Liver transplantation (LT) is the standard treatment for end-stage liver disease. The role of human leukocyte antigen (HLA) matching in LT remains unclear. Immunologic allograft injury and rejection continue to be concerns, especially when minimizing immunosuppression. While HLA matching currently has no established role in LT, non-HLA compatibility has attracted increased attention. We compared 666 LT recipient-donor pairs and identified genomic mismatches outside HLA segment in different protein groups and 40 common gene deletions. We evaluated the associations with LT outcomes using adjusted Cox models. Quartiles of missense variants coding for all proteins were associated with late rejection with an adjusted hazard ratio (aHR) 0.812 (95% confidence interval [CI]: 0.674-0.977, P-value 0.028). Deletion mismatches tagged by rs11985201 and rs2342606 were associated with AR with aHR 1.483 (95% CI: 1.066-2.062, P-value 0.019) and aHR 1.373 (95% CI: 1.011-1.865, P-value 0.042), respectively. Deletion mismatch in rs2174926 was associated with graft loss with aHR 2.332 (95% CI: 1.145-4.752, P-value 0.020) and in rs1944862 with late rejection with aHR 2.341 (95% CI: 1.326-4.130, P-value 0.003). False detection rates <0.05 were not reached. In conclusion, genome-wide mismatches may contribute to LT complications. However, robust large-scale studies are essential for validation.

The authors have declared no competing interest.

The study was partially supported by funding from the Government of Finland VTR funding (to FRCBS). FÅ received grants from Mary and Georg Ehrnrooth Foundation and Medicinska Understödsföreningen Liv och Hälsa.

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The study conforms to the principles of the Declaration of Helsinki and has been approved by the ethics committee of Helsinki University Hospital (HUS/155/2021), the Finnish Medicines Agency Fimea (FIMEA/2021/004031), and Abdominal Center, Helsinki University Hospital (HUS/155/2021/68).

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