Purpose of Review A clear link between excessive alcohol consumption and cardiovascular disease (CVD) has been established, but no consensus exists on the effects of moderate alcohol consumption on CVD. Recent Findings A lower risk of coronary heart disease and myocardial infarction among moderate drinkers compared to abstainers has been consistently observed in epidemiological studies and meta-analyses of these studies. However, ambiguity remains on the effect of alcohol on other CVDs and all-cause mortality. Short-term randomized controlled trials (RCT) have identified potentially beneficial effects of alcohol consumption on cardiovascular risk factors, but studies investigating genetic polymorphisms that influence alcohol consumption (i.e., Mendelian randomization) have yielded inconclusive results. To date, a long-term RCT providing causal evidence is lacking but urgently needed. Summary Triangulation of evidence from different study designs, including long-term RCTs, pragmatic trials and the evaluation of policy measures, combined will lead to the best available evidence.

Background We investigated the causal associations between the genetic liability to cardiovascular and lifestyle risk factors and peripheral artery disease (PAD), using a Mendelian randomization approach. Methods and Results We performed a 2‐sample inverse‐variance weighted Mendelian randomization analysis, multiple sensitivity analyses to assess pleiotropy and multivariate Mendelian randomization analyses to assess mediating/confounding factors. European‐ancestry genomic summary data ( P <5×10 −8 ) for type 2 diabetes, lipid‐fractions, smoking, alcohol and coffee consumption, physical activity, sleep, and education level were selected. Genetic associations with PAD were extracted from the Million‐Veteran‐Program genome‐wide association studies (cases=31 307, controls=211 753, 72% European‐ancestry) and the GoLEAD‐SUMMIT genome‐wide association studies (11 independent genome‐wide association studies, European‐ancestry, cases=12 086, controls=449 548). Associations were categorized as robust (Bonferroni‐significant ( P <0.00294), consistent over PAD‐cohorts/sensitivity analyses), suggestive ( P value: 0.00294–0.05, associations in 1 PAD‐cohort/inconsistent sensitivity analyses) or not present. Robust evidence for genetic liability to type 2 diabetes, smoking, insomnia, and inverse associations for higher education level with PAD were found. Suggestive evidence for the genetic liability to higher low‐density lipoprotein cholesterol, triglyceride‐levels, alcohol consumption, and inverse associations for high‐density lipoprotein cholesterol, and increased sleep duration were found. No associations were found for physical activity and coffee consumption. However, effects fully attenuated for low‐density lipoprotein cholesterol and triglycerides after correcting for apoB, and for insomnia after correcting for body mass index and lipid‐fractions. Nonsignificant attenuation by potential mediators was observed for education level and type 2 diabetes. Conclusions Detrimental effects of smoking and type 2 diabetes, but not of low‐density lipoprotein cholesterol and triglycerides, on PAD were confirmed. Lower education level and insomnia were identified as novel risk factors for PAD; however, complete mediation for insomnia and incomplete mediation for education level by downstream risk factors was observed.

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