Causal relationship between circulating cytokines and the risk of systemic sclerosis: A bidirectional Mendelian-randomization study

Abstract

Abstract Objectives Systemic sclerosis (SSc) is an autoimmune disease characterized by immune dysfunction, vasculopathy, and fibrosis. While cytokines likely contribute to SSc pathogenesis, it is unclear whether particular cytokines play a causal role. We aimed to investigate potential causal relationships between circulating cytokines and SSc using Mendelian randomization. Methods We conducted a bidirectional two-sample Mendelian randomization study using summary data from published genome-wide association studies of SSc (2,313 cases, 15,881 controls) and 43 cytokines (up to 31,781 individuals). Single nucleotide polymorphisms associated with cytokine levels were selected as instruments to proxy genetically determined circulating concentrations. Potential causal relationships between exposures and outcomes were investigated primarily through inverse variance weighted Mendelian randomization analysis. To substantiate the robustness of our findings, we additionally conducted several complementary sensitivity analyses utilizing alternative Mendelian randomization methods, including MR-Egger, weighted median, simple and weighted mode, and MR-PRESSO. Results Among the cytokines analyzed, tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) demonstrated a significant causal association, whereby genetically predicted lower TRAIL levels increased SSc risk. Other circulating cytokines including TGF-β, IL-6, and PDGF, have no causal relationship with SSc. Conclusion Our findings implicate reduced circulating TRAIL level as a potential causal factor in SSc risk, providing novel insights into disease pathogenesis. These findings position TRAIL as a putative upstream regulator in SSc, suggesting modulation of the TRAIL signaling cascade may represent a promising therapeutic approach in SSc.