HLA-A Disparities Illustrate Challenges for Ranking the Impact of HLA Mismatches on Bone Marrow Transplant Outcomes in the United States

Number of mismatched amino acid residues in each HLA-A disparity in 4226 donor-recipient pairs.

Structure of HLA^∗6801. Amino acids that are observed in the largest number of different mismatch combinations are distributed throughout the peptide binding domain. The side chains of the amino acids that are observed in the largest number of different mismatch combinations are shown on an HLA-A^∗6801 structure (2HLA in the Protein Data Bank). Molecular graphics images were produced using the UCSF Chimera package from the Resource for Biocomputing, Visualization, and Informatics at the University of California, San Francisco.

Amino acid differences that are involved in HLA-A disparities are distributed throughout the peptide binding domain, present in both low-resolution (LR) and high-resolution (HR) mismatches, and often accompanied by mismatches (MM) at HLA-B, -C, and -DRB1 loci. The position and side-chain orientation of each mismatched amino acid are indicated below the x-axis (A = alpha helix, B = beta sheet, and C = connecting loop). The amino acids that are most frequently mismatched line the peptide binding groove of the HLA molecule. Most of the mismatched amino acids are involved in both low- and high-resolution mismatches.