Original Articles
Transforming growth factor-beta (TGF-β1) genotype and lung allograft fibrosis

Paper presented in the ISHLT 17th Annual Meeting, April 2–5th, 1997, London, UK.
https://doi.org/10.1016/S1053-2498(98)00024-2Get rights and content

Abstract

Background

TGF-β1 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-β1 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-β1 production by cells activated in vitro. We tested the hypothesis that inheritance of alleles of the TGF-β1 gene conferring higher production of TGF-β1 may be responsible for over-expression of TGF-β1 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-β1 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-β1 genotypes (p < .03).

Conclusions

Homozygosity for arginine at codon 25 of the leader sequence of TGF-β1, 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 25 arginine allele is a marker for poor post-transplant prognosis and recipient survival.

Section snippets

Patients and specimens

Biopsy specimens from 91 consecutive lung transplant performed in the Wythenshawe Lung Transplant Program between January 1990 and March 1996 were analysed. Patient demographics and surgical procedures are summarised in Table I. A total of 780 transbronchial biopsies from all the recipients were reviewed to classify and score rejection, infection and lung fibrosis. For genotype analysis a blood sample was obtained from each patient and, for comparison, blood samples were collected from 96

TGF-β1 gene polymorphism in patients and normal controls

Patients’ demographics, mortality and type of procedure are summarised in Table 1. We have identified 2 polymorphisms in the leader sequence of TGF-β1 gene, located at codon 10 (amino acid +10) and codon 25 (amino acid +25). At codon 10 there are two alternatives either leucine (L) and proline (P). The distribution of codon 10 alleles was similar in the lung transplant recipients regardless of pretransplant pathology, with the exception of the cystic fibrosis patients who showed a trend towards

Discussion

Lung allografts are usually exposed to multiple injuries as a result of ischaemia and reperfusion, acute rejection or infection, which may damage either pulmonary epithelium or capillary endothelium. Lesions are focal and homogeneous or generalised in distribution. Leakage of serum proteins, inflammatory cells and platelets into the interstitial and alveolar space is apparent several hours after injury.11 Marked increases in total DNA content soon after injury reflect dramatic increases in

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