PT  - JOURNAL ARTICLE
AU  - Allara, Elias
AU  - Morani, Gabriele
AU  - Carter, Paul
AU  - Gkatzionis, Apostolos
AU  - Zuber, Verena
AU  - Foley, Christopher N
AU  - Rees, Jessica MB
AU  - Mason, Amy M
AU  - Bell, Steven
AU  - Gill, Dipender
AU  - Butterworth, Adam S
AU  - Angelantonio, Emanuele Di
AU  - Peters, James
AU  - Burgess, Stephen
TI  - Genetic determinants of lipids and cardiovascular disease outcomes: a wide-angled Mendelian randomization investigation
AID  - 10.1101/668970
DP  - 2019 Jan 01
TA  - bioRxiv
PG  - 668970
4099  - http://biorxiv.org/content/early/2019/06/14/668970.short
4100  - http://biorxiv.org/content/early/2019/06/14/668970.full
AB  - Aims To systematically investigate causal relationships between circulating lipids and cardiovascular outcomes, using a Mendelian randomization approach.Methods and Results In the primary analysis, we performed two-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.For LDL-cholesterol, in addition to the expected positive associations with coronary artery disease (CAD) risk (odds ratio per 1 standard deviation increase [OR], 1.45; 95% confidence interval [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). The positive associations of genetically-predicted LDL-cholesterol and triglycerides with heart failure and aortic stenosis appeared to be mediated by CAD.Conclusion 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 risk of thromboembolism.