– Research Scientist, Arbor Research Collaborative for Health, United States
Aim: We hypothesized that HLA class I Ag mismatches between divergent allele families [LG1] involving donors carrying an allele characterized by amino acid mismatches associated with increased risk of graft failure could be linked with increased risk of graft failure.
Methods: We analyzed data on 166,918 adult deceased-donor kidney recipients from Scientific Registry of Transplant Recipients (SRTR) 2010 - 2023 data. We used Cox proportional hazards models controlling for donor and recipient factors (e.g. demographics, comorbidities), year of transplant (to control for secular trends in improved transplant recipient survival). Several HLA AA-MM positions that distinctively separated divergent HLA allele families were found in prior work to be associated with increased risk of GF. Based on those findings, we hypothesized that HLA class I Ag mismatches between divergent allele families could be linked with increased risk of graft failure.
Results: Transplants involving specific antigen mismatches (AgMM) that cross certain HLA allele lineages [LG1] represented between 3% -25% of these transplants. Transplants involving AgMM where the donors had A*01, A*25, A*26, C*04, C*05, and C*17 were associated with roughly 1-5% increased risk of 1st-year graft failure (albeit with p>0.1) after adjusting for other patient and donor characteristics. Similarly, transplants involving A*30 (p <.001), A*36 (p=.56), C*08 (p=.04), or B AgMM (p=.01) corresponding to leucine at position 103 as opposed to valine were associated with 7%-15% increased risk, and A*80 (p=.01) was associated with 46% increased risk. Adjusting for class II antigen mismatches (DRB1, DQA1, and DQB1) on top of the other patient and donor characteristics did not appreciably change the results (not shown).
Conclusion: HLA class I AgMM between divergent allele lineages involving donors carrying an allele characterized by some specific AA substitutions are associated with increased risk of graft failure, adjusted for recipient and donor characteristics. This risk appears to vary between AgMM. Footnotes: *Donor leucine103, recipient Valine103 (or methionine) AND does not carry Leucine103. Amino acid substitutions that characterize these HLA alleles: HLA-A: Serine instead of arginine at position 17 distinguish HLA-A30 from most of other alleles; isoleucine 73 instead of threonine distinguish A31 and A33 from most of all other alleles; Alanine 76 instead of valine distinguish A1, A36, A25, A26, and A80 from most of all other alleles. HLA-B: Leucine103 instead of valine characterize most of [B13, B45, B49, B50, 48:02, 82], [B54, B55, most B56], [B35, B53, B58], and B59. HLA-C: Asparagine 114 instead of aspartic acid separates HLA-C4, C5, C8, and C17 from most other HLA-C alleles
