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

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).

Keywords: HLA; graft failure; identity-by-descent; identity-by-state; kidney transplant; shared genetic ancestry; transplant.

Figure 1.. Correlation between total HLA mismatches and PIHAT across HLA (p = 3.57x10 ^-223 and r ² of 0.48).

Total mismatches were calculated across HLA-A, B and DR using typing by serology. PIHAT (measure of IBD) was calculated for HLA-A, B and DR individual and combined by summing the PIHAT scores for each locus.

Figure 2.. Correlation between total HLA mismatches and DST across HLA (p= 5.74x10 ^-222 and r ² = 0.47).

Total mismatches were calculated across HLA-A, B and DR using typing by serology. DST (measure of IBS) was calculated for HLA-A, B and DR individual and combined by summing the DST scores for each loci.