Genetic modification of obesity-associated disability progression in multiple sclerosis.

BACKGROUND: Obesity has been associated with adverse outcomes in multiple sclerosis (MS), but whether its influence on disability progression differs according to immunogenetic background remains unclear. We investigated whether associations between obesity at diagnosis and subsequent disability progression vary by HLA-A*02:01 status. METHODS: Using data from two Swedish population-based case-control studies, we included 2117 individuals with MS, disease duration ≤5 years at study inclusion, and available HLA genotyping. Obesity was defined as body mass index (BMI) >30 kg/m2. Participants were followed through the Swedish MS registry for confirmed disability worsening (CDW), time to Expanded Disability Status Scale (EDSS) 3 and 4, and longitudinal Expanded Disability Status Scale (EDSS) trajectories. Hazard ratios (HRs) were estimated using adjusted Cox regression models, and mixed-effects models were used to evaluate disability trajectories over time. RESULTS: Among individuals lacking HLA-A*02:01, obesity was associated with an increased risk of CDW (HR 1.49, 95% CI 1.12-1.82), EDSS 3 (HR 1.90, 95% CI 1.30-2.79), and EDSS 4 (HR 2.30, 95% CI 1.33-3.73). No corresponding associations were observed among HLA-A02:01-positive individuals. Analyses treating BMI as a continuous variable yielded similar findings. Additive interaction analyses further supported a joint effect of obesity and absence of HLA-A*02:01 on disability progression. Longitudinal models demonstrated the highest predicted EDSS trajectories among obese HLA-A*02:01-negative individuals. CONCLUSIONS: Obesity at diagnosis was associated with worse disability outcomes primarily among individuals lacking HLA-A*02:01, suggesting that HLA class I-related immune pathways may modify the influence of excess adiposity on MS disease progression.