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Class II Human Leukocyte Antigen Variants Associate With Risk of Pegaspargase Hypersensitivity
Author(s) -
Liu Yiwei,
Yang Wenjian,
Smith Colton A.,
Cheng Cheng,
Karol Seth E.,
Larsen Eric C.,
Winick Naomi,
Carroll William L.,
Loh Mig L.,
Raetz Elizabeth A.,
Hunger Stephen P.,
Winter Stuart S.,
Dunsmore Kimberly P.,
Devidas Meenakshi,
Yang Jun J.,
Evans William E.,
Jeha Sima,
Pui ChingHon,
Inaba Hiroto,
Relling Mary V.
Publication year - 2021
Publication title -
clinical pharmacology and therapeutics
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.941
H-Index - 188
eISSN - 1532-6535
pISSN - 0009-9236
DOI - 10.1002/cpt.2241
Subject(s) - human leukocyte antigen , allele , haplotype , single nucleotide polymorphism , genetics , immunology , genome wide association study , biology , medicine , genotype , antigen , gene
We conducted the first human leukocyte antigen (HLA) allele and genome‐wide association study to identify loci associated with hypersensitivity reactions exclusively to the PEGylated preparation of asparaginase (pegaspargase) in racially diverse cohorts of pediatric leukemia patients: St Jude Children’s Research Hospital’s Total XVI (TXVI, n = 598) and Children’s Oncology Group AALL0232 ( n = 2,472) and AALL0434 ( n = 1,189). Germline DNA was genotyped using arrays. Genetic variants not genotyped directly were imputed. HLA alleles were imputed using SNP2HLA or inferred using BWAkit. Analyses between genetic variants and hypersensitivity were performed in each cohort first using cohort‐specific covariates and then combined using meta‐analyses. Nongenetic risk factors included fewer intrathecal injections ( P = 2.7 × 10 −5 in TXVI) and male sex ( P = 0.025 in AALL0232). HLA alleles DQB1*02:02 , DRB1*07:01 , and DQA1*02:01 had the strongest associations with pegaspargase hypersensitivity ( P < 5.0 × 10 −5 ) in patients with primarily European ancestry (EA), with the three alleles associating in a single haplotype. The top allele HLA‐DQB1*02:02 was tagged by HLA‐DQB1 rs1694129 in EAs ( r 2 = 0.96) and less so in non‐EAs. All single nucleotide polymorphisms associated with pegaspargase hypersensitivity reaching genome‐wide significance in EAs were in class II HLA loci, and were partially replicated in non‐EAs, as is true for other HLA associations. The rs9958628 variant, in ARHGAP28 (previously linked to immune response in children) had the strongest genetic association ( P = 8.9 × 10 −9 ) in non‐EAs. The HLA‐DQB1*02:02 ‐ DRB1*07:01 ‐ DQA1*02:01 associated with hypersensitivity reactions to pegaspargase is the same haplotype associated with reactions to non‐PEGylated asparaginase, even though the antigens differ between the two preparations.