Causal Association of Cardiovascular Risk Factors and Lifestyle Behaviors With Peripheral Artery Disease: A Mendelian Randomization Approach

Abstract

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.

Mendelian randomization for cardiovascular diseases: principles and applications

“…The MR design has been used to investigate the potential causal associations of lifestyle factors, including smoking, alcohol and coffee consumption, physical activity, and sleep patterns, with risk of CVD. A consistent association has been reported for genetic liability to smoking with increased risk of most CVDs, 48 , 59 , 73–75 with the strongest magnitude of association observed for peripheral artery disease and abdominal aortic aneurysm. 73–75 …”

“… 24 A non-linear MR analysis in the UK Biobank showed that light alcohol drinking was associated with a minimal increase in coronary artery disease risk and that the risk increased exponentially at higher intakes. 78 Mendelian randomization studies have provided suggestive evidence that genetically predicted higher alcohol consumption is associated with increased risk of abdominal aortic aneurysm, 27 atrial fibrillation, 27 , 78 heart failure, 78 and peripheral artery disease 27 , 59 but not with aortic valve stenosis and venous thromboembolism 27 in European populations.…”

Lack of causal association between cheese intake and risk of peripheral vascular diseases: A two‐sample Mendelian randomization study

“…This observation implied that education level is an important upstream factor in determining health outcomes. It is plausible that a higher education level promoted the adoption of healthier lifestyle choices, consequently reducing the likelihood of being exposed to various health risks [33,34]. Secondly, the data from previous studies were obtained on the basis of self-reported cheese intake.…”

The causal relationship between cheese intake and peripheral vascular disease: A two-sample mendelian randomization study

“…This observation implied that education level is an important upstream factor in determining health outcomes. It is plausible that a higher education level promoted the adoption of healthier lifestyle choices, consequently reducing the likelihood of being exposed to various health risks [29][30]. Secondly, the data from previous studies were obtained based on self-reported cheese intake.…”