Two tagging single‐nucleotide polymorphisms to captureHLA‐DRB1*07:01–DQA1*02:01–DQB1*02:02haplotype associated with asparaginase hypersensitivity

Abstract

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 rs7775228as 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.

Class II Human Leukocyte Antigen Variants Associate With Risk of Pegaspargase Hypersensitivity

“…Although we observed fewer reactions among EA patients in the AALL0434 cohort (all with T‐ALL) than other protocol cohorts ( P = 1.1 × 10 –7 vs. AALL0232, P = 9.4 × 10 –6 vs. TXVI), we cannot conclude that T‐ALL patients were at lower or higher risk for this toxicity because (i) treatment among the three cohorts differed, especially in intrathecal therapy, radiotherapy, and the use of nelarabine; (ii) risk for hypersensitivity did not differ by lineage within the TXVI cohort ( P = 0.99 adjusting for intrathecal therapy); and (iii) adverse event reporting practice may have differed among protocols. The same group also identified the combination of rs28383172 and rs7775228 as a tag for the risk HLA haplotype 29 . This is also true in EA patients in our study: 98.3% (403 out of 410) of the carriers of minor alleles for both SNPs harbored the risk HLA haplotype; 99.7% (1,753 out of 1,758) of the rest were absent for the risk haplotype.…”

Distinctive cross-ancestry genetic architecture for age-related macular degeneration

“…Two SNPs (rs28383172 and rs7775228) were recently reported to tag the haplotype with high sensitivity and specificity ( 81 ), both of which are genotyped on the MVP array. We phased genotypes using SHAPEIT4 ( 82 ) and designated the risk haplotypes as those with G and C alleles, respectively.…”