Early-life tobacco smoke exposure and incident rheumatoid arthritis: mediated by allostatic load and joint effects with polygenic risk.

OBJECTIVES: Rheumatoid arthritis (RA) is a widespread autoimmune disorder. Early-life environmental exposures may contribute to RA, and tobacco smoke represents an important modifiable factor. This study aimed to examine whether early-life tobacco smoke exposure affects incident RA risk, and to clarify the potential mediating role of allostatic load (AL) and interactive effects with genetic susceptibility. METHODS: Using questionnaire, biomarker, genetic, and linked health-record data from UK Biobank, we examined intrauterine tobacco smoke exposure (IUTSE; n = 427,037), age at tobacco use initiation (ATUI; n = 414,318) and RA cases. Cox models evaluated associations between early-life tobacco exposure and RA risk. Mediation analysis quantified AL's mediating effect. Additive and multiplicative interaction examined genetic susceptibility interactions. RESULTS: IUTSE was associated with higher RA risk (HR = 1.15, 95% CI: 1.08, 1.21). Compared with never-smokers, individuals who started tobacco smoking in childhood, adolescence, and adulthood exhibited elevated RA risk, with corresponding HRs of 1.74 (95% CI: 1.39, 2.17), 1.56 (95% CI: 1.29, 1.88), and 1.47 (95% CI: 1.22, 1.76). Mediation analyses indicated statistically significant but small indirect effects of AL. The indirect effect for IUTSE was 1.001 (95% CI: 1.001, 1.002) and for tobacco use during childhood, adolescence, and adulthood were 1.009 (95% CI: 1.005, 1.013), 1.006 (95% CI: 1.003, 1.009), and 1.006 (95% CI: 1.003, 1.009). High genetic risk with IUTSE (HR = 1.93, 95% CI: 1.75, 2.13) or childhood initiation (HR = 2.89, 95% CI: 2.17, 3.86) increased RA risk. CONCLUSION: Early-life tobacco smoke exposure elevates RA risk in adulthood, with limited mediation by AL and modification by genetic predisposition.