Unraveling the inflammatory bridge: genomic evidence identifies TNFRSF9 as a potential biomarker linking Sjögren’s syndrome to total risk non-Hodgkin lymphoma

Background
Patients with Sjögren’s syndrome (SS) are at significantly increased risk of developing non-Hodgkin lymphoma (NHL). However, effective biomarkers to identify the subgroup of SS patients who will progress to lymphoma are currently lacking. This study aims to elucidate the causal mechanisms linking SS to NHL and to identify circulating inflammatory protein biomarkers for risk stratification.

Methods
Employing a Mendelian randomization framework and leveraging summary data from large-scale genome-wide association studies, we systematically evaluated the causal effect of SS on NHL (total effect) and the potential mediating roles of 91 circulating inflammatory proteins. The analysis comprised three core steps: total effect assessment, mediator screening, and validation.

Results
Genetic evidence confirms that SS is a causal risk factor for NHL (OR = 1.400, 95% CI 1.012–1.938). Among the 91 candidate proteins, 14 showed a causal association with SS. Further validation, however, identified tumor necrosis factor receptor superfamily member 9 (TNFRSF9) as the sole protein that was both significantly upregulated by SS and independently capable of increasing NHL risk (OR = 1.797, 95% CI 1.087–2.970). Mediation analysis quantified its clinical relevance: TNFRSF9 mediates approximately 18% of the SS-associated lymphoma risk.

Conclusion
This study not only establishes a causal relationship between SS and NHL but, more importantly, identifies circulating TNFRSF9 as a key functional biomarker linking autoimmunity to lymphomagenesis. This finding suggests that circulating TNFRSF9 levels emerge as a candidate biomarker worthy of further investigation. Future prospective clinical studies are needed to correlate serum TNFRSF9 levels with lymphoma development.