Interaction between smoking and HLA-A*02:01 in multiple sclerosis progression

Background: Gene–environment interactions between smoking and HLA genotypes have been reported in multiple sclerosis (MS) susceptibility, although their relevance beyond disease onset remains unclear. Objectives: To examine whether the effect of smoking on disability progression differs according to HLA-A*02:01 and HLA-DRB1*15:01 status. Methods: Patients from two population-based case–control cohorts were classified by smoking status at diagnosis and by HLA-A*02:01 and HLA-DRB1*15:01 status and were followed for up to 15 years through the Swedish MS registry ( n = 6807). Cox regression models were used to estimate hazard ratios (HRs) with 95% confidence intervals (CIs) for 24-week confirmed disability worsening (CDW) and time to Expanded Disability Status Scale (EDSS) 3, 4, and 6. Interaction was assessed on the additive scale. Results: Compared with HLA-A*02:01 -positive non-smokers, smoking at diagnosis was associated with a higher risk of disability progression primarily among individuals who lacked HLA-A*02:01 , with consistently elevated risks of CDW (HR = 1.15, 95% CI = 1.06–1.26), EDSS 3 (HR = 1.26, 95% CI = 1.08–1.47), and EDSS 4 (HR = 1.50, 95% CI = 1.25–1.79). No clear effect of smoking was observed among HLA-A*02:01 carriers, and no evidence of interaction was detected between smoking and HLA-DRB1*15:01 . Conclusion: These findings suggest that the impact of smoking on MS progression varies according to immunogenetic background.