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.