Assessing the causality of IFN-γ and IFN-γ receptor 1/2 with systemic lupus erythematosus risk using genetic data

Background The interferon-gamma (IFN-γ) signaling pathway is activated in Systemic lupus erythematosus (SLE). This study aims to assess the causal association between IFN-γ, IFN-γR1, and IFN-γR2 and SLE within a bidirectional Mendelian-randomization design. Methods Genetic instruments of exposure to IFN-γ, IFN-γR1, and IFN-γR2 were derived from the large genome-wide association study (GWAS), including 3,301 sample size. Instrumental variables for SLE were selected from another independent GWAS analysis comprising 7,219 cases and 15,991 controls with European ancestry. Bi-directional two-sample MR was performed using inverse variance weighting (IVW), MR-Egger regression, and weighted median methods. A series of sensitivity analyses were conducted to assess the robustness of the results. Results The IVW showed IFN-γ had a positive causal association with the risk of SLE [OR 1.24 (95% CI 0.85, 2.26), P = 0.018]. IFN-γR2 was found to have a negative correlation with the onset of SLE [OR 0.85 (95% CI 0.73, 0.99), P = 0.034]. However, no genetic association was detected between IFN-γR1 and SLE [OR 0.97 (95% CI 0.79, 1.19), P = 0.768]. Evidence from bidirectional MR did not support reverse causality. Weighted median regression also showed directionally similar estimates. Conclusion Higher levels of IFN-γ or lower levels of IFN-γR2 are significantly associated with an increased risk of SLE, providing insights into the pathogenesis of SLE.