Multidimensional donor–recipient HLA genetic features in relation to post-liver transplant infection risk

Introduction: Post-liver transplant infection is a major determinant of patient prognosis, yet its genetic determinants remain unclear. HLA genes, the primary histocompatibility antigens, play a central role in adaptive immune responses. However, unlike kidney transplantation, HLA’s role in immune defense after liver transplantation is often overlooked because of the liver’s immune-privileged status. This study aimed to investigate donor–recipient HLA genetic features and their association with post-transplant infection risk from a multidimensional perspective.
Methods: Whole-genome sequencing was performed on pre-transplant blood samples from 157 donor–recipient pairs undergoing non-tumor liver transplantation (50 with post-transplant infection, 107 without). Donor and recipient single-nucleotide variants, HLA typing, and copy number variations, along with T cell status, were analyzed based on the sequencing data.
Results: Post-liver transplant infection was associated with significantly poorer overall survival compared with non-infected patients. At the level of classical HLA typing (HLA-A, B, C, DRB1, and DQB1, commonly used in kidney transplantation), total mismatch counts were positively correlated with infection risk, and mismatches in non-classical HLA-G also showed a positive association with infection risk. These findings suggest that, although traditional HLA typing is not routinely required in liver transplantation, higher HLA incompatibility may increase recipient susceptibility to post-transplant infection. Beyond classical HLA typing, additional HLA genetic layers were examined. At the single-nucleotide variant level, a protective HLA donor–recipient allele mismatch genotype (donor heterozygous [0/1], recipient homozygous [1/1]) was significantly associated with reduced infection risk, challenging the conventional view that "more mismatches are always detrimental" and suggesting that specific donor–recipient allele combinations may enhance post-transplant immune defense. At the structural variant level, HLA-B copy number loss markedly increased infection risk and was significantly associated with reduced T cell fraction and TCR diversity, indicating a potential mechanism through impaired T cell-mediated immunity.
Conclusion: Post-liver transplant infection significantly affects patient survival, and multidimensional donor–recipient HLA genetic features are closely associated with infection risk, potentially mediated through recipient T cell status. These findings suggest that systematic analysis of HLA genetic variation may provide a novel genetic basis for predicting post-transplant infection.