Integration of single-cell cis-expression quantitative trait locus and Mendelian randomization analyses identifies a...

ObjectiveArthritis, including rheumatoid arthritis, gonarthrosis, and gouty arthritis, poses a substantial public health challenge. Regulatory T cells are critical for immune homeostasis, and their dysfunction contributes to arthritis pathogenesis; however, the specific gene regulatory programs causally influencing disease susceptibility remain elusive. We aimed to identify regulatory T cell-specific therapeutic targets using single-cell cis-expression quantitative trait locus and Mendelian randomization.MethodsWe integrated single-cell regulatory T cell cis-expression quantitative trait locus data with genome-wide association study results from FinnGen R12 (16,314 rheumatoid arthritis, 61,356 gonarthrosis, and 12,342 gouty arthritis cases). Two-sample Mendelian randomization was employed to infer causality, using the inverse-variance weighted method, with rigorous sensitivity analyses conducted to ensure robustness.ResultsThe analysis revealed distinct causal associations. In rheumatoid arthritis, upregulation of DexD/H-box helicase 60 like (DDX60L) significantly increased the disease risk (odds ratio = 2.10), whereas OAS1 expression served as a protective factor (odds ratio = 0.65). For gonarthrosis, OAS1 again demonstrated a protective effect (odds ratio = 0.897), whereas janus kinase and microtubule interacting protein 2 (JAKMIP2) was identified as a modest risk factor (odds ratio = 1.019). Conversely, no significant regulatory T cell-specific causal signals were observed for gouty arthritis.ConclusionsOAS1 is a cross-disease regulatory T cell protector, whereas DDX60L and JAKMIP2 are disease-specific risk amplifiers. Engineering high-OAS1/low-DDX60L/low-JAKMIP2 regulatory T cells offers a genetically grounded blueprint for rheumatoid arthritis and gonarthrosis but not for gouty arthritis.