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. Key Points • First genetic evidence establishing a causal link between Sjögren's syndrome and increased risk of non-Hodgkin lymphoma using Mendelian randomization. • TNFRSF9 is identified as a key inflammatory mediator, upregulated by Sjögren's syndrome and independently driving lymphoma risk. • Mediation analysis quantifies that TNFRSF9 accounts for approximately 18% of the total causal effect of Sjögren's syndrome on lymphoma. • A novel biomarker and potential therapeutic target, circulating TNFRSF9 may enable risk stratification in Sjögren's syndrome patients.