Mendelian randomization of blood lipids for coronary heart disease.

Holmes, MV; Asselbergs, FW; Palmer, TM; Drenos, F; Lanktree, MB; Nelson, CP; Dale, CE; Padmanabhan, S; Finan, C; Swerdlow, DI; +59 more...Tragante, V; van Iperen, EP; Sivapalaratnam, S; Shah, S; Elbers, CC; Shah, T; Engmann, J; Giambartolomei, C; White, J; Zabaneh, D; Sofat, R; McLachlan, S; UCLEB consortium; Doevendans, PA; Balmforth, AJ; Hall, AS; North, KE; Almoguera, B; Hoogeveen, RC; Cushman, M; Fornage, M; Patel, SR; Redline, S; Siscovick, DS; Tsai, MY; Karczewski, KJ; Hofker, MH; Verschuren, WM; Bots, ML; van der Schouw, YT; Melander, O; Dominiczak, AF; Morris, R; Ben-Shlomo, Y; Price, J; Kumari, M; Baumert, J; Peters, A; Thorand, B; Koenig, W; Gaunt, TR; Humphries, SE; Clarke, R; Watkins, H; Farrall, M; Wilson, JG; Rich, SS; de Bakker, PI; Lange, LA; Davey Smith, G; Reiner, AP; Talmud, PJ; Kivimäki, M; Lawlor, DA; Dudbridge, FORCID logo; Samani, NJ; Keating, BJ; Hingorani, AD; Casas, JP and (2014) Mendelian randomization of blood lipids for coronary heart disease. European heart journal, 36 (9). pp. 539-550. ISSN 0195-668X DOI: 10.1093/eurheartj/eht571
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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.


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