{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,22]],"date-time":"2026-05-22T10:05:38Z","timestamp":1779444338754,"version":"3.53.1"},"reference-count":21,"publisher":"Wiley","issue":"4","license":[{"start":{"date-parts":[[2026,4,5]],"date-time":"2026-04-05T00:00:00Z","timestamp":1775347200000},"content-version":"vor","delay-in-days":4,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"},{"start":{"date-parts":[[2026,4,1]],"date-time":"2026-04-01T00:00:00Z","timestamp":1775001600000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"funder":[{"DOI":"10.13039\/100006260","name":"Rheumatology Research Foundation","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100006260","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["acrjournals.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["ACR Open Rheumatology"],"published-print":{"date-parts":[[2026,4]]},"abstract":"\n Objective<\/jats:title>\n \n Gain\u2010of\u2010function variants in\n IDH1<\/jats:italic>\n and\n IDH2<\/jats:italic>\n are enriched among individuals with coexisting myeloid neoplasms and autoimmune diseases. However, the association between\n IDH1<\/jats:italic>\n \/\n IDH2<\/jats:italic>\n variants and rheumatic diseases independent of hematologic neoplasms remains unclear. We investigated the association between rare gain\u2010of\u2010function and loss\u2010of\u2010function genetic variants in\n IDH1<\/jats:italic>\n and\n IDH2<\/jats:italic>\n and immune\u2010mediated rheumatic diseases.\n <\/jats:p>\n <\/jats:sec>\n \n Methods<\/jats:title>\n \n Individuals with gain\u2010of\u2010function and loss\u2010of\u2010function variants in\n IDH1\/IDH2<\/jats:italic>\n were identified by whole genome sequencing in the UK Biobank and the All of Us Research Program. These individuals were matched 1:10 to controls without\n IDH1<\/jats:italic>\n or\n IDH2<\/jats:italic>\n variants by age, sex, and ancestry. The frequency of immune\u2010mediated rheumatic diseases in the presence and absence of\n IDH1\/IDH2<\/jats:italic>\n variants was compared using chi\u2010square or Fisher exact tests.\n <\/jats:p>\n <\/jats:sec>\n \n Results<\/jats:title>\n \n Fifty\u2010five individuals with\n IDH1<\/jats:italic>\n or\n IDH2<\/jats:italic>\n gain\u2010of\u2010function variants without pre\u2010existing hematologic neoplasms were identified in the UK Biobank. These individuals had a significantly higher frequency of incident immune\u2010mediated rheumatic diseases compared to matched controls (11 of 55 [20%] vs 20 of 550 [4%], odds ratio [OR]\u00a0=\u00a06.6,\n P<\/jats:italic>\n \u00a0=\u00a02.7\u2009\u00d7\u200910\n \u22125<\/jats:sup>\n ), mainly polymyalgia rheumatica (6 of 11) and rheumatoid arthritis (5 of 11). Replication in the All of Us cohort identified 65 individuals with gain\u2010of\u2010function variants and confirmed an increased odds of incident immune\u2010mediated rheumatic diseases compared to controls (OR\u00a0=\u00a07.7,\n P<\/jats:italic>\n \u2009<\u20095\u2009\u00d7\u200910\n \u22124<\/jats:sup>\n ), predominantly rheumatoid arthritis. There was no association between loss\u2010of\u2010function variants in\n IDH1\/IDH2<\/jats:italic>\n and immune\u2010mediated rheumatic diseases in either cohort.\n <\/jats:p>\n <\/jats:sec>\n \n Conclusion<\/jats:title>\n \n Rare gain\u2010of\u2010function variants in\n IDH1<\/jats:italic>\n \/\n IDH2<\/jats:italic>\n are associated with increased risk of immune\u2010mediated rheumatic diseases, particularly rheumatoid arthritis and polymyalgia rheumatica.\n <\/jats:p>\n \n \n \n image<\/jats:alt-text>\n <\/jats:graphic>\n <\/jats:boxed-text>\n <\/jats:p>\n <\/jats:sec>","DOI":"10.1002\/acr2.90034","type":"journal-article","created":{"date-parts":[[2026,4,5]],"date-time":"2026-04-05T23:53:55Z","timestamp":1775433235000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Rare Gain\u2010of\u2010Function Variants in\n \n IDH1<\/i>\n <\/scp>\n and\n \n IDH2<\/i>\n <\/scp>\n Confer Increased Risk of Immune\u2010Mediated Rheumatic Diseases"],"prefix":"10.1002","volume":"8","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-0074-3659","authenticated-orcid":false,"given":"Mahmut S.","family":"Kaymakci","sequence":"first","affiliation":[{"name":"Department of Medicine University of Pittsburgh Medical Center Pittsburgh Pennsylvania"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mehmet","family":"Hocao\u011flu","sequence":"additional","affiliation":[{"name":"Division of Rheumatology and Clinical Immunology, Department of Medicine University of Pittsburgh Medical Center Pittsburgh Pennsylvania"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kenneth J.","family":"Warrington","sequence":"additional","affiliation":[{"name":"Division of Rheumatology, Department of Medicine Mayo Clinic Rochester Minnesota"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3884-962X","authenticated-orcid":false,"given":"Amr H.","family":"Sawalha","sequence":"additional","affiliation":[{"name":"Departments of Pediatrics, Medicine, and Immunology University of Pittsburgh School of Medicine Pittsburgh Pennsylvania"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2026,4,5]]},"reference":[{"key":"e_1_2_7_2_1","doi-asserted-by":"publisher","DOI":"10.1126\/sciadv.aaw4543"},{"key":"e_1_2_7_3_1","doi-asserted-by":"publisher","DOI":"10.1038\/leu.2016.275"},{"key":"e_1_2_7_4_1","doi-asserted-by":"publisher","DOI":"10.1038\/nature10860"},{"key":"e_1_2_7_5_1","doi-asserted-by":"publisher","DOI":"10.1182\/blood.2023023593"},{"key":"e_1_2_7_6_1","first-page":"2214","article-title":"A practical approach to curate clonal hematopoiesis of indeterminate potential in human genetic data sets","volume":"141","author":"Vlasschaert 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Rheumatology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/acrjournals.onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/acr2.90034","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/acrjournals.onlinelibrary.wiley.com\/doi\/full-xml\/10.1002\/acr2.90034","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/acrjournals.onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/acr2.90034","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,5,22]],"date-time":"2026-05-22T09:25:07Z","timestamp":1779441907000},"score":1,"resource":{"primary":{"URL":"https:\/\/acrjournals.onlinelibrary.wiley.com\/doi\/10.1002\/acr2.90034"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,4]]},"references-count":21,"journal-issue":{"issue":"4","published-print":{"date-parts":[[2026,4]]}},"alternative-id":["10.1002\/acr2.90034"],"URL":"https:\/\/doi.org\/10.1002\/acr2.90034","archive":["Portico"],"relation":{},"ISSN":["2578-5745","2578-5745"],"issn-type":[{"value":"2578-5745","type":"print"},{"value":"2578-5745","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,4]]},"assertion":[{"value":"2026-01-10","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication 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