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Two tagging single‐nucleotide polymorphisms to capture HLA ‐ DRB1*07:01–DQA1*02:01–DQB1*02:02 haplotype associated with asparaginase hypersensitivity
Author(s) -
Kutszegi Nóra,
Gézsi András,
F. Semsei Ágnes,
Müller Judit,
Simon Réka,
Kovács Erika Rozália,
Hegedüs Katalin,
Kovács Gábor T.,
Szalai Csaba,
Erdélyi Dániel J.
Publication year - 2021
Publication title -
british journal of clinical pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.216
H-Index - 146
eISSN - 1365-2125
pISSN - 0306-5251
DOI - 10.1111/bcp.14664
Subject(s) - haplotype , single nucleotide polymorphism , genotype , snp , asparaginase , population , human leukocyte antigen , genetics , immunology , biology , medicine , gene , antigen , leukemia , lymphoblastic leukemia , environmental health
Aims Asparaginase (ASP) hypersensitivity is a well‐known challenge in the treatment of lymphoblastic malignancies. In terms of cost considerations, the cheap native Escherichia coli ASP, the most immunogenic form of this medication, is used in the first line in middle‐income countries. Previously, the role of the HLA‐DRB1*07:01–DQA1*02:01–DQB1*02:02 haplotype had been established to associate with E. coli ASP hypersensitivity. We investigated a possible cost‐effective genetic testing method to identify patients harbouring the risk HLA haplotype in order to pave the way for safer ASP treatment. Methods In 241 patients with previously determined HLA‐DRB1*07:01–DQA1*02:01–DQB1*02:02 haplotype and known ASP hypersensitivity status, 4 candidate HLA‐tagging single‐nucleotide polymorphisms (SNP)s were measured, and the performance of the different sets of these tag SNPs was evaluated. Results We identified a combination of 2 SNPs — rs28383172 and rs7775228 — as a tag for HLA‐DRB1*07:01–DQA1*02:01–DQB1*02:02 haplotype with sensitivity and specificity values >95%. In line with previous findings, we found complete concordance between HLA‐DRB1*07:01 and rs28383172. With bioinformatics methods, the results were also confirmed in the 1000 Genomes dataset in different ethnic groups. Conclusion Rs28383172 and rs7775228 are suitable for identifying HLA‐DRB1*07:01–DQA1*02:01–DQB1*02:02 carriers. Compared to the rest of the population, patients with hypersensitivity‐prone genotype would benefit more from the administration of less immunogenic PEGylated ASP before the hypersensitivity evolves, incurring minimal extra cost.