Renal failure after clinical heart transplantation is associated with the TGF-beta 1 codon 10 gene polymorphism

Background: To determine whether genetic factors are involved in the develo pment of renal dysfunction due to cyclosporine nephrotoxicity, we analyzed 2 polymorphisms in the signal sequence of the transforming growth factor (T GF)-beta 1 gene; codon 10 (Leu(10) --> Pro) and codon 25 (Arg(25) --> Pro). Method: Using sequence specific oligonucleotide probing, we analyzed both T OP-beta 1 gene polymorphisms in cardiac allograft recipients (n = 168) who survived at least 1 year with minimal follow-up of 7 years. Patients receiv ed cyclosporine and steroids as maintenance immunosuppressive therapy. Rena l dysfunction was defined as a serum creatinine greater than or equal to 25 0 mu mol/liter. Results: Renal dysfunction was observed in 2% (3/168) of the patients at 1 year, in 7% (11/160) at 3 years, in 12% (18/152) at 5 years, and in 20% (26 /131) at 7 years post-transplantation. The genotypic distributions for TOP- beta 1 codon 10 were 7% Pro/Pro, 61% Pro/Leu, and 32% Leu/Leu, and for codo n 25 these percentages were 1% Pro/Pro, 12% Pro/Arg, and 87% Arg/Arg. We fo und an association between the TGF-beta 1 genotype encoding proline at codo n 10 and renal dysfunction. At 7 years post-transplantation, 26% (23/89) of the patients with the heterozygous Pro/Leu or homozygous Pro/Pro genotype had renal dysfunction vs only 7% (3/42) of the patients with the homozygous Leu/Leu genotype (p = 0.017). For the TGF-beta 1 codon 25 genotypes, we fo und no association between TGF-beta 1 genotypes and renal dysfunction. Conclusion: Our data support the hypothesis that TGF-beta 1 is involved in the process leading to renal insufficiency in cyclosporine-treated cardiac allograft recipients. In these patients the presence of TGF-beta 1 Pro(10) might be a risk factor.