GENOTYPIC VARIATION IN THE TRANSFORMING GROWTH-FACTOR-BETA-1 GENE - ASSOCIATION WITH TRANSFORMING GROWTH FACTOR-PI PRODUCTION, FIBROTIC LUNG-DISEASE, AND GRAFT FIBROSIS AFTER LUNG TRANSPLANTATION

Background, Transforming growth factor (TGF)-beta 1 is a profibrogenet ic cytokine that has been implicated in the development of fibrosis in transplanted tissues. In this study, we have analyzed the genetic reg ulation of TGF-beta 1 production in lung transplant recipients. Method . A polymerase chain reaction-single-stranded conformational polymorph ism technique was used to detect polymorphisms in the TGF-beta 1 gene from genomic DNA, Polymorphisms were shown to correlate with in vitro TGF-beta 1 production by stimulated lymphocytes, A single-specific oli gonucleotide probe hybridization method was devised to screen for thes e polymorphisms in lung transplant groups and controls. Results. We ha ve identified five polymorphisms in the TGF-beta 1 gene: two in the pr omoter region at positions -800 and -509, one at position +72 in a non translated region, and two in the signal sequence at positions +869 an d +915, The polymorphism at position +915 in the signal sequence, whic h changes codon 25 (arginine-->proline), is associated with interindiv idual variation in levels of TGF-beta 1 production, Stimulated lymphoc ytes of homozygous genotype (arginine/arginine) from control individua ls produced significantly more TGF-beta 1 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 fibr otic lung condition, there was an increase in the frequency of the hig h-producer TGF-beta 1 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 pat hology (P<0.004) (n=50), This allele was also associated with allograf t fibrosis in transbronchial biopsies when compared with controls (P<0 .03) and with nonallograft fibrosis (P<0.01). Conclusion, The producti on of TGF-beta 1 is under genetic control, and this in turn influences the development of lung fibrosis. Hence, the TGF-beta 1 genotype has prognostic significance in transplant recipients.