Smoking and risk of restless leg syndrome: a systematic review, meta-analysis, and Mendelian randomisation.

Background: Although the link between smoking and various sleep disorders has been well-established, it is still unknown whether smoking increases the risk of restless legs syndrome (RLS). We investigated this association using a meta-analysis and explored the causality through Mendelian randomisation (MR). Methods: We searched six databases for studies reporting associations between smoking and RLS in overall adults, and the results were presented as odds ratios (ORs) with 95% confidence intervals (CIs). We performed sensitivity, subgroup and meta-regression analyses to identify potential sources of heterogeneity. We obtained data used in MR analyses from the UK Biobank and the Genome-wide Association Studies Catalogue. We applied the inverse-variance weighted method, MR Egger, weighted median, simple mode and weighted mode for data analyses, and further conducted pleiotropy and heterogeneity tests, as well as leave-one-out analyses. Results: Based on 30 studies, we found that smoking was associated with increased risk of RLS (OR = 1.40; 95% CI = 1.17, 1.67, P < 0.001), with the risk significantly increased (P = 0.04) in pregnant women (OR = 2.41; 95% CI = 1.39, 4.16, P = 0.002) than in the non-pregnant adults (OR = 1.30, 95% CI = 1.09, 1.55, P = 0.004), and in current smokers compared with former smokers (OR = 1.09; 95% CI = 1.02, 1.16, P = 0.01). We identified multi-centre studies, diagnostic criteria for RLS and participants' age as potential sources of heterogeneity; however, MR results did not show any causal association between smoking and RLS (OR = 0.50; 95% CI = 0.16, 1.56, P = 0.23). Conclusions: Although the meta-analysis suggested that smoking increases the risk of RLS, MR analyses did not provide evidence for a causal relationship. Future studies are needed to elucidate the biological mechanisms underlying this association. Registration: PROSPERO: CRD420251048406.