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 development of renal dysfunction due to cyclosporine nephrotoxicity, we analyzed 2 polymorphisms in the signal sequence of the transforming growth factor (TGF)-beta 1 gene; codon 10 (Leu(10) --> Pro) and codon 25 (Arg(25) --> Pro).


METHODS
Using sequence specific oligonucleotide probing, we analyzed both TGF-beta1 gene polymorphisms in cardiac allograft recipients (n = 168) who survived at least 1 year with minimal follow-up of 7 years. Patients received cyclosporine and steroids as maintenance immunosuppressive therapy. Renal dysfunction was defined as a serum creatinine > or = 250 micromol/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 TGF-beta1 codon 10 were 7% Pro/Pro, 61% Pro/Leu, and 32% Leu/Leu, and for codon 25 these percentages were 1% Pro/Pro, 12% Pro/Arg, and 87% Arg/Arg. We found an association between the TGF-beta 1 genotype encoding proline at codon 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-beta1 codon 25 genotypes, we found no association between TGF-beta 1 genotypes and renal dysfunction.


CONCLUSIONS
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.
Baan
C C
CC
Department of Internal Medicine, University Hospital Rotterdam-Dijkzigt, Rotterdam, The Netherlands. baan@inw1.azr.nl
Balk
A H
AH
Holweg
C T
CT
van Riemsdijk
I C
IC
Maat
L P
LP
Vantrimpont
P J
PJ
Niesters
H G
HG
Weimar
W
W
D000328:Adult; D016572:Cyclosporine / Q000009:adverse effects*; D005260:Female; D005838:Genotype; D016027:Heart Transplantation / Q000276:immunology; D006801:Humans; D007166:Immunosuppressive Agents / Q000009:adverse effects*; D007930:Leucine; D008297:Male; D008875:Middle Aged; D011110:Polymorphism, Genetic; D011392:Proline; D051437:Renal Insufficiency / Q000139:chemically induced* / Q000235:genetics*; D017422:Sequence Analysis, DNA; D016212:Transforming Growth Factor beta / Q000737:chemistry / Q000235:genetics*
D007166:Immunosuppressive Agents; D016212:Transforming Growth Factor beta; D016572:Cyclosporine; D011392:Proline; D007930:Leucine