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Genetic Determinants of Lipids and Cardiovascular Disease Outcomes: A Wide-Angled Mendelian Randomization Investigation.

Allara, E; Morani, G; Carter, P; Gkatzionis, A; Zuber, V; Foley, CN; Rees, JMB; Mason, AM; Bell, S; Gill, D; et al. Allara, E; Morani, G; Carter, P; Gkatzionis, A; Zuber, V; Foley, CN; Rees, JMB; Mason, AM; Bell, S; Gill, D; Lindström, S; Butterworth, AS; Di Angelantonio, E; Peters, J; Burgess, S; INVENT consortium (2019) Genetic Determinants of Lipids and Cardiovascular Disease Outcomes: A Wide-Angled Mendelian Randomization Investigation. Circ Genom Precis Med, 12 (12). e002711. ISSN 2574-8300 https://doi.org/10.1161/CIRCGEN.119.002711
SGUL Authors: Gill, Dipender Preet Singh

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Abstract

BACKGROUND: Evidence from randomized trials has shown that therapies that lower LDL (low-density lipoprotein)-cholesterol and triglycerides reduce coronary artery disease (CAD) risk. However, there is still uncertainty about their effects on other cardiovascular outcomes. We therefore performed a systematic investigation of causal relationships between circulating lipids and cardiovascular outcomes using a Mendelian randomization approach. METHODS: In the primary analysis, we performed 2-sample multivariable Mendelian randomization using data from participants of European ancestry. We also conducted univariable analyses using inverse-variance weighted and robust methods, and gene-specific analyses using variants that can be considered as proxies for specific lipid-lowering medications. We obtained associations with lipid fractions from the Global Lipids Genetics Consortium, a meta-analysis of 188 577 participants, and genetic associations with cardiovascular outcomes from 367 703 participants in UK Biobank. RESULTS: For LDL-cholesterol, in addition to the expected positive associations with CAD risk (odds ratio [OR] per 1 SD increase, 1.45 [95% CI, 1.35-1.57]) and other atheromatous outcomes (ischemic cerebrovascular disease and peripheral vascular disease), we found independent associations of genetically predicted LDL-cholesterol with abdominal aortic aneurysm (OR, 1.75 [95% CI, 1.40-2.17]) and aortic valve stenosis (OR, 1.46 [95% CI, 1.25-1.70]). Genetically predicted triglyceride levels were positively associated with CAD (OR, 1.25 [95% CI, 1.12-1.40]), aortic valve stenosis (OR, 1.29 [95% CI, 1.04-1.61]), and hypertension (OR, 1.17 [95% CI, 1.07-1.27]), but inversely associated with venous thromboembolism (OR, 0.79 [95% CI, 0.67-0.93]) and hemorrhagic stroke (OR, 0.78 [95% CI, 0.62-0.98]). We also found positive associations of genetically predicted LDL-cholesterol and triglycerides with heart failure that appeared to be mediated by CAD. CONCLUSIONS: Lowering LDL-cholesterol is likely to prevent abdominal aortic aneurysm and aortic stenosis, in addition to CAD and other atheromatous cardiovascular outcomes. Lowering triglycerides is likely to prevent CAD and aortic valve stenosis but may increase thromboembolic risk.

Item Type: Article
Additional Information: © 2019 The Authors. Circulation: Genomic and Precision Medicine is published on behalf of the American Heart Association, Inc., by Wolters Kluwer Health, Inc. This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution, and reproduction in any medium, provided that the original work is properly cited.
Keywords: Mendelian randomization, aortic valve stenosis, epidemiology, lipids, venous thromboembolism, Adult, Aged, Cardiovascular Diseases, Cholesterol, LDL, Europe, European Continental Ancestry Group, Female, Genetic Predisposition to Disease, Genome-Wide Association Study, Humans, Male, Mendelian Randomization Analysis, Middle Aged, Odds Ratio, Risk Factors, Triglycerides, INVENT consortium, Humans, Cardiovascular Diseases, Genetic Predisposition to Disease, Triglycerides, Odds Ratio, Risk Factors, Adult, Aged, Middle Aged, European Continental Ancestry Group, Europe, Female, Male, Cholesterol, LDL, Genome-Wide Association Study, Mendelian Randomization Analysis
SGUL Research Institute / Research Centre: Academic Structure > Infection and Immunity Research Institute (INII)
Journal or Publication Title: Circ Genom Precis Med
ISSN: 2574-8300
Language: eng
Dates:
DateEvent
December 2019Published
22 November 2019Published Online
15 November 2019Accepted
Publisher License: Creative Commons: Attribution 4.0
Projects:
Project IDFunderFunder ID
G0800270Medical Research Councilhttp://dx.doi.org/10.13039/501100000265
RG/13/13/30194British Heart Foundationhttp://dx.doi.org/10.13039/501100000274
MC_QA137853Medical Research CouncilUNSPECIFIED
MR/L003120/1Medical Research Councilhttp://dx.doi.org/10.13039/501100000265
MC_UU_00002/7Medical Research CouncilUNSPECIFIED
MC_PC_17228Medical Research CouncilUNSPECIFIED
RG/18/13/33946British Heart FoundationUNSPECIFIED
MR/S004068/1Medical Research Councilhttp://dx.doi.org/10.13039/501100000265
MC_UU_12013/3Medical Research Councilhttp://dx.doi.org/10.13039/501100000265
SP/09/002British Heart Foundationhttp://dx.doi.org/10.13039/501100000274
RG/08/014British Heart Foundationhttp://dx.doi.org/10.13039/501100000274
HEALTH-F2-2012-279233Seventh Framework Programmehttp://dx.doi.org/10.13039/501100004963
BTRU-2014-10024National Institute for Health Researchhttp://dx.doi.org/10.13039/501100000272
204623/Z/16/ZWellcome Trusthttp://dx.doi.org/10.13039/100004440
PubMed ID: 31756303
Go to PubMed abstract
URI: https://openaccess.sgul.ac.uk/id/eprint/112802
Publisher's version: https://doi.org/10.1161/CIRCGEN.119.002711

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