Exploratory Mendelian Randomization Provides Hypothesis-Generating Evidence for a Possible Nicotine-Related Mechanism in Sarcoidosis

Objective: We explored whether the inverse association between smoking and sarcoidosis observed in observational studies may involve nicotine-related mechanisms. Methods: Genetic summary statistics were sourced from the largest available genome-wide association studies, covering smoking initiation, age of onset, daily cigarette consumption (CigDay), smoking cessation, lifetime smoking exposure, and nicotine metabolite ratio (NMR). Multivariable Mendelian randomization (MVMR) estimated the association of genetically predicted NMR with sarcoidosis risk after adjusting for CigDay, with univariable MR (UVMR) as supportive evidence. Results: Higher NMR was associated with higher sarcoidosis risk after adjusting for CigDay (OR = 1.08, 95% CI: 1.01–1.16, p = 0.018). UVMR showed that current smokers had lower risk than former smokers (OR = 0.44, 95% CI: 0.25–0.76, p = 0.003), whereas associations for current and former smoking versus never smoking, and for nicotine metabolites, were null. Conclusions: This exploratory MR study provides hypothesis-generating evidence that genetically predicted faster nicotine metabolism may be associated with higher sarcoidosis risk, compatible with a possible role of nicotine-related mechanisms but not establishing a causal effect or a clinical effect of nicotine. These results should not justify smoking, which remains strongly harmful. Future studies should investigate the immune regulatory pathways through which nicotine metabolism may influence sarcoidosis pathogenesis.