Abstract

Background: Sjogren's Syndrome (SS) is a complex autoimmune disease influenced by genetics, yet its genetic underpinnings remain elusive. This study investigates the genetic correlation and potential causative link between cytokine cycling levels and SS.

Methods: Genome-Wide Association Studies (GWAS) were conducted with 8,293 and 14,824 European participants to identify cytokines. The GWAS dataset for SS, comprising 368,028 individuals of European ancestry (2,495 cases and 365,533 controls), was sourced from the Finnish biological sample library. Single Nucleotide Polymorphisms (SNPs) associated with SS were identified using Linkage Disequilibrium Score (LDSC) regression for Mendelian Randomization (MR) analysis. The Inverse Variance Weighted (IVW) method was the primary analytical approach. Additional methods including MR Egger, weighted median, and weighted mode were employed for robustness assessment. Heterogeneity testing, horizontal pleiotropy testing and steiger testing were conducted for sensitivity analysis. Reverse MR analysis was performed to assess the potential for a reverse causal relationship between SS and cytokines.

Results: LDSC regression analysis identified 46 cytokines for bidirectional MR analysis with SS. The IVW method revealed significant associations of genetically predicted cytokines IL10RB (P=0.019, OR=1.138, 95% CI: 1.021-1.267) and CXCL11 (P=0.015, OR=1.269, 95% CI: 1.048-1.537) with increased SS risk. The absence of heterogeneity and horizontal pleiotropy in sensitivity analysis underscores the robustness of these findings.

Conclusion: The study suggests a potential causal relationship between genetically predicted cytokines and SS, particularly through IL10RB and CXCL11 cycles. Further research is warranted to elucidate the biological mechanisms by which cytokine cycling levels influence SS.

Keywords: Cytokines; Sjogren's syndrome; Mendelian randomization; Bidirectional; Linkage disequilibrium score regression analysis