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., 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 None., 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 F., Samani NJ., Keating BJ., Hingorani AD., Casas JP.
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.