GENOTYPIC VARIATION IN THE TRANSFORMING GROWTH FACTOR-β1 GENE: Association with Transforming Growth Factor-β1 Production, Fibrotic Lung Disease, and Graft Fibrosis after Lung Transplantation

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Background.Transforming growth factor (TGF)-β1 is a profibrogenetic cytokine that has been implicated in the development of fibrosis in transplanted tissues. In this study, we have analyzed the genetic regulation of TGF-β1 production in lung transplant recipients.Method.A polymerase chain reaction-single-stranded conformational polymorphism technique was used to detect polymorphisms in the TGF-β1 gene from genomic DNA. Polymorphisms were shown to correlate with in vitro TGF-β1 production by stimulated lymphocytes. A single-specific oligonucleotide probe hybridization method was devised to screen for these polymorphisms in lung transplant groups and controls.Results.We have identified five polymorphisms in the TGF-β1 gene: two in the promoter region at positions -800 and -509, one at position +72 in a nontranslated region, and two in the signal sequence at positions +869 and +915. The polymorphism at position +915 in the signal sequence, which changes codon 25 (arginine→proline), is associated with interindividual variation in levels of TGF-β1 production. Stimulated lymphocytes of homozygous genotype (arginine/arginine) from control individuals produced significantly more TGF-β1 in vitro (10037±745 pg/ml) compared with heterozygous (arginine/proline) individuals (6729±883 pg/ml; P<0.02). In patients requiring lung transplantation for a fibrotic lung condition, there was an increase in the frequency of the high-producer TGF-β1 allele (arginine). This allele was significantly associated with pretransplant fibrotic pathology (P<0.02) (n=45) when compared with controls (n=107) and with pretransplant nonfibrotic pathology (P<0.004) (n=50). This allele was also associated with allograft fibrosis in transbronchial biopsies when compared with controls (P<0.03) and with nonallograft fibrosis (P<0.01).Conclusion.The production of TGF-β1 is under genetic control, and this in turn influences the development of lung fibrosis. Hence, the TGF-β1 genotype has prognostic significance in transplant recipients.

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