Transforming growth factor-beta (TGF-beta(1)) genotype and lung allograft fibrosis

Background: TGF-beta(1) is a prosclerotic cytokine implicated in fibrotic p rocesses. Fibrosis of the pulmonary parenchyma and airways is a frequent pr esentation in lung transplant recipients before and after transplantation. There are two genetic polymorphisms in the DNA sequence encoding the leader sequence of the TGF-beta(1) protein, located at codon 10 (either leucine o r proline) and at codon 25 (either arginine or proline). The codon 25 argin ine allele is associated with higher TGF-beta(1) production by cells activa ted in vitro. We tested the hypothesis that inheritance of alleles of the T GF-beta(1) gene conferring higher production of TGF-beta(1) may be responsi ble for over-expression of TGF-beta(1) in transplant recipients resulting i n lung allograft fibrosis. Methods: We extracted DNA from leukocytes collected from 91 pulmonary trans plants performed at our centre and 96 normal healthy volunteers between May 1990 and September 1995. Part of the first exon was amplified by PCR. Samp les were genotyped by using sequence specific oligonucleotide probes. Results: The distribution of codon 10 alleles was similar in a normal healt hy control group and in lung transplant recipients, regardless of their pre transplant lung pathology. By contrast, there was a significant difference in the frequency of codon 25 alleles between the control and transplant gro ups. In the normal control group 81% were codon 25 arginine/arginine (A/A) homozygotes, 19% were arginine/proline (A/P) heterozygotes and none were pr oline/proline (P/P) homozygotes. The distribution of codon 25 alleles was s imilar in lung transplant recipients who did not have a significant fibrosi s in pretransplant pathology, but in transplant recipients who came to tran splantation 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 pati ents developed lung allograft fibrosis, and of these 92.3% (36 of 39 recipi ents) were of homozygous codon 25 A/A high TGF-beta(1) producer genotype (p < .001). Lung transplant recipients who were homozygous for both codon 10 L/L and codon 25 AIA showed poor survival compared with all other TGF-beta( 1) genotypes (p < .03). Conclusions: Homozygosity for arginine at codon 25 of the leader sequence o f TGF-beta(1), that correlates with higher TGF-b production in vitro, is as sociated 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 f or poor post-transplant prognosis and recipient survival.