Complex Linkage Disequilibrium Effects in HLA-DPB1 Expression and Molecular Mismatch Analyses of Transplantation Outcomes.

ABSTRACT

BACKGROUND: HLA molecular mismatch (MM) is a risk factor for de novo donor-specific antibody (dnDSA) development in solid organ transplantation. 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 three HLA-DP-mismatched solid organ transplantation pairs were retrospectively analyzed. MM was computed using amino acids (aa), eplets, and, supplementarily, Grantham/Epstein scores. DPB1 alleles were classified as rs9277534-A (low-expression) or rs9277534-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 AAGX (recipientdonor) expression combination (X = A or G) demonstrated strong association with HLA-DP dnDSA (P = 0.001). MM was also associated with HLA-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 AAGX expression status retained a strong association (relative risk = 18.6, P = 0.007 with eplet; relative risk = 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 single-nucleotide polymorphism and polymorphisms along HLA-DPB1. CONCLUSIONS: The MM and expression risk factors each appear to be strong predictors of HLA-DP dnDSA and to possess clinical utility; however, these 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 dnDSA risk assessment and possibly transplantation overall.