Rare Gain‐of‐Function Variants in <scp> <i>IDH1</i> </scp> and <scp> <i>IDH2</i> </scp> Confer Increased Risk of Immune‐Mediated Rheumatic Diseases

OBJECTIVE: Gain-of-function variants in IDH1 and IDH2 are enriched among individuals with coexisting myeloid neoplasms and autoimmune diseases. However, the association between IDH1/IDH2 variants and rheumatic diseases independent of hematologic neoplasms remains unclear. We investigated the association between rare gain-of-function and loss-of-function genetic variants in IDH1 and IDH2 and immune-mediated rheumatic diseases. METHODS: Individuals with gain-of-function and loss-of-function variants in IDH1/IDH2 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 IDH1 or IDH2 variants by age, sex, and ancestry. The frequency of immune-mediated rheumatic diseases in the presence and absence of IDH1/IDH2 variants was compared using chi-square or Fisher exact tests. RESULTS: ), predominantly rheumatoid arthritis. There was no association between loss-of-function variants in IDH1/IDH2 and immune-mediated rheumatic diseases in either cohort. CONCLUSION: Rare gain-of-function variants in IDH1/IDH2 are associated with increased risk of immune-mediated rheumatic diseases, particularly rheumatoid arthritis and polymyalgia rheumatica.