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

Abstract

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. 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. 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. Early-life tobacco smoke exposure elevates RA risk in adulthood, with limited mediation by AL and modification by genetic predisposition.