Carboxypeptidase B2 gene polymorphisms in the donor associate with kidney allograft loss

IntroductionPlasma carboxypeptidase B2 (CPB2) is an enzyme that cleaves C-terminal amino acids from proteins, thereby regulating their activities. CPB2 has anti-inflammatory and anti-fibrinolytic properties and can therefore be protective or harmful in disease. We explored the impact of functional carboxypeptidase B2 gene (CPB2) polymorphisms on graft survival following kidney transplantation.MethodsWe performed a longitudinal cohort study to evaluate the association of functionalCPB2polymorphisms (rs2146881, rs3742264, rs1926447, rs3818477) and complement polymorphisms (rs2230199, rs17611) with long-term allograft survival in 1,271 kidney transplant pairs from the University Medical Center Groningen in The Netherlands.ResultsThe high-producingCPB2rs3742264 polymorphism in the donor was associated with a reduced risk of graft loss following kidney transplantation (hazard ratio, 0.71 for the A-allele; 95%-CI, 0.55–0.93;P=0.014). In fully adjusted models, the association between the CPB2 polymorphism in the donor and graft loss remained significant. The protective effect of the high-producingCPB2variant in the donor could be mitigated by the hazardous effect of gain-of-function complement polymorphisms. Additionally, we compiled a genetic risk score of the fourCPB2variants in the recipients and donors, which was independently associated with long-term allograft survival. Furthermore, this genetic risk score substantially improved risk prediction for graft loss beyond currently used clinical predictors.ConclusionKidney allografts from deceased donors possessing a high-producing CPB2 polymorphism are at a lower risk of graft loss after kidney transplantation. Furthermore, our findings suggest that CPB2 might have a protective effect on graft loss through its ability to inactivate complement anaphylatoxins.EssentialsCarboxypeptidase B2 (CPB2) is a metalloprotease with anti-fibrinolytic and anti-inflammatory properties.We investigated the impact ofCPB2polymorphisms on graft loss after kidney transplantation.The rs3742264-A SNP in the donor, linked to higher CPB2 levels, decreased the risk of graft loss.CPB2 could have a protective effect on graft survival by inactivating complement anaphylatoxins.