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Mendelian randomization of blood lipids for coronary heart disease

Research output: Contribution to journalJournal articlepeer-review

  • 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 Zabaneh
  • Reecha 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
  • UCLEB Consortium
<mark>Journal publication date</mark>1/03/2015
<mark>Journal</mark>European Heart Journal
Issue number9
Number of pages12
Pages (from-to)539-550
Publication StatusPublished
Early online date28/01/14
<mark>Original language</mark>English


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.

Bibliographic note

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