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, Tom R Gaunt, James G Wilson, George Davey Smith, Debbie A Lawlor, UCLEB Consortium

Research output: Contribution to journalArticle (Academic Journal)peer-review

315 Citations (Scopus)

Abstract

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
Pages (from-to)539-550
Number of pages11
JournalEuropean Heart Journal
Volume36
Issue number9
DOIs
Publication statusPublished - 27 Jan 2014

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