Assessment of HLA-DPB1 genetic variation using an HLA-DP tool and its implications in clinical transplantation

Abstract

HLA-DP is a classic transplantation antigen mediating alloreactivity through T-cell epitope (TCE) diversity and expression level. A current challenge is integrating these functional features into the prospective selection of candidate unrelated donors for transplantation. Genetically, HLA-DPB1 exon 2 defines permissive and non-permissive TCE groups, and exons 2 and 3 (in linkage with rs9277534) inform low- and high-expression allotypes. In this study, we analyze 356,272 exon 2 - exon 3 phased sequences from individuals across five self-identified race and ethnicity categories: White, Hispanic, Asian or Pacific Islander, Black or African American, and American Indian or Alaskan Native. This sequence dataset reveals the complex relationship between TCE and expression models and the importance of exon 3 sequence data. We also studied archived donor search lists for 2,545 patients who underwent transplantation from an HLA-11/12 unrelated donor mismatched for a single HLA-DPB1 allele. Depending on the order in which TCE and expression criteria are considered, some patients have different TCE- and expression-favorable donors. Additionally, this dataset reveals many expression-favorable alternatives exist in the search lists. To improve the selection of candidate donors, we provide, disseminate, and automate our findings through our multi-faceted tool called ExPAT (Expression of HLA-DPAssessment Tool), consisting of a public web application, Python package, and analysis pipeline.