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

Research output: Contribution to journalArticlepeer-review

502 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

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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