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

Abstract

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.

Synergistic impact of three complement polymorphisms in the donor, not the recipient, on long-term kidney allograft survival

“…27 In addition to the additive effects of complement polymorphisms shown here, we have previously demonstrated the possibility of genetic compensation by different complement variants with opposing effects. 35 Overall, these data present compelling evidence that instead of focusing solely on individual complement polymorphisms or complement genes for graft loss risk assessment, we should analyze the repertoire of common complement variants.…”

“…Patients receiving a first single kidney transplantation at the University Medical Center Groningen (UMCG) between March 1993 and February 2008 were selected for this study. [31][32][33][34][35][36] Subsequent, exclusion criteria consisted of perioperative technical complications (3 pairs excluded), lack of available DNA (65 pairs excluded), loss of follow-up (4 pairs excluded), retransplantation at the time of recruitment (22 pairs excluded) and simultaneous transplantation of other organs (65 pairs excluded). In summary, we began with 1430 kidney transplant pairs, and after applying exclusion criteria, we included 1271 kidney transplant pairs in this study.…”