Association between TNFSF13 SNPs and progression to end-stage renal disease in IgA nephropathy patients

IgA nephropathy (IgAN) is a leading cause of end-stage renal disease (ESRD) and exhibits considerable variability in disease progression. Genetic factors that influence disease progression remain poorly understood.

This was a retrospective nested case-control study conducted within a cohort of 312 biopsy-confirmed IgAN patients who were followed up at The Second Hospital of Jiaxing. Patients who progressed to ESRD (n = 56) were matched with non-progressors (n = 112) based on age, sex, and disease duration. Genotyping for tumor necrosis factor ligand superfamily member 13 (TNFSF13) single nucleotide polymorphisms (SNPs) was performed using TaqMan assays, and TNFSF13 mRNA expression was measured by quantitative real-time PCR. Multivariable Firth penalized likelihood logistic regression was used to assess associations between SNPs and progression to ESRD.

Among the four TNFSF13 single nucleotide polymorphisms SNPs, only rs3803800 was significantly associated with ESRD progression. Carriers of the A allele (AG/AA) had a 2.6-fold higher risk of progression than GG homozygotes (OR = 2.902, 95% CI 1.012-8.684, P = 0.048). In addition, A-allele carriers exhibited lower baseline eGFR (55.84 ± 7.45 vs. 60.98 ± 6.13 mL/min/1.73m², P = 0.020), higher serum IgA levels (2.93 ± 0.74 vs. 1.90 ± 0.76 g/L, P < 0.001), and elevated TNFSF13 mRNA expression in the progression group, while plasma soluble APRIL levels did not differ between carriers and non-carriers.

The rs3803800 A allele may be an independent genetic risk factor for ESRD progression in IgAN, associated with lower baseline eGFR and higher serum IgA levels. These findings suggest that TNFSF13 genetic variants, particularly rs3803800, may influence IgAN progression through dysregulated IgA-mediated immune responses, providing a basis for future research on targeted therapies for IgAN.