Abstract
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, P(adj) < 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.