Mendelian randomization of blood lipids for coronary heart disease

Holmes, Michael V. and Asselbergs, Folkert W. and Palmer, Tom M. and Drenos, Fotios and Lanktree, Matthew B. and Nelson, Christopher P. and Dale, Caroline E. and Padmanabhan, Sandosh and Finan, Chris and Swerdlow, Daniel I. and Tragante, Vinicius and van Iperen, Erik P. A. and Sivapalaratnam, Suthesh and Shah, Sonia and Elbers, Clara C. and Shah, Tina and Engmann, Jorgen and Giambartolomei, Claudia and White, Jon and Zabaneh, Delilah and Sofat, Reecha and McLachlan, Stela and Doevendans, Pieter A. and Balmforth, Anthony J. and Hall, Alistair S. and North, Kari E. and Almoguera, Berta and Hoogeveen, Ron C. and Cushman, Mary and Fornage, Myriam and Patel, Sanjay R. and Redline, Susan and Siscovick, David S. and Tsai, Michael Y. and Karczewski, Konrad J. and Hofker, Marten H. and Verschuren, W. Monique and Bots, Michiel L. and van der Schouw, Yvonne T. and Melander, Olle and Dominiczak, Anna F. and Morris, Richard and Ben-Shlomo, Yoav and Price, Jackie and Kumari, Meena and Baumert, Jens and Peters, Annette and Thorand, Barbara and Koenig, Wolfgang and Gaunt, Tom R. (2015) Mendelian randomization of blood lipids for coronary heart disease. European Heart Journal, 36 (9). pp. 539-550. ISSN 0195-668X

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.