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

Elias Allara, Gabriele Morani, Paul Carter, Apostolos Gkatzionis, Verena Zuber, Christopher N Foley, Jessica Mb Rees, Amy M Mason, Steven Bell, Dipender Gill, Sara Lindstroem, Adam S Butterworth, Emanuele Di Angelantonio, James Peters, Stephen Burgess

Research output: Contribution to journalArticlepeer-review


Background - Evidence from randomized trials has shown that therapies that lower low-density lipoprotein (LDL)-cholesterol and triglycerides reduce coronary artery disease (CAD) risk. However, there is still uncertainty regarding 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 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. Results - For LDL-cholesterol, in addition to the expected positive associations with 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) and haemorrhagic 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.

Original languageEnglish
JournalCirculation: Genomic and Precision Medicine
Early online date22 Nov 2019
Publication statusE-pub ahead of print - 22 Nov 2019


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