A Combined HLA Molecular Mismatch and Expression Analysis for Evaluating HLA-DPB1 de novo Donor-Specific Antibody Risk in Pediatric Solid Organ Transplantation: Implications for Solid Organ & Hematopoietic Stem Cell Transplantation

Abstract

Background. HLA molecular mismatch (MM) has been shown to be a risk factor for de novo donor-specific antibody (dnDSA) development in solid organ transplantation (SOT). HLA expression differences have also been associated with adverse outcomes in hematopoietic cell transplantation. We sought to study both MM and expression in assessing dnDSA risk. Methods. One-hundred-and-three HLA-DP-mismatched SOT pairs were retrospectively analysed. MM was computed using amino acids (aa), eplets and, supplementarily, Grantham/Epstein scores. DPB1 alleles were classified as rs9277534-A (low-expression) or -G (high-expression) linked. To determine the associations between risk factors and dnDSA, logistic regression, linkage disequilibrium (LD) and population-based analyses were performed. Results. A high-risk AA:GX (recipient:donor) expression combination (X=A or G) demonstrated strong association with DP-dnDSA (p=0.001). MM was also associated with DP-dnDSA when evaluated by itself (eplet_p=0.007, aa_p=0.003, Grantham_p=0.005, Epstein_p=0.004). When attempting to determine the relative individual effects of the risk factors in multivariable analysis, only AA:GX expression status retained a strong association (RR=18.6, p=0.007 with eplet; RR=15.8, p=0.02 with aa), while MM was no longer significant (eplet_p=0.56, aa_p=0.51). Importantly, these risk factors are correlated, due to LD between the expression-tagging SNP and polymorphisms along HLA-DPB1. Conclusions. The MM and expression risk factors each appear to be strong predictors of DP-dnDSA and to possess clinical utility; however, the two risk factors are closely correlated. These metrics may represent distinct ways of characterizing a common overlapping dnDSA risk profile, but they are not independent. Further, we demonstrate the importance and detailed implications of LD effects in risk assessment of dnDSA and possibly transplantation overall.