Genome-wide survival study identifies a novel non-HLA donor-recipient genetic mismatch associated with kidney allograft survival

Abstract

Abstract BACKGROUND Despite a sharp rise in kidney graft short-term survival rates and better donor-recipient HLA matching, mid- and long-term survival have not sufficiently improved over the past decades. Several studies suggest that non- HLA factors could be involved in kidney allograft injury, but no validated marker has yet been identified. Here, we aimed at finding genetic variations and mismatches associated with graft function and survival. METHODS Using genome-wide strategies, we tested the recipients’ and donors’ common variations (SNPs and CNVs), and the donor-recipient genetic mismatches for association with 1-year kidney graft function and with time-to-death-censored kidney graft failure in a monocentric European cohort of 1,482 complete donor-recipient pairs. We validated our findings through a meta-analysis in two independent European cohorts gathering a total of 1,842 additional complete pairs. RESULTS We did not identify any significant association with 1-year graft function. However, we discovered four non- HLA mismatches (3 SNPs and 1 CNV) associated with time-to-kidney graft failure. One signal in a regulatory region upstream the TOM1L1 gene (p=6.3×10 -9 , HR=4.1) was successfully replicated in the validation cohorts (p meta -analysis =6.7×10 - 9 , HR=2.9) and ranked among the top 50 rejection-specific genes in a pan-organ transcriptomics study. This locus was also associated with time-to-cellular and humoral rejection (p=0.02) in the discovery cohort in patients achieving primary graft function. CONCLUSIONS By running one of the largest ever performed kidney transplantation genomic analyses, we identified and confirmed a novel donor-recipient genetic mismatch in a biologically relevant non- HLA locus associated with kidney allograft failure. Lay Summary Despite significant advances in immunosuppression, kidney transplant recipients remain at risk of graft rejection and, in more severe cases, graft failure, which can lead to retransplantation, return to dialysis, or even patient death. Donor-recipient HLA compatibility is integrated into kidney transplant clinical care, as this genetic region is key for immunity and graft tolerance. However, several studies suggest that compatibility outside of the HLA region could also influence graft survival. We aimed at investigating this hypothesis in a cohort of 1,482 donor-recipient pairs and found a novel genetic region involved in kidney graft dysfunction that was validated after meta-analysis of two independent cohorts. These findings contribute to a better understanding of the impact of donor-recipient genetic compatibility on kidney transplant outcomes.