title: HLA-DRB1*07:01 is associated with a higher risk of asparaginase allergies.
abstract: Asparaginase is a therapeutic enzyme used to treat leukemia and lymphoma, with immune responses resulting in suboptimal drug exposure and a greater risk of relapse. To elucidate whether there is a genetic component to the mechanism of asparaginase-induced immune responses, we imputed human leukocyte antigen (HLA) alleles in patients of European ancestry enrolled on leukemia trials at St. Jude Children's Research Hospital (n = 541) and the Children's Oncology Group (n = 1329). We identified a higher incidence of hypersensitivity and anti-asparaginase antibodies in patients with HLA-DRB1*07:01 alleles (P = 7.5 × 10(-5), odds ratio [OR] = 1.64; P = 1.4 × 10(-5), OR = 2.92, respectively). Structural analysis revealed that high-risk amino acids were located within the binding pocket of the HLA protein, possibly affecting the interaction between asparaginase epitopes and the HLA-DRB1 protein. Using a sequence-based consensus approach, we predicted the binding affinity of HLA-DRB1 alleles for asparaginase epitopes, and patients whose HLA genetics predicted high-affinity binding had more allergy (P = 3.3 × 10(-4), OR = 1.38). Our results suggest a mechanism of allergy whereby HLA-DRB1 alleles that confer high-affinity binding to asparaginase epitopes lead to a higher frequency of reactions. These trials were registered at www.clinicaltrials.gov as NCT00137111, NCT00549848, NCT00005603, and NCT00075725.
authors: Department of Pharmaceutical Sciences, and.
authors: Christian A
authors: CA
authors: Fernandez
authors: Department of Pharmaceutical Sciences, and.
authors: Colton
authors: C
authors: Smith
authors: Department of Pharmaceutical Sciences, and.
authors: Wenjian
authors: W
authors: Yang
authors: Department of Structural Biology, St. Jude Children's Research Hospital, Memphis, TN;
authors: Mihir
authors: M
authors: Daté
authors: Department of Structural Biology, St. Jude Children's Research Hospital, Memphis, TN;
authors: Donald
authors: D
authors: Bashford
authors: Maine Children's Cancer Program, Scarborough, ME;
authors: Eric
authors: E
authors: Larsen
authors: Department of Hematology and Oncology, Cook Children's Medical Center, Fort Worth, TX;
authors: W Paul
authors: WP
authors: Bowman
authors: Department of Pharmaceutical Sciences, and.
authors: Chengcheng
authors: C
authors: Liu
authors: Department of Pharmaceutical Sciences, and.
authors: Laura B
authors: LB
authors: Ramsey
authors: Department of Pharmaceutical Sciences, and.
authors: Tamara
authors: T
authors: Chang
authors: Department of Pathology, St. Jude Children's Research Hospital, Memphis, TN;
authors: Victoria
authors: V
authors: Turner
authors: Department of Pediatrics, University of California School of Medicine, San Francisco, CA;
authors: Mignon L
authors: ML
authors: Loh
authors: Department of Pediatrics, New York University Medical Center, NY;
authors: Elizabeth A
authors: EA
authors: Raetz
authors: University of Texas Southwestern Medical Center, Dallas, TX;
authors: Naomi J
authors: NJ
authors: Winick
authors: Section of Pediatric Hematology/Oncology/Bone Marrow Transplantation and Center for Cancer and Blood Disorders, University of Colorado Denver School of Medicine, Children's Hospital Colorado, Aurora, CO;
authors: Stephen P
authors: SP
authors: Hunger
authors: Department of Pediatrics, New York University Medical Center, NY;
authors: William L
authors: WL
authors: Carroll
authors: Center for Public Health Genomics, University of Virginia, Charlottesville, VA;
authors: Suna
authors: S
authors: Onengut-Gumuscu
authors: Center for Public Health Genomics, University of Virginia, Charlottesville, VA;
authors: Wei-Min
authors: WM
authors: Chen
authors: Genetics Institute, University of Florida, Gainesville, FL;
authors: Patrick
authors: P
authors: Concannon
authors: Center for Public Health Genomics, University of Virginia, Charlottesville, VA;
authors: Stephen S
authors: SS
authors: Rich
authors: Department of Epidemiology, University of Texas M. D. Anderson Cancer Center, Houston, TX;
authors: Paul
authors: P
authors: Scheet
authors: Department of Oncology, St. Jude Children's Research Hospital, Memphis, TN; and.
authors: Sima
authors: S
authors: Jeha
authors: Department of Oncology, St. Jude Children's Research Hospital, Memphis, TN; and.
authors: Ching-Hon
authors: CH
authors: Pui
authors: Department of Pharmaceutical Sciences, and.
authors: William E
authors: WE
authors: Evans
authors: Department of Biostatistics, College of Medicine, University of Florida, Gainesville, FL.
authors: Meenakshi
authors: M
authors: Devidas
authors: Department of Pharmaceutical Sciences, and.
authors: Mary V
authors: MV
authors: Relling
mesh_terms: D000293:Adolescent; D000328:Adult; D000483:Alleles; D000906:Antibodies / Q000097:blood / Q000276:immunology; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000009:adverse effects*; D001215:Asparaginase / Q000008:administration & dosage / Q000009:adverse effects*; D002648:Child; D002675:Child, Preschool; D004342:Drug Hypersensitivity / Q000097:blood / Q000235:genetics / Q000276:immunology; D000939:Epitopes / Q000097:blood / Q000235:genetics / Q000276:immunology; D005260:Female; D059811:HLA-DRB1 Chains / Q000235:genetics / Q000276:immunology; D006801:Humans; D007223:Infant; D007938:Leukemia / Q000188:drug therapy* / Q000235:genetics / Q000276:immunology / Q000473:pathology; D008297:Male; D012307:Risk Factors
chemical_list: D000906:Antibodies; D000970:Antineoplastic Agents; D000939:Epitopes; D059811:HLA-DRB1 Chains; C456920:HLA-DRB1*07 antigen; D001215:Asparaginase