy of Finland. A.D.H. and J.P.C. are supported by the National Institute of Health Research University College London Hospitals Biomedical Research Centre. Funding to pay the Open Access publication charges for this article was provided by RCUK.

Funding Information:
the CAD cases for the BHF-FHS Study was funded by the British Heart Foundation. Controls were collected as part of the Wellcome Trust Case Control Consortium Study. Genotyping was funded by the British Heart Foundation and the European Union FP6 Cardio-genics Study. The BHF-FHS study is part of the portfolio of research supported by the Leicester NIHR Biomedical Research Unit in Cardiovascular Disease. BRHS (British Regional Heart Study). BRHS has been funded by principally by a series of programme and project grants from the British Heart Foundation (BHF), with additional support from the UK Medical Research Council, the Department of Health (England), the Institute of Alcohol Studies, the Stroke Association, the BUPA Foundation, the Wellcome Trust and National Institute for Health Research School of Primary Care Research. DNA extraction was funded by a BHF Senior Fellowship. BWHHS (British Women’s Heart and Health Study). BWHHS is supported by funding from the British Heart Foundation and the Department of Health Policy Research Programme (England). We thank the BWHHS data collection team, General Practitioners who helped with recruitment of participants and the participants. We thank all of the participants and the general practitioners, research nurses, and data management staff who supported data collection and preparation. The BWHHS is coordinated by Shah Ebrahim (PI), D.L., and J.-P.C., with genotyping funded by the BHF (PG/07/131/24254, PI T.G.). CAPS (The Caerphilly Prospective study). The CAPS study was undertaken by the former MRC Epidemiology Unit (South Wales) and was funded by the Medical Research Council of the United Kingdom. CARe (Candidate gene Association Resource). The CARe Consortium wishes to acknowledge the support of the National Heart, Lung, and Blood Institute and the contributions of the research institutions, study investigators, fieldstaff,andstudyparticipantsincreatingthisresourceforbiomedical research (NHLBI contract number HHSN268200960009C). The following nine parent studies have contributed parent study data, ancillary study data, and DNA samples through the Massachusetts Institute of Technology-Broad Institute (N01-HC-65226) to create this genotype/phenotype database for wide dissemination to the biomedical research community: the Atherosclerosis Risk in Communities (ARIC) study, the Cardiovascular Health Study (CHS), the Cleveland Family Study (CFS), the Cooperative Study of Sickle Cell Disease (CSSCD), the Coronary Artery Risk Development in Young Adults (CARDIA) study, the Framingham Heart Study (FHS), the Jackson Heart Study (JHS), the Multi-Ethnic Study of Atherosclerosis (MESA), and the Sleep Heart Health Study (SHHS). The ARIC study is carried out as a collaborative study supported by National Heart, Lung, and Blood Institute contracts N01-HC-55015, N01-HC-55016, N01-HC-55018, N01-HC-55019, N01-HC-55020, N01-HC-55021, and N01-HC-55022. The authors thank the staff and participants of the ARIC studyfortheirimportantcontributions.MESAwasconductedandsup-ported by contracts N01-HC-95159 through N01-HC-95169 and RR-024156 from the National Heart, Lung, and Blood Institute (NHLBI). The authors thank the participants of the MESA study, the Coordinating Center, MESA investigators, and study staff for their valuable contributions. A full list of participating MESA investigators and institutions can be found at The Edinburgh Artery Study has been supported by grants from the British Heart Foundation. ELSA (English Longitudinal Study of Ageing). ELSA is funded by the National Institute on Aging in the US (R01 AG017644; R01AG1764406S1) and by a consortium of UK Government departments involved in areas related to the ageing process (including: Department for Communities and Local Government, Department for Transport, Department for Work and Pensions, Department of Health, HM Revenue and Customs and Office for National Statistics). EPIC-NL (European Prospective Investigation into Cancer and Nutrition in the Netherlands). The EPIC-NL study was funded by ‘Europe against Cancer’ Programme of the European Commission (SANCO), Dutch Ministry of Public Health, Welfare and Sports (VWS), Netherlands Cancer Registry (NKR), LK Research Funds, Dutch Prevention Funds, Dutch Cancer Society; ZonMW the Netherlands Organisation for Health Research and Development, World Cancer Research Fund (WCRF) (The Netherlands). Genotyping was funded by IOP Genomics grant IGE05012 from Agentschap NL. KORA (Cooperative Health Research in the Region of Augsburg). The KORA research platform was initiated and financed by the Helmholtz Zentrum München–German Research Center for Environmental Health, Neuherberg, Germany, which is funded by the German Federal Ministry of Education and Research (BMBF) and by the State of Bavaria. Part of this work was financed by the German National Genome Research Network (NGFNPlus, project number 01GS0834), by the German Research Foundation (TH-784/ 2-1 and TH-784/2-2), by the European Foundation for the Study of Diabetes and through additional funds from the Helmholtz Zentrum München, the German Diabetes Center and the University of Ulm. Furthermore, KORA research was supported within the Munich Center of Health Sciences (MC Health), Ludwig-Maximilians-Universität München as part of LMUinnovativ. NORDIL (Nordic Diltiazem study). The NORDIL clinical study was supported by a grant from Pharmacia. Genetic studies were supported by the British Heart Foundation (grant number CH/98001, RG/07/005/23633 to A.F.D.) and European Union Ingenious HyperCare Consortium: Integrated Genomics, Clinical Research, and Care in Hypertension (grant number LSHM-C7-2006-037093). Genotyping was supported by the British Heart Foundation (grant number PG/07/131/24254 to P.B.M.). We thank Prof. Thomas Hedner (Department of Clinical Pharmacology, Sahlgrenska Academy, Gotheburg, Sweden) and Prof. Sverre Kjeldsen (Ullevaal University Hospital, University of Oslo, Oslo, Norway), who are investigators of the NORDIL study. PROCARDIS (Precocious Coronary Artery Disease). The PROCARDIS consortium genotyping was funded by the British Heart Foundation (BHF) and EC Sixth Framework Programme (LSHM-CT-2007-037273) and the sample collection by AstraZeneca AB and the BHF. R.C., M.F., and H.W. are supported by the BHF Centre for Research Excellence; M.F. and H.W. acknowledge support from a Wellcome Trust core award (090532/Z/09/Z). R.C. acknowledges support from the MRC; Anders Hamsten obtained support for this project from the Swedish Heart-Lung Foundation, the Swedish Medical Research Council (8691), the Knut and Alice Wallenberg Foundation, the Karolinska Institute and the Stockholm County Council (560183). UCLEB (University College London-London School of Hygiene and Tropical Medicine-Edinburgh-Bristol). The UCLEB consortium is funded by a British Heart Foundation programme grant (ref RG/10/12/28456). WHI (Women’s Health Initiative). The WHI program is funded by the National Heart, Lung, and Blood Institute, National Institutes of Health, U.S. Department of Health and Human Services through contracts N01WH 22110, 24152, 32100-2, 32105-6, 32108-9, 32111-13, 32115, 32118-32119, 32122, 42107-26, 42129-32, and 44221. WHII (Whitehall II study). The Whitehall II study is supported by the Medical Research Council, the British Heart Foundation, the National Heart, Lung, and Blood Institute, and the National Institute for Aging. The Whitehall II study CardioChip studies were funded by the British Heart Foundation and we gratefully thank the subjects and the investigators of this project.

Publisher Copyright:
© The Author 2014. Published by Oxford University Press on behalf of the European Society of Cardiology.


  • Aetiology
  • Epidemiology
  • Heart disease
  • Lipids
  • Mendelian randomization


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