PMID- 33768542
OWN - NLM
STAT- MEDLINE
DCOM- 20210914
LR  - 20220902
IS  - 1532-6535 (Electronic)
IS  - 0009-9236 (Print)
IS  - 0009-9236 (Linking)
VI  - 110
IP  - 3
DP  - 2021 Sep
TI  - Class II Human Leukocyte Antigen Variants Associate With Risk of Pegaspargase 
      Hypersensitivity.
PG  - 794-802
LID - 10.1002/cpt.2241 [doi]
AB  - 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 x 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 x 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 x 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.
CI  - (c) 2021 The Authors. Clinical Pharmacology & Therapeutics (c) 2021 American Society 
      for Clinical Pharmacology and Therapeutics.
FAU - Liu, Yiwei
AU  - Liu Y
AD  - Department of Pharmaceutical Sciences, St Jude Children's Research Hospital, 
      Memphis, Tennessee, USA.
FAU - Yang, Wenjian
AU  - Yang W
AUID- ORCID: 0000-0002-7305-5649
AD  - Department of Pharmaceutical Sciences, St Jude Children's Research Hospital, 
      Memphis, Tennessee, USA.
FAU - Smith, Colton A
AU  - Smith CA
AD  - Department of Pharmaceutical Sciences, St Jude Children's Research Hospital, 
      Memphis, Tennessee, USA.
FAU - Cheng, Cheng
AU  - Cheng C
AD  - Department of Biostatistics, St Jude Children's Research Hospital, Memphis, 
      Tennessee, USA.
FAU - Karol, Seth E
AU  - Karol SE
AD  - Department of Oncology, St Jude Children's Research Hospital, Memphis, Tennessee, 
      USA.
FAU - Larsen, Eric C
AU  - Larsen EC
AD  - Maine Children's Cancer Program, Scarborough, Maine, USA.
FAU - Winick, Naomi
AU  - Winick N
AD  - Department of Pediatrics, University of Texas Southwestern Medical Center, 
      Dallas, Texas, USA.
FAU - Carroll, William L
AU  - Carroll WL
AD  - Department of Pediatrics, New York University Grossman School of Medicine, New 
      York, New York, USA.
FAU - Loh, Mignon L
AU  - Loh ML
AD  - Department of Pediatrics, University of California School of Medicine, San 
      Francisco, California, USA.
FAU - Raetz, Elizabeth A
AU  - Raetz EA
AD  - Department of Pediatrics, New York University Grossman School of Medicine, New 
      York, New York, USA.
FAU - Hunger, Stephen P
AU  - Hunger SP
AD  - Department of Pediatrics, Children's Hospital of Philadelphia, Perelman School of 
      Medicine at The University of Pennsylvania, Philadelphia, Pennsylvania, USA.
FAU - Winter, Stuart S
AU  - Winter SS
AD  - Children's Minnesota Cancer and Blood Disorders Program, Children's Minnesota, 
      Minneapolis, Minnesota, USA.
FAU - Dunsmore, Kimberly P
AU  - Dunsmore KP
AD  - Department of Pediatrics, University of Virginia, Charlottesville, Virginia, USA.
FAU - Devidas, Meenakshi
AU  - Devidas M
AD  - Global Pediatric Medicine, St Jude Children's Research Hospital, Memphis, 
      Tennessee, USA.
FAU - Yang, Jun J
AU  - Yang JJ
AD  - Department of Pharmaceutical Sciences, St Jude Children's Research Hospital, 
      Memphis, Tennessee, USA.
FAU - Evans, William E
AU  - Evans WE
AD  - Department of Pharmaceutical Sciences, St Jude Children's Research Hospital, 
      Memphis, Tennessee, USA.
FAU - Jeha, Sima
AU  - Jeha S
AD  - Department of Oncology, St Jude Children's Research Hospital, Memphis, Tennessee, 
      USA.
FAU - Pui, Ching-Hon
AU  - Pui CH
AD  - Department of Oncology, St Jude Children's Research Hospital, Memphis, Tennessee, 
      USA.
FAU - Inaba, Hiroto
AU  - Inaba H
AD  - Department of Oncology, St Jude Children's Research Hospital, Memphis, Tennessee, 
      USA.
FAU - Relling, Mary V
AU  - Relling MV
AD  - Department of Pharmaceutical Sciences, St Jude Children's Research Hospital, 
      Memphis, Tennessee, USA.
LA  - eng
GR  - R01 CA142665/CA/NCI NIH HHS/United States
GR  - R01 CA 142665/GF/NIH HHS/United States
GR  - P50 115279/GF/NIH HHS/United States
GR  - P30 CA021765/CA/NCI NIH HHS/United States
GR  - P50 GM115279/GM/NIGMS NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
DEP - 20210421
PL  - United States
TA  - Clin Pharmacol Ther
JT  - Clinical pharmacology and therapeutics
JID - 0372741
RN  - 0 (Histocompatibility Antigens Class II)
RN  - 3WJQ0SDW1A (Polyethylene Glycols)
RN  - 7D96IR0PPM (pegaspargase)
RN  - EC 3.5.1.1 (Asparaginase)
SB  - IM
MH  - Alleles
MH  - Asparaginase/*genetics
MH  - Cohort Studies
MH  - Gene Frequency/genetics
MH  - Genome-Wide Association Study/methods
MH  - Genotype
MH  - Haplotypes/genetics
MH  - Histocompatibility Antigens Class II/*genetics
MH  - Humans
MH  - Polyethylene Glycols
MH  - Polymorphism, Single Nucleotide/*genetics
PMC - PMC8790808
MID - NIHMS1765892
EDAT- 2021/03/27 06:00
MHDA- 2021/09/15 06:00
PMCR- 2022/09/01
CRDT- 2021/03/26 07:16
PHST- 2020/12/30 00:00 [received]
PHST- 2021/03/13 00:00 [accepted]
PHST- 2021/03/27 06:00 [pubmed]
PHST- 2021/09/15 06:00 [medline]
PHST- 2021/03/26 07:16 [entrez]
PHST- 2022/09/01 00:00 [pmc-release]
AID - 10.1002/cpt.2241 [doi]
PST - ppublish
SO  - Clin Pharmacol Ther. 2021 Sep;110(3):794-802. doi: 10.1002/cpt.2241. Epub 2021 
      Apr 21.