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We investigated whether associations between obesity at diagnosis and subsequent disability progression vary by HLA-A*02:01 status.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      Using data from two Swedish population-based case\u2013control studies, we included 2117 individuals with MS, disease duration \u22645\u00a0years at study inclusion, and available HLA genotyping. Obesity was defined as body mass index (BMI) &gt;30\u00a0kg\/m\n                      <jats:sup>2<\/jats:sup>\n                      . 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.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>Among individuals lacking HLA-A*02:01, obesity was associated with an increased risk of CDW (HR 1.49, 95% CI 1.12\u20131.82), EDSS 3 (HR 1.90, 95% CI 1.30\u20132.79), and EDSS 4 (HR 2.30, 95% CI 1.33\u20133.73). 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.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>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.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1007\/s00415-026-14091-7","type":"journal-article","created":{"date-parts":[[2026,9,8]],"date-time":"2026-09-08T14:09:37Z","timestamp":1788876577000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Genetic modification of obesity-associated disability progression in multiple sclerosis"],"prefix":"10.1007","volume":"273","author":[{"given":"Jie","family":"Guo","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jing","family":"Wu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tomas","family":"Olsson","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lars","family":"Alfredsson","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6612-4749","authenticated-orcid":false,"given":"Anna Karin","family":"Hedstr\u00f6m","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,9,8]]},"reference":[{"key":"14091_CR1","doi-asserted-by":"publisher","first-page":"25","DOI":"10.1038\/nrneurol.2016.187","volume":"13","author":"T Olsson","year":"2017","unstructured":"Olsson T, Barcellos LF, Alfredsson L (2017) Interactions between genetic, lifestyle and environmental risk factors for multiple sclerosis. 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Participants provided written informed consent.","order":2,"name":"Ethics","label":"Standard Protocol Approvals, Registrations, and Patient Consents","group":{"name":"EthicsHeading","label":"Declarations"}}],"article-number":"578"}}