HLA-DRB1*07:01 is associated with a higher risk of asparaginase allergies
Year: 2014
Type: article
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.
Source: Blood
Authors: Christian A. Fernandez, Colton Smith, Wenjian Yang, Mihir Daté, Donald Bashford, Eric Larsen, W. Paul Bowman, Chengcheng Liu, Laura B. Ramsey, Tamara Chang, Victoria Turner, Mignon L. Loh, Elizabeth A. Raetz, Naomi J. Winick, Stephen P. Hunger, William L. Carroll, Suna Onengut-Gumuscu, Wei-Min Chen, Patrick Concannon, Stephen S. Rich, Paul Scheet, Sima Jeha, Ching-Hon Pui, William E. Evans, Meenakshi Devidas, Mary V. Relling
Institutions: St. Jude Children's Research Hospital, Cook Children's Medical Center, University of California, San Francisco, University of California San Francisco Medical Center, NYU Langone Health, New York University, The University of Texas Southwestern Medical Center, Children's Hospital Colorado, University of Colorado Anschutz, University of Colorado Denver, University of Virginia, University of Florida, The University of Texas MD Anderson Cancer Center
Language: English
Subfield: Pharmacology
Field: Medicine
Domain: Health Sciences
Open Access status: green
Awards: G1399567684, G1504112592, G1860110607, G2117365975, G22842288, G2634635869, G2901481919, Glucocorticoids in Lymphoblastic Leukemia, Pharmacogenomics of Childhood Leukemia ALL, Support for Human Specimen Banking in NCI-Sponsored Clinical Trials-(CGB), G3942302684, G421865639, Children's Oncology Group Statistics and Data Center, G46020690, G609259107, PHARMACOGENOMICS OF CHILDHOOD LEUKEMIA (ALL), G860380395, Cancer Center Support Grant (CCSG), G997771125
OpenAlex ID: W2154605350