The impact of genome-wide histocompatibility on liver transplantation outcomes

ABSTRACT Liver transplantation (LT) is the standard treatment for end-stage liver diseases. However, the role of human leukocyte antigen (HLA)-matching in LT remains unclear. Immunological allograft injury and rejection are ongoing concerns, particularly when efforts are made to minimize immunosuppression. Although HLA matching currently has no established role in LT, interest in non-HLA compatibility in the field of transplantation is growing. We compared 666 LT recipient-donor pairs and identified amino acid-changing genetic mismatches outside the HLA gene segment in different protein groups, and mismatches in 40 common gene deletions. We evaluated the association between mismatches and LT outcomes by using adjusted Cox models for missense variant mismatches and deletion analyses. The primary endpoints were acute rejection, late rejection, graft loss, and overall survival. Statistical significance was set at a false discovery rate (FDR) <0.05. Mismatches in missense variants coding for all proteins were associated with late rejection, with an adjusted hazard ratio (aHR) of 0.998 (95% confidence interval CI: 0.996–0.999; P = 0.011, FDR <0.05). Deletion mismatches tagged with rs11985201, rs2342606, rs2174926, and rs1944862 were identified as risk factors for LT outcomes. The sum of mismatches in deletion variants rs11985201, rs2342606, and rs1944862 was associated with time to acute rejection, with an aHR of 1.377 (95% CI: 1.139– 1.664, P = 0.001, FDR <0.05). Genome-wide mismatches outside of the HLA region contribute to the risk of LT complications. Robust, large-scale studies are required to validate these results.