Multivariable Mendelian Randomization Analysis Reveals the Protective Effect of Restless Legs Syndrome against Lower Limb Venous Diseases and Pulmonary Embolism

Abstract Objectives: Lower limb immobility is a significant risk factor for peripheral vascular diseases, such as venous thromboembolism (VTE). Restless legs syndrome (RLS) is characterized by an irresistible urge to move the lower limbs to alleviate discomfort. The impact of RLS on lower limb vascular diseases is unclear. Methods: This study used a two-sample Mendelian Randomization (MR) approach to assess the effect of RLS on the risk of seven arterial and seven venous diseases. Conducted in three stages, the study used different RLS datasets for discovery (Didriksen et al.) and replication (EU-RLS-GENE consortium) analyses across all the stages to ensure robust conclusions. Univariable MR (UVMR) was applied to analyze the causal relationship between RLS and 14 vascular diseases. Multivariable MR (MVMR) included covariates like BMI, smoking status, alcohol intake, and educational attainment. In the final stage, accelerometer-based physical activity at 12 different time were incorporated in MVMR analysis to determine if RLS influences lower limb vascular diseases by increasing limb activity. Results: RLS was associated with a reduced risk of six venous diseases, including varicose veins, superficial phlebitis, VTE, and pulmonary embolism. These findings remained robust after adjusting for covariates but lost significance after accounting for nighttime physical activity. Conclusion: RLS may lower the risk of venous diseases and pulmonary embolism by increasing nocturnal limb activity. This finding is particularly relevant for pregnant women and individuals with renal impairment, who are at high risk for both RLS and VTE. Further research is needed to validate these conclusions.