Polymorphisms of the tumour necrosis factor α gene at position - 308 and TNFd microsatellite in primary IgA nephropathy

Abstract

Background. The development of glomerular inflammation in immunoglobulin A nephropathy (IgAN) has been associated with various cytokines, including tumour necrosis factor α (TNFα). A biallelic polymorphism in the promoter region of the TNFα gene (TNFA), at position -308, has been described (TNFA-1 and TNFA-2) and is associated with increased TNFα production for the TNFA-2 allele. Another microsatellite polymorphism has been described for TNFd, which is functional and associated with increased production of TNFα for the d3 allele. Methods. We have studied these two polymorphisms in 242 Caucasian patients with biopsy-proven IgAN (169 male, 73 female), who were followed from 1990 to 1999, and in 210 appropriate local Caucasian controls (133 male, 77 female) for comparison of genotypes and allelic distribution. Results. The respective frequencies of A1/A1, A1/A2 and A2/A2 TNFA genotypes were 76.4, 22.3 and 1.3% in IgAN vs 78.1, 19.5 and 2.4% in controls (P = NS). For TNFd, the frequencies of the respective genotypes d3/d3, d3/non-d3 and non-d3/non-d3 were significantly different (X2 = 12.30, P = 0.002, Pc = 0.013) with an increased frequency of the low-producer genotype non-d3/non-d3 in IgAN patients (24 vs 12%). The combination of TNFA and TNFd polymorphisms demonstrated that compared with controls, patients with non-A2 and non-d3 alleles (low producers) were more common (18 vs 9%; P = 0.006). In the genotype/clinical phenotype correlations, we could not demonstrate significant differences between the different subgroups of patients. However, high-producer TNFα patients (A2 and d3 alleles) had more chronic renal failure than others (36.6 vs 22.9%) at last follow-up and their survival without chronic renal failure (Kaplan-Meier) was lower. Nevertheless, TNFα polymorphisms were not an independent risk factor for the progression of the disease. Conclusions. TNFA and TNFd polymorphisms seem to influence the occurrence or initiation of the disease, but do not play a significant role, if any, in the progression of IgA nephritis.