Rare Gain-of-Function Variants in IDH1 and IDH2 Confer Increased Risk of Immune-Mediated Rheumatic Diseases

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.

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.

Fifty-five individuals with IDH1 or IDH2 gain-of-function variants without pre-existing hematologic neoplasms were identified in the UK Biobank. These individuals had a significantly higher frequency of incident immune-mediated rheumatic diseases compared to matched controls (11 of 55 [20%] vs 20 of 550 [4%], odds ratio [OR] = 6.6, P = 2.7 × 10^-5), mainly polymyalgia rheumatica (6 of 11) and rheumatoid arthritis (5 of 11). Replication in the All of Us cohort identified 65 individuals with gain-of-function variants and confirmed an increased odds of incident immune-mediated rheumatic diseases compared to controls (OR = 7.7, P < 5 × 10^-4), predominantly rheumatoid arthritis. There was no association between loss-of-function variants in IDH1/IDH2 and immune-mediated rheumatic diseases in either cohort.

Rare gain-of-function variants in IDH1/IDH2 are associated with increased risk of immune-mediated rheumatic diseases, particularly rheumatoid arthritis and polymyalgia rheumatica.