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Mendelian randomization of blood lipids for coronary heart disease

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Title: Mendelian randomization of blood lipids for coronary heart disease
Authors: Holmes, MV
Asselbergs, FW
Palmer, TM
Drenos, F
Lanktree, MB
Nelson, CP
Dale, CE
Padmanabhan, S
Finan, C
Swerdlow, DI
Tragante, V
Van Iperen, EPA
Sivapalaratnam, S
Shah, S
Elbers, CC
Shah, T
Engmann, J
Giambartolomei, C
White, J
Zabaneh, D
Sofat, R
McLachlan, S
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, PIW
Lange, LA
Smith, GD
Reiner, AP
Talmud, PJ
Kivimaeki, M
Lawlor, DA
Dudbridge, F
Samani, NJ
Keating, BJ
Hingorani, AD
Casas, JP
Item Type: Journal Article
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.
Issue Date: 27-Jan-2014
Date of Acceptance: 27-Jan-2014
URI: http://hdl.handle.net/10044/1/41062
DOI: http://dx.doi.org/10.1093/eurheartj/eht571
ISSN: 1522-9645
Publisher: Oxford University Press
Start Page: 539
End Page: 550
Journal / Book Title: European Heart Journal
Volume: 36
Issue: 9
Copyright Statement: This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/3.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited.
Keywords: Science & Technology
Life Sciences & Biomedicine
Cardiac & Cardiovascular Systems
Cardiovascular System & Cardiology
Lipids
Heart disease
Mendelian randomization
Aetiology
Epidemiology
HIGH-DENSITY-LIPOPROTEIN
INSTRUMENTAL VARIABLES
CARDIOVASCULAR EVENTS
GENETIC-VARIANTS
CHOLESTEROL LEVELS
VASCULAR-DISEASE
RISK-FACTORS
METAANALYSIS
TRIALS
ATHEROSCLEROSIS
Case-Control Studies
Cholesterol, HDL
Coronary Artery Disease
Female
Gene Frequency
Genotype
Genotyping Techniques
Humans
Male
Mendelian Randomization Analysis
Middle Aged
Polymorphism, Single Nucleotide
Risk Assessment
Triglycerides
UCLEB consortium
Cardiovascular System & Hematology
1102 Cardiovascular Medicine And Haematology
Publication Status: Published
Appears in Collections:Department of Medicine (up to 2019)