Journal
EUROPEAN HEART JOURNAL
Volume 36, Issue 9, Pages 539-+Publisher
OXFORD UNIV PRESS
DOI: 10.1093/eurheartj/eht571
Keywords
Lipids; Heart disease; Mendelian randomization; Aetiology; Epidemiology
Categories
Funding
- UK Medical Research Council Population Health Scientist Fellowship [G0802432]
- UCL Hospitals NIHR Biomedical Research Centre
- Medical Research Council
- Rosetrees Foundation
- National Institute of Aging and the National Heart, Lung and Blood Institute [HL36310]
- British Heart Foundation [BHF RG 08/008, PG/07/133/24260]
- UK Medical Research Council
- US National Institutes of Health [NHLBI 33014]
- Du Pont Pharma, Wilmington, USA
- British Heart Foundation
- National Institute of Aging
- National Heart, Lung and Blood Institute and the Academy of Finland
- National Institute of Health Research University College London Hospitals Biomedical Research Centre
- RCUK
- ESRC [ES/J023299/1] Funding Source: UKRI
- MRC [MC_UU_12013/5, MC_UU_12013/8, MC_UU_12019/1, G1000718, MC_UU_12013/1, MR/K013351/1, MR/K006215/1, G0802432, MR/L01629X/1] Funding Source: UKRI
- British Heart Foundation [RG/13/2/30098, PG/13/66/30442, RG/10/12/28456, RG/08/008/25291] Funding Source: researchfish
- Chief Scientist Office [CZB/4/672] Funding Source: researchfish
- Economic and Social Research Council [ES/J023299/1] Funding Source: researchfish
- Medical Research Council [G0802432, MR/K013351/1, MC_UU_12013/8, MC_UU_12013/1, G1000718, MR/K006215/1, MC_UU_12013/5, MR/L01629X/1, MR/K006584/1, MC_UU_12019/1] Funding Source: researchfish
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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 priormeta-analysis (threshold P < 2 x 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 unrestrictedallele score (48SNPs) 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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