INTRODUCTION: Body mass index (BMI) has been implicated in various cardiovascular conditions, but its association with peripheral artery disease (PAD) in both real-world and genetic studies have been contentious and debated. METHODS: This study enrolled 6707 individuals from the National Health and Nutrition Examination Survey database to investigate the association between BMI and the risk of PAD. The weighted logistic regression, restricted cubic spline, and subgroup analysis were performed using real-world data. Mendelian randomization study was conducted using genetic data from the Genome-Wide Association Study. The inverse variance weighted method was used as the primary analysis approach, and a sensitivity analysis was conducted to identify pleiotropy and heterogeneity bias. RESULTS: Individuals with PAD had higher mean BMI values compared to those without PAD (28.82 ± 5.87 and 28.31 ± 5.42, P = 0.007). For the categorical variable of BMI, individuals in obesity class 2 (odds ratio [OR] = 1.532, 95% CI = 1.082-2.169
P = 0.013) and obesity class 3 (OR = 2.479, 95% CI = 1.515-4.056
P <
0.001) had a higher risk of PAD analyzed by weighted logistic regression. Subgroup analysis revealed that the association between BMI and PAD persisted. Given that a higher BMI is associated with PAD, we selected obesity for Mendelian randomization analysis and observed that obesity had a relationship with PAD (inverse variance weight: OR = 1.194, 95% CI = 1.099-1.296
P <
0.001). The reliable findings were validated by sensitive analysis (all P >
0.05). CONCLUSIONS: BMI is a robust risk factor for PAD. A higher BMI (especially ≥35 kg/m