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. 2019 Dec;12(12):e002711.
doi: 10.1161/CIRCGEN.119.002711. Epub 2019 Nov 22.

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

Elias Allara  1   2 , Gabriele Morani  3 , Paul Carter  1 , Apostolos Gkatzionis  4 , Verena Zuber  4   5 , Christopher N Foley  4 , Jessica M B Rees  1   6 , Amy M Mason  1   7 , Steven Bell  1   2 , Dipender Gill  5 , Sara Lindström  8 , Adam S Butterworth  1   2   7   9 , Emanuele Di Angelantonio  1   2   7   9 , James Peters  1   9 , Stephen Burgess  1   4 ; INVENT consortium
Affiliations

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

Elias Allara et al. Circ Genom Precis Med. 2019 Dec.

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.

Keywords: Mendelian randomization; aortic valve stenosis; epidemiology; lipids; venous thromboembolism.

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Figures

Figure 1.
Figure 1.
Multivariable Mendelian randomization estimates (odds ratio with 95% confidence interval per 1 standard deviation increase in lipid fraction) from polygenic analyses including all lipid-associated variants. HDL indicates high-density lipoprotein; and LDL, low-density lipoprotein.
Figure 2.
Figure 2.
Univariable Mendelian randomization estimates (odds ratio with 95% CI per 1 SD increase in lipid fraction) for variants in specific gene regions. Estimates are scaled to a unit SD increase in LDL-cholesterol for the HMGCR, PCSK9, and LDLR regions, and to a SD increase in triglycerides for the APOC3 and LPL regions.
See this image and copyright information in PMC

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