Association of C-509T and T869C polymorphisms of transforming growth factor-beta1 gene with susceptibility to and progression of IgA nephropathy

Abstract

Aims: Transforming growth factor (TGF)-beta1 is a cytokine with both beneficial anti-inflammatory effects and detrimental profibrotic activity in the pathophysiology and progression of glomerulonephritides. The transcriptional activity of the gene for TGF-beta1 and the plasma levels of TGF-beta1 protein are associated with C-509T polymorphism at the promoter region, and with T869C (Leu 10Pro) polymorphism at codon 10, of the TGF-beta1 gene.

Methods: Using PCR-RFLP and the amplification refractory mutation system PCR, we investigated the C-509T and T869C polymorphisms, respectively, to elucidate whether allele frequency differences exist between IgA nephropathy (IgAN) patients who were followed up for at least 3 years (n = 108) and a normal population (n = 55). We also determined the correlations between the TGF-beta1 polymorphisms and the progression of IgAN.

Results: In C-509T polymorphism, there were significant differences in genotype frequency between IgAN patients and normal controls (CC: CT: TT, 20:29:33 vs. 11:31:13, chi2 = 6.299, p = 0.043). In Kaplan-Meier survival analysis, the patients with TT genotype showed a poorer renal survival than those with CC + CT genotypes (p = 0.042). In T869C polymorphism, there were also significant differences in genotype frequency between IgAN patients and normal controls (TT : TC : CC, 4 : 79 : 25 vs. 0 : 52 : 2, chi2 = 12.552, p = 0.002). The initial serum creatinine (Scr) level was higher in the patients with CC genotype than in those with TT + TC genotypes. In Kaplan-Meier survival analysis, the patients with CC genotype showed a poorer renal survival than those with TT + TC genotypes, but not to a statistically significant extent (p = 0.076). In the combined survival analyses, the high TGF-beta1 producer group showed a poor renal survival rate (p = 0.014).

Conclusion: Compared to normal population, the frequencies of genotypes producing high TGF-beta1 protein were higher in IgAN patients. Moreover, patients with genotypes producing high TGF-beta1 plasma levels showed a poor renal survival rate.