A Functional TNFRSF13B Variant Disrupts B-Cell Enhancer Activity and Increases Susceptibility to EBV-Negative...

Background: The TNFRSF13B gene encodes TACI, a key regulator of B-cell survival and immune homeostasis. While variants in this gene are linked to immunodeficiency, their role in lymphoma development remains unclear. This study investigated whether the TNFRSF13B polymorphism rs4792800 (A>G) influences lymphoma risk.

We conducted a hospital-based case-control study including 200 histologically confirmed lymphoma patients and 119 healthy controls. Genotyping for rs4792800 was performed using allele-specific PCR. Logistic regression, adjusted for age and sex, calculated odds ratios (ORs) and 95% confidence intervals (CIs). Stratified analyses were performed by lymphoma subtype, cell lineage, and EBV status. Multiple testing was corrected using the false discovery rate (FDR). In silico analyses assessed regulatory potential and transcription factor binding. Results The G allele was significantly overrepresented in lymphoma cases versus controls (51.8% vs. 42.0%; allelic OR = 1.48, 95% CI 1.07-2.06, p = 0.018, q = 0.036). Under a recessive model, the GG genotype was associated with a 1.9-fold increased risk (95% CI 1.06-3.43, p = 0.031, q = 0.042). Subtype analysis revealed strong associations for diffuse large B-cell lymphoma (OR = 2.32, 95% CI 1.21-4.47, q = 0.036) and, exploratorily, for T-cell lymphoma (OR = 3.16, 95% CI 1.12-8.90, q = 0.087). The risk was significant in EBV-negative patients (OR = 1.99, q = 0.049) but not in the smaller EBV-positive subgroup. In silico analysis showed that rs4792800 resides within a B-cell-specific enhancer; the G allele disrupts an EBF1 binding motif (25.6% loss) while enhancing PAX5 binding (17.9% gain), predicting reduced TNFRSF13B expression and decreased TACI protein. Conclusion The rs4792800 GG genotype is associated with increased lymphoma risk, particularly in DLBCL and EBV-negative disease. These findings suggest that inherited variation impairing TACI-mediated immune surveillance contributes to lymphomagenesis independently of viral oncogenesis, though the T-cell lymphoma association requires validation.