Mendelian randomization of blood lipids for coronary heart disease

Holmes, M. V. et al. (2014) Mendelian randomization of blood lipids for coronary heart disease. European Heart Journal, 36(9), pp. 539-550. (doi:10.1093/eurheartj/eht571) (PMID:24474739) (PMCID:PMC4344957)

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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.

Item Type:Articles
Status:Published
Refereed:Yes
Glasgow Author(s) Enlighten ID:Padmanabhan, Professor Sandosh and Dominiczak, Professor Anna
Authors: Holmes, M. V., Asselbergs, F. W., Palmer, T. M., Drenos, F., Lanktree, M. B., Nelson, C. P., Dale, C. E., Padmanabhan, S., Finan, C., Swerdlow, D. I., Tragante, V., van Iperen, E. P.A., Sivapalaratnam, S., Shah, S., Elbers, C. C., Shah, T., Engmann, J., Giambartolomei, C., White, J., Zabaneh, D., Sofat, R., McLachlan, S., Doevendans, P. A., Balmforth, A. J., Hall, A. S., North, K. E., Almoguera, B., Hoogeveen, R. C., Cushman, M., Fornage, M., Patel, S. R., Redline, S., Siscovick, D. S., Tsai, M. Y., Karczewski, K. J., Hofker, M. H., Verschuren, W. M., Bots, M. L., van der Schouw, Y. T., Melander, O., Dominiczak, A. F., Morris, R., Ben-Shlomo, Y., Price, J., Kumari, M., Baumert, J., Peters, A., Thorand, B., Koenig, W., Gaunt, T. R., Humphries, S. E., Clarke, R., Watkins, H., Farrall, M., Wilson, J. G., Rich, S. S., de Bakker, P. I.W., Lange, L. A., Davey Smith, G., Reiner, A. P., Talmud, P. J., Kivimäki, M., Lawlor, D. A., Dudbridge, F., Samani, N. J., Keating, B. J., Hingorani, A. D., and Casas, J. P.
College/School:College of Medical Veterinary and Life Sciences > Institute of Cardiovascular and Medical Sciences
Journal Name:European Heart Journal
Journal Abbr.:Eur. heart j.
Publisher:Oxford University Press
ISSN:0195-668X
ISSN (Online):1522-9645
Copyright Holders:Copyright © 2014 The Authors
First Published:First published in European Heart Journal 36(9):539-550
Publisher Policy:Reproduced under a Creative Commons License

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