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

• Published in: Rheumatology & autoimmunity (Print) 2024-06, Vol.4 (2), p.109-118
• Main Authors: Chang, Minjing, Yao, Kaixin, Hao, Jiawei, Long, Yinqi, Qiao, Lulin, Zhang, Yaru, Ma, Kexin, He, Peifeng
• Format: Article
• Language: English
• Subjects: interferon‐γ; interferon‐γ receptor; Mendelian randomization; risk factor; single‐nucleotide polymorphism; systemic lupus erythematosus
• ISSN: 2767-1410; 2767-1429
• DOI: 10.1002/rai2.12125

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. This study aims to assess the causal association between Interferon‐γ (IFN‐γ), IFN‐γ receiver α (IFN‐γR1), IFN‐γ receiver β (IFN‐γR2) and Systemic lupus erythematosus (SLE) within a bidirectional Mendelian‐randomization design. Bidirectional 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. Our study provides new insights into the role of IFN‐γ, IFN‐γR1, and IFN‐γR2 in the treatment of SLE. Key points Higher levels of interferon (IFN)‐γ are associated with an increased risk of SLE. In contrast, IFN‐γ receptor 1 (IFN‐γR1) and IFN‐γ receptor 2 (IFN‐γR2) levels were not causally related to SLE risk. This shows that IFN‐γ plays an important role in SLE, and inhibition of IFN‐γ levels plays a potential role in the treatment of SLE. IFN‐γR, mainly IFNγR2, plays a role in SLE and IFN‐γR2 is a pote