A functional TGFB1 polymorphism in the donor associates with long-term graft survival after kidney transplantation

Introduction Improvement of long-term outcomes in kidney transplantation remains one of the most pressing challenges, yet drug development is stagnating. Human genetics offers an opportunity for much-needed target validation in transplantation. Conflicting data exists about the effect of transforming growth factor beta 1 (TGF-beta1) on kidney transplant survival, since TGF-beta1 has profibrotic and protective effects. We therefore the impact of a recently discovered functional TGBF1 polymorphism on long term kidney graft survival. Methods We performed an observational cohort study analyzing recipient and donor DNA in 1,271-kidney transplant pairs from the University Medical Center Groningen in The Netherlands and associated a low-producing TGBF1 polymorphism (rs1800472 C>T) with 5, 10, and 15-year death-censored kidney graft survival. Results Donor genotype frequencies of s1800472 in TGBF1 differed significantly between patients with and without graft loss (P=0.042). Additionally, the low-producing TGBF1 polymorphism in the donor was associated with an increased risk of graft loss following kidney transplantation (HR 2.13 for the T allele; 95%-CI 1.16-3.90; P=0.015). The incidence of graft loss within 15 years of follow-up was 16.4% in the CC-genotype group and 28.9% in the CT-genotype group. After adjustment for transplant-related covariates, the association between the TGBF1 polymorphism in the donor and graft loss remained significant. In contrast, there was no association between the TGBF1 polymorphism in the recipient and graft loss. Conclusion Kidney allografts possessing a low-producing TGBF1 polymorphism have a higher risk of late graft loss. Our study adds to a growing body of evidence that TGFbeta1 is beneficial, rather than harmful, for kidney transplant survival.