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Hypersensitivity reactions are the most frequent dose-limiting adverse reactions to
-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
and
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
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
and
alleles had significantly higher risk of developing asparaginase hypersensitivity compared to non-carriers [
=4.56×10
; OR=2.86 (1.73-4.75) and
=1.85×10
; OR=2.99 (1.68-5.31); n=359, respectively]. After haplotype reconstruction, the
haplotype was associated with an increased risk. After inferring the
alleles the
haplotype was associated with the highest risk of asparaginase hypersensitivity [
=1.22×10
; OR=5.00 (2.43-10.29); n=257]. Significantly fewer T-cell ALL patients carried the
allele and the associated haplotype than did pre-B-cell ALL patients (6.5%;
19.2%, respectively;
=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.