Genetic Evidence Linking Circulating Epidermal Growth Factor to Sjögren's Syndrome Risk.

Abstract

Background: This study aimed to explore the potential causal correlations between circulating expression levels of six growth factors - epidermal growth factor (EGF), vascular endothelial growth factor (VEGF), fibroblast growth factor (FGF), transforming growth factor-beta (TGF-β), platelet-derived growth factor (PDGF), and nerve growth factor (NGF) - and the risk of developing Sjögren's syndrome (SS), from the perspective of genetic variation, using a Mendelian Randomization (MR) approach.

Methods: Genetic data related to SS and the six growth factors were obtained from the IEU OpenGWAS project [GWAS IDs: "finn-b-M13_SJOGREN" (SS), "ebi-a-GCST90010212" (EGF), "ebi-a-GCST90011995" (VEGF), "ebi-a-GCST004459" (FGF), "ebi-a-GCST90000481" (TGF-β), "ebi-a-GCST004432" (PDGF), and "prot-b-40" (NGF)]. A two-sample MR analysis was conducted to estimate the causal effect of each growth factor on SS risk. Five complementary MR methods were employed to ensure robustness: Inverse Variance Weighted (IVW), MR-Egger, Weighted Median, Simple Mode, and MR-PRESSO. We further assessed heterogeneity and horizontal pleiotropy using Cochran's Q test and MR-Egger intercept, and performed leave-one-out analyses to test the sensitivity and reliability of the results.

Results: The MR analysis provided evidence supporting a causal association between elevated EGF levels and increased SS risk. Both IVW (p = 0.0485, OR [95%] = 1.0696 [1.0004 - 1.1436]) and MR-PRESSO (p = 0.0406, OR [95% CI] = 1.0684 [1.0080 - 1.1325]) yielded statistically significant results. No significant causal associations were observed between SS and the other five growth factors across all MR methods. Sensitivity analyses supported the robustness of the observed association between EGF and SS.

Conclusions: The findings suggest that elevated circulating EGF levels may play a causal role in the development of Sjögren's syndrome, supporting EGF as a potential biomarker for early diagnosis and risk prediction. These results provide novel insights into the pathogenesis of SS and highlight EGF as a potential target for future diag-nostic and therapeutic strategies. Further research is needed to explore the clinical utility of growth factor-targeted approaches for SS prevention and treatment.