HLA-DRB1*07: 01-HLA-DQA1*02:01-HLADQB1* 02:02 haplotype is associated with a high risk of asparaginase hypersensitivity in acute lymphoblastic leukemia

Nóra Kutszegi, Xiaoqing Yang, András Gézsi, Géza Schermann, Dániel J. Erdélyi, Ágnes F. Semsei, Krisztina M. Gábor, Judit C. Sági, Gábor T. Kovács, A. Falus, Hongyun Zhang, C. Szalai

Research output: Contribution to journalArticle

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Abstract

Hypersensitivity reactions are the most frequent dose-limiting adverse reactions to Escherichia coli-derived asparaginase in pediatric acute lymphoblastic leukemia (ALL) patients. The aim of the present study was to identify associations between sequence-based Human Leukocyte Antigen Class II region alleles and asparaginase hypersensitivity in a Hungarian ALL population. Four-digit typing of HLA-DRB1 and HLA-DQB1 loci was performed in 359 pediatric ALL patients by using next-generation sequencing method. Based on genotypic data of the two loci, haplotype reconstruction was carried out. In order to investigate the possible role of the HLA-DQ complex, the HLADQA1 alleles were also inferred. Multivariate logistic regression analysis and a Bayesian network-based approach were applied to identify relevant genetic risk factors of asparaginase hypersensitivity. Patients with HLA-DRB1*07:01 and HLA-DQB1*02:02 alleles had significantly higher risk of developing asparaginase hypersensitivity compared to non-carriers [P=4.56x10-5; OR=2.86 (1.73-4.75) and P=1.85x10-4; OR=2.99 (1.68- 5.31); n=359, respectively]. After haplotype reconstruction, the HLADRB1* 07:01-HLA-DQB1*02:02 haplotype was associated with an increased risk. After inferring the HLA-DQA1 alleles the HLA-DRB1*07:01-HLA-DQA1*02:01-HLA-DQB1*02:02 haplotype was associated with the highest risk of asparaginase hypersensitivity [P=1.22x10-5; OR=5.00 (2.43-10.29); n=257]. Significantly fewer T-cell ALL patients carried the HLA-DQB1*02:02 allele and the associated haplotype than did pre-B-cell ALL patients (6.5%; vs. 19.2%, respectively; P=0.047). In conclusion, we identified a haplotype in the Human Leukocyte Antigen Class II region associated with a higher risk of asparaginase hypersensitivity. Our results confirm that variations in HLA-D region might influence the development of asparaginase hypersensitivity.

Original languageEnglish
Pages (from-to)1578-1586
Number of pages9
JournalHaematologica
Volume102
Issue number9
DOIs
Publication statusPublished - Aug 31 2017

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Asparaginase
Precursor Cell Lymphoblastic Leukemia-Lymphoma
Haplotypes
Hypersensitivity
Alleles
HLA Antigens
HLA-D Antigens
Pediatrics
HLA-DQ Antigens
Precursor T-Cell Lymphoblastic Leukemia-Lymphoma
HLA-DRB1 Chains
B-Lymphoid Precursor Cells
HLA-DRB1*07 antigen
HLA-DQA1 antigen
Logistic Models
Regression Analysis
HLA-DQB1 antigen
Escherichia coli
Population

ASJC Scopus subject areas

  • Hematology

Cite this

HLA-DRB1*07 : 01-HLA-DQA1*02:01-HLADQB1* 02:02 haplotype is associated with a high risk of asparaginase hypersensitivity in acute lymphoblastic leukemia. / Kutszegi, Nóra; Yang, Xiaoqing; Gézsi, András; Schermann, Géza; Erdélyi, Dániel J.; Semsei, Ágnes F.; Gábor, Krisztina M.; Sági, Judit C.; Kovács, Gábor T.; Falus, A.; Zhang, Hongyun; Szalai, C.

In: Haematologica, Vol. 102, No. 9, 31.08.2017, p. 1578-1586.

Research output: Contribution to journalArticle

Kutszegi, N, Yang, X, Gézsi, A, Schermann, G, Erdélyi, DJ, Semsei, ÁF, Gábor, KM, Sági, JC, Kovács, GT, Falus, A, Zhang, H & Szalai, C 2017, 'HLA-DRB1*07: 01-HLA-DQA1*02:01-HLADQB1* 02:02 haplotype is associated with a high risk of asparaginase hypersensitivity in acute lymphoblastic leukemia', Haematologica, vol. 102, no. 9, pp. 1578-1586. https://doi.org/10.3324/haematol.2017.168211
Kutszegi, Nóra ; Yang, Xiaoqing ; Gézsi, András ; Schermann, Géza ; Erdélyi, Dániel J. ; Semsei, Ágnes F. ; Gábor, Krisztina M. ; Sági, Judit C. ; Kovács, Gábor T. ; Falus, A. ; Zhang, Hongyun ; Szalai, C. / HLA-DRB1*07 : 01-HLA-DQA1*02:01-HLADQB1* 02:02 haplotype is associated with a high risk of asparaginase hypersensitivity in acute lymphoblastic leukemia. In: Haematologica. 2017 ; Vol. 102, No. 9. pp. 1578-1586.
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abstract = "Hypersensitivity reactions are the most frequent dose-limiting adverse reactions to Escherichia coli-derived asparaginase in pediatric acute lymphoblastic leukemia (ALL) patients. The aim of the present study was to identify associations between sequence-based Human Leukocyte Antigen Class II region alleles and asparaginase hypersensitivity in a Hungarian ALL population. Four-digit typing of HLA-DRB1 and HLA-DQB1 loci was performed in 359 pediatric ALL patients by using next-generation sequencing method. Based on genotypic data of the two loci, haplotype reconstruction was carried out. In order to investigate the possible role of the HLA-DQ complex, the HLADQA1 alleles were also inferred. Multivariate logistic regression analysis and a Bayesian network-based approach were applied to identify relevant genetic risk factors of asparaginase hypersensitivity. Patients with HLA-DRB1*07:01 and HLA-DQB1*02:02 alleles had significantly higher risk of developing asparaginase hypersensitivity compared to non-carriers [P=4.56x10-5; OR=2.86 (1.73-4.75) and P=1.85x10-4; OR=2.99 (1.68- 5.31); n=359, respectively]. After haplotype reconstruction, the HLADRB1* 07:01-HLA-DQB1*02:02 haplotype was associated with an increased risk. After inferring the HLA-DQA1 alleles the HLA-DRB1*07:01-HLA-DQA1*02:01-HLA-DQB1*02:02 haplotype was associated with the highest risk of asparaginase hypersensitivity [P=1.22x10-5; OR=5.00 (2.43-10.29); n=257]. Significantly fewer T-cell ALL patients carried the HLA-DQB1*02:02 allele and the associated haplotype than did pre-B-cell ALL patients (6.5{\%}; vs. 19.2{\%}, respectively; P=0.047). In conclusion, we identified a haplotype in the Human Leukocyte Antigen Class II region associated with a higher risk of asparaginase hypersensitivity. Our results confirm that variations in HLA-D region might influence the development of asparaginase hypersensitivity.",
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T2 - 01-HLA-DQA1*02:01-HLADQB1* 02:02 haplotype is associated with a high risk of asparaginase hypersensitivity in acute lymphoblastic leukemia

AU - Kutszegi, Nóra

AU - Yang, Xiaoqing

AU - Gézsi, András

AU - Schermann, Géza

AU - Erdélyi, Dániel J.

AU - Semsei, Ágnes F.

AU - Gábor, Krisztina M.

AU - Sági, Judit C.

AU - Kovács, Gábor T.

AU - Falus, A.

AU - Zhang, Hongyun

AU - Szalai, C.

PY - 2017/8/31

Y1 - 2017/8/31

N2 - Hypersensitivity reactions are the most frequent dose-limiting adverse reactions to Escherichia coli-derived asparaginase in pediatric acute lymphoblastic leukemia (ALL) patients. The aim of the present study was to identify associations between sequence-based Human Leukocyte Antigen Class II region alleles and asparaginase hypersensitivity in a Hungarian ALL population. Four-digit typing of HLA-DRB1 and HLA-DQB1 loci was performed in 359 pediatric ALL patients by using next-generation sequencing method. Based on genotypic data of the two loci, haplotype reconstruction was carried out. In order to investigate the possible role of the HLA-DQ complex, the HLADQA1 alleles were also inferred. Multivariate logistic regression analysis and a Bayesian network-based approach were applied to identify relevant genetic risk factors of asparaginase hypersensitivity. Patients with HLA-DRB1*07:01 and HLA-DQB1*02:02 alleles had significantly higher risk of developing asparaginase hypersensitivity compared to non-carriers [P=4.56x10-5; OR=2.86 (1.73-4.75) and P=1.85x10-4; OR=2.99 (1.68- 5.31); n=359, respectively]. After haplotype reconstruction, the HLADRB1* 07:01-HLA-DQB1*02:02 haplotype was associated with an increased risk. After inferring the HLA-DQA1 alleles the HLA-DRB1*07:01-HLA-DQA1*02:01-HLA-DQB1*02:02 haplotype was associated with the highest risk of asparaginase hypersensitivity [P=1.22x10-5; OR=5.00 (2.43-10.29); n=257]. Significantly fewer T-cell ALL patients carried the HLA-DQB1*02:02 allele and the associated haplotype than did pre-B-cell ALL patients (6.5%; vs. 19.2%, respectively; P=0.047). In conclusion, we identified a haplotype in the Human Leukocyte Antigen Class II region associated with a higher risk of asparaginase hypersensitivity. Our results confirm that variations in HLA-D region might influence the development of asparaginase hypersensitivity.

AB - Hypersensitivity reactions are the most frequent dose-limiting adverse reactions to Escherichia coli-derived asparaginase in pediatric acute lymphoblastic leukemia (ALL) patients. The aim of the present study was to identify associations between sequence-based Human Leukocyte Antigen Class II region alleles and asparaginase hypersensitivity in a Hungarian ALL population. Four-digit typing of HLA-DRB1 and HLA-DQB1 loci was performed in 359 pediatric ALL patients by using next-generation sequencing method. Based on genotypic data of the two loci, haplotype reconstruction was carried out. In order to investigate the possible role of the HLA-DQ complex, the HLADQA1 alleles were also inferred. Multivariate logistic regression analysis and a Bayesian network-based approach were applied to identify relevant genetic risk factors of asparaginase hypersensitivity. Patients with HLA-DRB1*07:01 and HLA-DQB1*02:02 alleles had significantly higher risk of developing asparaginase hypersensitivity compared to non-carriers [P=4.56x10-5; OR=2.86 (1.73-4.75) and P=1.85x10-4; OR=2.99 (1.68- 5.31); n=359, respectively]. After haplotype reconstruction, the HLADRB1* 07:01-HLA-DQB1*02:02 haplotype was associated with an increased risk. After inferring the HLA-DQA1 alleles the HLA-DRB1*07:01-HLA-DQA1*02:01-HLA-DQB1*02:02 haplotype was associated with the highest risk of asparaginase hypersensitivity [P=1.22x10-5; OR=5.00 (2.43-10.29); n=257]. Significantly fewer T-cell ALL patients carried the HLA-DQB1*02:02 allele and the associated haplotype than did pre-B-cell ALL patients (6.5%; vs. 19.2%, respectively; P=0.047). In conclusion, we identified a haplotype in the Human Leukocyte Antigen Class II region associated with a higher risk of asparaginase hypersensitivity. Our results confirm that variations in HLA-D region might influence the development of asparaginase hypersensitivity.

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