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Although HLA DRB1*15:01 represents the strongest genetic risk factor for MS susceptibility, conferring approximately threefold increased risk, whether this allele similarly influences disease progression remains contentious.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>This systematic review was conducted to clarify the relationship between HLA polymorphisms and the course of multiple sclerosis from inception through November 2025. A three-level random effects meta-analysis was used to account for statistical non-independence. Study quality was evaluated using Q GENIE criteria.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      In total, 56 eligible studies were selected, comprising 22,145 participants; 35 studies contributed 276 effect sizes to quantitative synthesis. The pooled estimate indicated a modest overall association between HLA variants and MS progression (Odds Ratio (OR) 1.30, 95% CI 1.09 to 1.55,\n                      <jats:italic>p<\/jats:italic>\n                      \u2009=\u20090.003). HLA DRB1*15 showed no significant association with disease progression (OR 1.10, 95% CI 0.79 to 1.51,\n                      <jats:italic>p<\/jats:italic>\n                      \u2009=\u20090.57). Exploratory subgroup analysis revealed significant regional heterogeneity (QM\u2009=\u200910.48,\n                      <jats:italic>p<\/jats:italic>\n                      \u2009=\u20090.033): Asian (OR 1.70,\n                      <jats:italic>p<\/jats:italic>\n                      \u2009&lt;\u20090.001) and North American (OR 1.95,\n                      <jats:italic>p<\/jats:italic>\n                      \u2009&lt;\u20090.001) studies suggested significant effects, whereas European studies showed no effect (OR 1.02,\n                      <jats:italic>p<\/jats:italic>\n                      \u2009=\u20090.92). Three alleles demonstrated significant adverse associations: HLA DRB1*04 (OR 1.79, 95% CI 1.33 to 2.42), HLA DRB1*09 (OR 4.21, 95% CI 1.93 to 9.18), and HLA DRB1*03 (OR 1.44, 95% CI 1.01 to 2.05).\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>This systematic review suggests that multiple sclerosis susceptibility and progression appear governed by distinct genetic architectures.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1186\/s12883-026-05100-3","type":"journal-article","created":{"date-parts":[[2026,6,24]],"date-time":"2026-06-24T03:05:17Z","timestamp":1782270317000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["The HLA paradox across populations in multiple sclerosis progression: a systematic review"],"prefix":"10.1186","volume":"26","author":[{"given":"Zhila","family":"Maghbooli","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Erfan","family":"Nasir","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fatemeh","family":"Mahdavinasab","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mohammad Ali","family":"Sahraian","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Arash","family":"Shirvani","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,6,24]]},"reference":[{"key":"5100_CR1","doi-asserted-by":"publisher","unstructured":"Walton C, King R, Rechtman L, Kaye W, Leray E, Marrie RA, et al. 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