Genome-wide analysis links NFATC2 with asparaginase hypersensitivity

Christian A. Fernandez, Colton Smith, Wenjian Yang, Charles G. Mullighan, Chunxu Qu, Eric Larsen, W. Paul Bowman, Chengcheng Liu, Laura B. Ramsey, Tamara Chang, Seth E. Karol, Mignon L. Loh, Elizabeth A. Raetz, Naomi J. Winick, Stephen P. Hunger, William L. Carroll, Sima Jeha, Ching Hon Pui, William E. Evans, Meenakshi DevidasMary V. Relling

Research output: Contribution to journalArticle

42 Scopus citations

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 5 154), Total XV (n 5 498), and Total XVI (n 5 271), or Children's Oncology Group protocols POG 9906 (n 5 222) and AALL0232 (n 5 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 5 4.1 3 10-8 ; odds ratio [OR] 5 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 5 1.1 3 10-3 and 0.03, respectively). The top ranked nonsynonymous polymorphism was rs17885382 in HLA-DRB1 (P 5 3.2 3 10-6 ;OR5 1.63), which is in near complete linkage disequilibrium with the HLA-DRB107:01 allele we previously observed in a candidate gene study. The strongest risk factors for asparaginase allergy are variants within genes regulating the immune response.

Original languageEnglish
Pages (from-to)69-75
Number of pages7
JournalBlood
Volume126
Issue number1
DOIs
StatePublished - 2 Jul 2015

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