Reporting a Rare HLA Allele with Sequence Analysis Prevents Potentially Lethal Allopurinol Hypersensitivity Reaction

Abstract Introduction/Objective In addition to their essential role in histocompatibility testing, human leukocyte antigen (HLA) alleles have informative pharmacogenomic and disease associations. For example, HLA-B*58:01 carriers have 100- fold greater risk of allopurinol hypersensitivity syndrome (AHS), a lethal T-cell mediated Type IV reaction with a 20- 25% mortality rate. To prevent AHS, patients are tested for carrier status before treatment. Methods/Case Report Patient presented for workup of intermittently flaring right knee pain and uricemia. Uric acid is elevated, plain film imaging is ordered, arthrocentesis is planned, and HLA testing is performed to inform uricemia treatment. Next generation sequencing (NGS) typing reveals the patient carries HLA-B*58:11. Sequence analysis demonstrates the allele’s open reading frame differs from HLA-B*58:01 by a single I194V substitution. Amino acid sequences of peptide binding regions (PBR) encoded by these alleles are identical. Presentation of allopurinol/oxypurinol peptides to T-cells by B*58:01 is the putative mechanism underlying AHS pathogenesis. Identical protein sequence in the PBR of B*58:11 favors similar function. Findings are reported and treatment with allopurinol foregone. Results (if a Case Study enter NA) NA Conclusion High resolution HLA testing is essential to appropriately interpret and report results for disease risk and pharmacogenomics assessments. However, NGS detects rare alleles that have yet to be associated with a disease process. When pathogenesis is thought to be linked to the PBR, rare HLA alleles with identical or similar PBR to disease associated alleles may confer similar risk. In this case, NGS identified PBR similarity between the patient’s allele and an established AHS risk allele. Although B*58:11 has not been shown to be associated with AHS, likely due to low prevalence, the risk was deemed sufficient to select an alternative therapy and potentially prevent a lethal drug reaction.