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

Introduction: Plasma 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. Methods: We performed a longitudinal cohort study to evaluate the association of functional CPB2 polymorphisms (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. Results: The high-producing CPB2 rs3742264 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-producing CPB2 variant 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 four CPB2 variants 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. Conclusion: Kidney 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. ### Competing Interest Statement FP owns stock in Appelis, Iveric Bio, InflaRx and Omeros. AFA is a consultant for Ionis Pharmaceuticals and CSL Behring. JMT and VMH are consultants for Q32 Bio, Inc., a company developing complement inhibitors. Both also hold stock and may receive royalty income from Q32 Bio, Inc. BPD has served as a consultant for Apellis Pharmaceuticals, Alexion AstraZeneca Rare Disease, Novartis Pharmaceuticals, and Arrowhead Pharmaceuticals. The remaining authors of this paper declare that they have no competing interests. ### Funding Statement This study did not receive any funding. ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: Ethical approval for this study and the study protocol was given by the Institutional Review Board of the University Medical Center Groningen in Groningen, The Netherlands (Medical Ethical Committee 2014/077). The study protocol adhered to the Declaration of Helsinki. All subjects provided written informed consent. I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes Anonymized data produced in the present study are available upon reasonable request to the authors.