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

Background::The interferon-γ (IFN-γ) signaling pathway is activated in systemic lupus erythematosus (SLE). This study aimed to assess the causal association between IFN-γ, IFN-γ receptor 1 (IFN-γR1), and IFN-γR2 and SLE using a bidirectional Mendelian randomization (MR) design.Methods::Genetic instruments for exposure to IFN-γ, IFN-γR1, and IFN-γR2 were derived from a large genome-wide association study (GWAS) that included a sample size of 3301 participants. Instrumental variables for SLE were selected from another independent GWAS analysis comprising 5201 cases and 6099 controls with European ancestry. Bidirectional two-sample MR was performed using inverse variance weighting, MR-Egger regression, and weighted median methods. A series of sensitivity analyses were conducted to assess the robustness of the results.Results::The inverse variance weighting showed that IFN-γ had a positive causal association with the risk of SLE (odd ratio [OR] = 1.24, 95% confidence interval [CI]: 1.03–1.47, p = 0.018). IFN-γR2 levels were not associated with SLE risk after adjustment for multiple comparisons (OR= 0.85, 95% CI: 0.73–0.99, p= 0.034). No genetic association was also 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. The weighted median regression also showed directionally similar estimates. Conclusion::Higher levels of IFN-γ are significantly associated with an increased risk of SLE, providing insights into the pathogenesis of SLE.