Mendelian randomization of blood lipids for coronary heart disease

Publication type

Journal Article


Publication date

March 15, 2015


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.

Published in

European Heart Journal

Volume and page numbers

Volume: 36 , p.539 -550






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

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

Open Access article

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