1028-LBP: Association of mismatched polymorphic amino acid residues in HLA with chronic rejection of kidney transplants

Abstract

The success of kidney transplantation relies heavily upon the compatibility of the HLA genes between donor and recipient, but the high degree of polymorphism among these genes in the population makes finding an ideal match difficult. However, it is unclear whether specific amino acids are particularly critical in determining histocompatibility. To investigate this possibility, we introduce a novel method of comparing donor and recipient genotypes and explore its efficacy in predicting transplant rejection. Using typing data of the HLA-A, -B, -C, and -DRB1 genes for 580 paired donors and recipients of a kidney transplant, we developed a method of allele estimation that used population frequency information to estimate amino acid sequence information. Using this sequence data we tested a number of metrics for measuring differences between donor and recipient genotypes, and looked for associations between mismatched residues and chronic rejection. Preliminary analysis of a cohort of 348 transplants with Caucasian recipients indicate a high association between residue mismatches in HLA-B and chronic rejection, primarily in residues 69 and 71 with p < 0.005 and α < 0.16, and in residue 66 with p < 0.001 and α < 0.2. Residues 69 and 71 are not directly involved in peptide binding, but residue 66 is active in binding pockets A and B. All three residues are polymorphic, with variants that differ significantly in their properties. Residue mismatches at any of these sites generally co-occur with broad motif mismatches across multiple binding pockets. Association between HLA residue mismatches and chronic rejection was observed in cases where the residues’ properties differed significantly, and when the value of the residue is linked to broader motif changes. Future investigations will consider the impact of functional changes in residues in addition to statistical characterization of these predictive sites, and how these factors relate to transplant compatibility assessment.