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 Devidas; Mary V. Relling

doi:10.1182/blood-2015-02-628800

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 journal › Article › peer-review

70 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 language	English
Pages (from-to)	69-75
Number of pages	7
Journal	Blood
Volume	126
Issue number	1
DOIs	https://doi.org/10.1182/blood-2015-02-628800
State	Published - 2 Jul 2015
Externally published	Yes

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Fernandez, C. A., Smith, C., Yang, W., Mullighan, C. G., Qu, C., Larsen, E., Bowman, W. P., Liu, C., Ramsey, L. B., Chang, T., Karol, S. E., Loh, M. L., Raetz, E. A., Winick, N. J., Hunger, S. P., Carroll, W. L., Jeha, S., Pui, C. H., Evans, W. E., ... Relling, M. V. (2015). Genome-wide analysis links NFATC2 with asparaginase hypersensitivity. Blood, 126(1), 69-75. https://doi.org/10.1182/blood-2015-02-628800

@article{81ecef4595d849ee8e2dfbb6bbb201c9,

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 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.",

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

note = "Publisher Copyright: {\textcopyright} 2015 by The American Society of Hematology.",

year = "2015",

month = jul,

day = "2",

doi = "10.1182/blood-2015-02-628800",

language = "English",

volume = "126",

pages = "69--75",

journal = "Blood",

issn = "0006-4971",

publisher = "Elsevier B.V.",

number = "1",

}

Fernandez, CA, Smith, C, Yang, W, Mullighan, CG, Qu, C, Larsen, E, Bowman, WP, Liu, C, Ramsey, LB, Chang, T, Karol, SE, Loh, ML, Raetz, EA, Winick, NJ, Hunger, SP, Carroll, WL, Jeha, S, Pui, CH, Evans, WE, Devidas, M & Relling, MV 2015, 'Genome-wide analysis links NFATC2 with asparaginase hypersensitivity', Blood, vol. 126, no. 1, pp. 69-75. https://doi.org/10.1182/blood-2015-02-628800

TY - JOUR

T1 - Genome-wide analysis links NFATC2 with asparaginase hypersensitivity

AU - Fernandez, Christian A.

AU - Smith, Colton

AU - Yang, Wenjian

AU - Mullighan, Charles G.

AU - Qu, Chunxu

AU - Larsen, Eric

AU - Bowman, W. Paul

AU - Liu, Chengcheng

AU - Ramsey, Laura B.

AU - Chang, Tamara

AU - Karol, Seth E.

AU - Loh, Mignon L.

AU - Raetz, Elizabeth A.

AU - Winick, Naomi J.

AU - Hunger, Stephen P.

AU - Carroll, William L.

AU - Jeha, Sima

AU - Pui, Ching Hon

AU - Evans, William E.

AU - Devidas, Meenakshi

AU - Relling, Mary V.

PY - 2015/7/2

Y1 - 2015/7/2

N2 - 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.

AB - 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.

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U2 - 10.1182/blood-2015-02-628800

DO - 10.1182/blood-2015-02-628800

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SN - 0006-4971

VL - 126

SP - 69

EP - 75

JO - Blood

JF - Blood

IS - 1

ER -

Genome-wide analysis links NFATC2 with asparaginase hypersensitivity

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