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.

Keywords: cardiometabolic risk factors; cigarette smoking; education; health risk behaviors; hypercholesterolemia; mendelian randomization analysis; peripheral artery disease.

Figure 1. The association between cardiovascular risk factors and lifestyle behaviors with peripheral artery disease using the inverse variance‐weighted Mendelian randomization method.

Odds ratios represent the associations of peripheral artery disease with listed risk factors. GoLEAD‐SUMMIT indicates genome‐wide association study, executed by the GoLEAD‐SUMMIT consortium; GWAS, Genome wide association study; HDL, high‐density lipoprotein; LDL, low‐density lipoprotein; MVP, Genome wide association study on peripheral artery disease, executed by the Million veteran program; MVPA, moderate‐to‐vigorous physical activity; OR, odds ratio; PAD, peripheral artery disease; and SNP, single nucleotide polymorphism.

Figure 2. Overview of the associations of cardiovascular risk factors and lifestyle behaviors with peripheral artery disease.

All results can be found in Figure 1 and Table S2 and S3. *Bonferroni corrected significance level of P<0.00294 (0.05 divided by 17 risk factors). IWV indicates Inverse variance‐weighted method; HDL, high‐density lipoprotein; LDL, low‐density lipoprotein; MVPA, moderate‐to‐vigorous physical activity; MR‐PRESSO, Mendelian Randomization Pleiotropy Residual Sum and Outlier; NA, not applicable; and PAD, peripheral artery disease.