title: Genome-wide analysis links NFATC2 with asparaginase hypersensitivity.
abstract: Asparaginase is used to treat acute lymphoblastic leukemia (ALL); however, hypersensitivity reactions can lead to suboptimal asparaginase exposure. Our objective was to use a genome-wide approach to identify loci associated with asparaginase hypersensitivity in children with ALL enrolled on St. Jude Children's Research Hospital (SJCRH) protocols Total XIIIA (n = 154), Total XV (n = 498), and Total XVI (n = 271), or Children's Oncology Group protocols POG 9906 (n = 222) and AALL0232 (n = 2163). Germline DNA was genotyped using the Affymetrix 500K, Affymetrix 6.0, or the Illumina Exome BeadChip array. In multivariate logistic regression, the intronic rs6021191 variant in nuclear factor of activated T cells 2 (NFATC2) had the strongest association with hypersensitivity (P = 4.1 × 10(-8); odds ratio [OR] = 3.11). RNA-seq data available from 65 SJCRH ALL tumor samples and 52 Yoruba HapMap samples showed that samples carrying the rs6021191 variant had higher NFATC2 expression compared with noncarriers (P = 1.1 × 10(-3) and 0.03, respectively). The top ranked nonsynonymous polymorphism was rs17885382 in HLA-DRB1 (P = 3.2 × 10(-6); OR = 1.63), which is in near complete linkage disequilibrium with the HLA-DRB1*07:01 allele we previously observed in a candidate gene study. The strongest risk factors for asparaginase allergy are variants within genes regulating the immune response.
authors.affiliation: Department of Pharmaceutical Sciences, and.
authors.forename: Christian A
authors.initials: CA
authors.lastname: Fernandez
authors.affiliation: Department of Pharmaceutical Sciences, and.
authors.forename: Colton
authors.initials: C
authors.lastname: Smith
authors.affiliation: Department of Pharmaceutical Sciences, and.
authors.forename: Wenjian
authors.initials: W
authors.lastname: Yang
authors.affiliation: Department of Pathology, St. Jude Children's Research Hospital, Memphis, TN;
authors.forename: Charles G
authors.initials: CG
authors.lastname: Mullighan
authors.affiliation: Department of Pathology, St. Jude Children's Research Hospital, Memphis, TN;
authors.forename: Chunxu
authors.initials: C
authors.lastname: Qu
authors.affiliation: Maine Children's Cancer Program, Scarborough, ME;
authors.forename: Eric
authors.initials: E
authors.lastname: Larsen
authors.affiliation: Department of Hematology and Oncology, Cook Children's Medical Center, Fort Worth, TX;
authors.forename: W Paul
authors.initials: WP
authors.lastname: Bowman
authors.affiliation: Department of Pharmaceutical Sciences, and.
authors.forename: Chengcheng
authors.initials: C
authors.lastname: Liu
authors.affiliation: Department of Pharmaceutical Sciences, and.
authors.forename: Laura B
authors.initials: LB
authors.lastname: Ramsey
authors.affiliation: Department of Oncology, St. Jude Children's Research Hospital, Memphis, TN;
authors.forename: Tamara
authors.initials: T
authors.lastname: Chang
authors.affiliation: Department of Oncology, St. Jude Children's Research Hospital, Memphis, TN;
authors.forename: Seth E
authors.initials: SE
authors.lastname: Karol
authors.affiliation: Department of Pediatrics, University of California School of Medicine, San Francisco, CA;
authors.forename: Mignon L
authors.initials: ML
authors.lastname: Loh
authors.affiliation: Department of Pediatrics, University of Utah, Salt Lake City, UT;
authors.forename: Elizabeth A
authors.initials: EA
authors.lastname: Raetz
authors.affiliation: University of Texas Southwestern Medical Center, Dallas, TX;
authors.forename: Naomi J
authors.initials: NJ
authors.lastname: Winick
authors.affiliation: Division of Pediatric Oncology and Center for Childhood Cancer Research, Children's Hospital of Philadelphia, Philadelphia, PA;
authors.forename: Stephen P
authors.initials: SP
authors.lastname: Hunger
authors.affiliation: Department of Pediatrics, New York University Medical Center, New York, NY; and.
authors.forename: William L
authors.initials: WL
authors.lastname: Carroll
authors.affiliation: Department of Oncology, St. Jude Children's Research Hospital, Memphis, TN;
authors.forename: Sima
authors.initials: S
authors.lastname: Jeha
authors.affiliation: Department of Oncology, St. Jude Children's Research Hospital, Memphis, TN;
authors.forename: Ching-Hon
authors.initials: CH
authors.lastname: Pui
authors.affiliation: Department of Pharmaceutical Sciences, and.
authors.forename: William E
authors.initials: WE
authors.lastname: Evans
authors.affiliation: Department of Biostatistics, Colleges of Medicine, Public Health & Health Professions, University of Florida, Gainesville, FL.
authors.forename: Meenakshi
authors.initials: M
authors.lastname: Devidas
authors.affiliation: Department of Pharmaceutical Sciences, and.
authors.forename: Mary V
authors.initials: MV
authors.lastname: Relling
mesh_terms: D000293:Adolescent; D000328:Adult; D001215:Asparaginase / Q000627:therapeutic use*; D002648:Child; D002675:Child, Preschool; D004342:Drug Hypersensitivity / Q000453:epidemiology / Q000235:genetics*; D056947:Enzyme Replacement Therapy / Q000009:adverse effects; D005260:Female; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study; D059811:HLA-DRB1 Chains / Q000235:genetics; D006801:Humans; D007223:Infant; D008297:Male; D050778:NFATC Transcription Factors / Q000235:genetics*; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000188:drug therapy / Q000453:epidemiology / Q000235:genetics; D055815:Young Adult
chemical_list: D059811:HLA-DRB1 Chains; D050778:NFATC Transcription Factors; C494006:NFATC2 protein, human; D001215:Asparaginase