Transforming growth factor-beta (TGF-beta1) genotype and lung allograft fibrosis.
BACKGROUND
TGF-beta1 is a prosclerotic cytokine implicated in fibrotic processes. Fibrosis of the pulmonary parenchyma and airways is a frequent presentation in lung transplant recipients before and after transplantation. There are two genetic polymorphisms in the DNA sequence encoding the leader sequence of the TGF-beta1 protein, located at codon 10 (either leucine or proline) and at codon 25 (either arginine or proline). The codon 25 arginine allele is associated with higher TGF-beta1 production by cells activated in vitro. We tested the hypothesis that inheritance of alleles of the TGF-beta1 gene conferring higher production of TGF-beta1 may be responsible for over-expression of TGF-beta1 in transplant recipients resulting in lung allograft fibrosis.


METHODS
We extracted DNA from leukocytes collected from 91 pulmonary transplants performed at our centre and 96 normal healthy volunteers between May 1990 and September 1995. Part of the first exon was amplified by PCR. Samples were genotyped by using sequence specific oligonucleotide probes.


RESULTS
The distribution of codon 10 alleles was similar in a normal healthy control group and in lung transplant recipients, regardless of their pretransplant lung pathology. By contrast, there was a significant difference in the frequency of codon 25 alleles between the control and transplant groups. In the normal control group 81% were codon 25 arginine/arginine (A/A) homozygotes, 19% were arginine/proline (A/P) heterozygotes and none were proline/proline (P/P) homozygotes. The distribution of codon 25 alleles was similar in lung transplant recipients who did not have a significant fibrosis in pretransplant pathology, but in transplant recipients who came to transplantation with lung fibrosis 98% (41 of 42 patients) were homozygous for the codon 25 A/A allele (p < .05). After lung transplantation 39 of 91 patients developed lung allograft fibrosis, and of these 92.3% (36 of 39 recipients) were of homozygous codon 25 A/A high TGF-beta1 producer genotype (p < .001). Lung transplant recipients who were homozygous for both codon 10 L/L and codon 25 A/A showed poor survival compared with all other TGF-beta1 genotypes (p < .03).


CONCLUSIONS
Homozygosity for arginine at codon 25 of the leader sequence of TGF-beta1 that correlates with higher TGF-b production in vitro, is associated with fibrotic lung pathology before lung transplantation and with the development of fibrosis in the graft. In combination with the codon 10 leucine allele, homozygosity for the codon 25arginine allele is a marker for poor post-transplant prognosis and recipient survival.
Cardiothoracic Transplant Unit, Wythenshawe Hospital Manchester, UK.
A
A
El-Gamel
M R
MR
Awad
P S
PS
Hasleton
N A
NA
Yonan
J A
JA
Hutchinson
C S
CS
Campbell
A H
AH
Rahman
A K
AK
Deiraniya
P J
PJ
Sinnott
I V
IV
Hutchinson
D000293:Adolescent; D000328:Adult; D000483:Alleles; D000595:Amino Acid Sequence / Q000235:genetics; D003062:Codon; D005091:Exons; D005260:Female; D005786:Gene Expression Regulation / Q000502:physiology; D005838:Genotype; D006084:Graft Rejection / Q000235:genetics* / Q000401:mortality / Q000473:pathology; D006801:Humans; D008168:Lung / Q000473:pathology; D016040:Lung Transplantation / Q000473:pathology*; D008297:Male; D008875:Middle Aged; D015345:Oligonucleotide Probes; D016133:Polymerase Chain Reaction; D011401:Promoter Regions, Genetic; D011658:Pulmonary Fibrosis / Q000235:genetics* / Q000401:mortality / Q000473:pathology; D012016:Reference Values; D015996:Survival Rate; D016212:Transforming Growth Factor beta / Q000235:genetics*
D003062:Codon; D015345:Oligonucleotide Probes; D016212:Transforming Growth Factor beta