The relationship between donor-recipient genetic distance and long-term kidney transplant outcome.

Caragh P Stapleton,Gianpiero L Cavalleri,Peter J Conlon,Graham M Lord,Uk And Ireland Renal Transplant Consortium

doi:10.12688/hrbopenres.13021.1

Abstract

Background: We set out to quantify shared genetic ancestry between unrelated kidney donor-recipient pairs and test it as a predictor of time to graft failure. Methods: In a homogenous, unrelated, European cohort of deceased-donor kidney transplant pairs (n pairs = 1,808), we calculated, using common genetic variation, shared ancestry at the genic (n loci=40,053) and genomic level. We conducted a sub-analysis focused on transmembrane protein coding genes (n transcripts=8,637) and attempted replication of a previously published nonsynonymous transmembrane mismatch score. Measures of shared genetic ancestry were tested in a survival model against time to death-censored graft failure. Results: Shared ancestry calculated across the human leukocyte antigen (HLA) significantly associated with graft survival in individuals who had a high serological mismatch (n pairs = 186) with those who did not have any HLA mismatches indicating that shared ancestry calculated specific loci can capture known associations with genes impacting graft outcome. None of the other measures of shared ancestry at a genic level, genome-wide scale, transmembrane subset or nonsynonymous transmembrane mismatch score analysis were significant predictors of time to graft failure. Conclusions: In a large unrelated, deceased-donor European ancestry renal transplant cohort, shared donor-recipient genetic ancestry, calculated using common genetic variation, has limited value in predicting transplant outcome both on a genomic scale and at a genic level (other than at the HLA loci).

Highlights

Organ allocation is a major issue in the field of transplantation
Dataset is composed of donor recipient pairs who were paired by preferential human leukocyte antigen (HLA) matching and skewed towards pairs with fewer mismatches, we focused on the subset of transplant pairs with 0, 5 or 6 serological HLA mismatches
Our findings show that shared donor-recipient genetic ancestry, beyond 3rd degree relative, has limited value in predicting transplant outcome both on a genomic scale and at a genic level in deceased donor European ancestry renal transplant pairs

Summary

Introduction

Organ allocation is a major issue in the field of transplantation. It is vital that organs are matched in a way that facilitates the best possible outcome for the recipient and for the transplanted organ, so that the organ goes to the person for whom it will last the longest. A perfect HLA “match” does not guarantee a successful outcome and in individuals with zero HLA mismatches, acute rejection and early graft failure are still present[3] This indicates that other, potentially genetic, factors influence graft outcome and the success of the transplant. Methods: In a homogenous, unrelated, European cohort of deceaseddonor kidney transplant pairs (n pairs = 1,808), we calculated, using common genetic variation, shared ancestry at the genic (n loci=40,053) and genomic level. None of the other measures of shared ancestry at a genic level, genome-wide scale, transmembrane subset or nonsynonymous transmembrane mismatch score analysis were significant predictors of time to graft failure. Conclusions: In a large unrelated, deceased-donor European ancestry renal transplant cohort, shared donor-recipient genetic ancestry, calculated using common genetic variation, has limited value in Invited Reviewers version 1

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Discussion

Conclusion