Disentangling Nicotine vs Non-Nicotine Components of Tobacco Exposure in Psoriasis and Psoriatic Arthritis: A Multivariable and Trans-Ethnic Mendelian Randomization Study

Objective: To disentangle tobacco constituents in psoriasis, we contrasted nicotine exposure—proxied by the nicotine metabolite ratio (NMR)—with smoking intensity (cigarettes per day, CPD) and evaluated cross-ancestry effects. Methods: This study applied multivariable Mendelian randomization (MR) jointly modeling genetically proxied NMR (instrumented using variants from a European-ancestry GWAS) and CPD to estimate their independent effects on liability to psoriasis and psoriatic arthritis (PsA). Chronic obstructive pulmonary disease (COPD) served as a positive control. Cross-ancestry generalizability was tested using a trans-ethnic MR (TEMR) framework under conditional likelihood with Nelder–Mead optimization. Sensitivity analyses assessed pleiotropy, heterogeneity, directionality (Steiger), MRLap, RadialMR, and multiple testing (Benjamini–Hochberg). Results: NMR showed an independent association with higher PsA risk irrespective of CPD (OR = 1.104, 95% CI: 1.039– 1.174). CPD retained an independent effect on overall psoriasis after conditioning on NMR (OR = 1.305, 95% CI: 1.082– 1.573), while the NMR effect on psoriasis attenuated (P > 0.05). In univariable MR, genetically predicted NMR increased psoriasis risk in Europeans (EUR; OR = 1.032, 95% CI: 1.013– 1.051). CPD associated with psoriasis in EUR (OR = 1.130, 95% CI: 1.031– 1.239) and strongly in Hispanics (HIS; OR = 1.448, 95% CI: 1.434– 1.463), with suggestive evidence in East Asians. Reverse-direction MR indicated psoriasis liability correlated with lower CPD across EUR, EAS, AFR, and HIS (β < 0, Padj < 0.05). Conclusion: This study supports ancestry-specific differences and suggests distinct roles of nicotine-related versus non-nicotine tobacco smoke constituents in psoriasis and its subtypes, while the underlying biological mechanisms remain to be clarified.