The Association Between L-Asparaginase Hypersensitivity and Genetic Variants in Japanese Childhood ALL Patients
Authors: Tanaka Yoichi , Urayama Kevin Y , Kawaguchi Takahisa , Mori Makiko , Hasegawa Daisuke , Ishimaru Sae , Taneyama Yuichi , Terada Kazuki , Yanagimachi Masakatsu , Ota Setsuo , Takahashi Hiroyuki , Inukai Takeshi , Toyama Daisuke , Keino Dai , Moriwaki Koichi , Takagi Masatoshi , Fujimura Junya , Sekinaka Yujin , Nakamura Kozue , Sato Yuya , Matsuo Keitaro , Ohara Akira , Koh Katsuyoshi , Matsuda Fumihiko , Manabe Atsushi 
Published: October 2019

Abstract
Background
L-asparaginase is important in successfully treating childhood acute lymphoblastic leukemia (ALL). However, some patients experience hypersensitivity, mechanisms for which have not been fully elucidated. Previous studies, predominately based on populations of European ancestry, have described L-asparaginase hypersensitivity associations with genetic variant tagging the NFATC2, GRIA1, ASNS, and HLA-DRB1genes. The aim of this study was to evaluate the association between L-asparaginase hypersensitivity and genetic variants in Japanese childhood ALL patients.
Methods
This study included 472 Japanese children with ALL who received E. coli derived L-asparaginase comprising 6000 U/m2 intravenously or 10000 U/m2 subcutaneously according to the Tokyo Children's Cancer Study Group (TCCSG) L84-11, L89-12, L92-13, L95-14, L99-15, L04-16, and more recent protocols. L-asparaginase hypersensitivity was defined as experience of fever, rash, and other allergic reaction after L-asparaginase infusion. Through an ongoing genome-wide association study, patient DNA from saliva were genotyped using the Illumina platform and genome-wide single nucleotide polymorphism (SNP) imputation was performed using the 1000 Genomes Project Phase I Version 3 as the reference population. Tests of association between childhood ALL and SNP genotypes across the candidate loci, NFATC2, GRIA1, and ASNS, were performed using logistic regression and assuming a log-additive model of inheritance.
Results
We observed 47 (10%) hypersensitivity patients, of which 32 patients could not be infused again. These L-asparaginase hypersensitivities were not associated with patients' gender and age in this population. SNPs previously reported in NFATC2 rs6021191, GRIA1 rs4958351, and ANSN rs3832526 were not significantly associated with L-asparaginase hypersensitivity (P = 0.76, 0.99, and 0.53, respectively). For confirmation, the NFATC2 rs6021191 SNP was directly genotyped in a large subset of the ALL patients, but no association was observed (P = 0.44; 377 patients). Evaluation of other variants within those genes and flanking regions showed evidence of association with rs11482430 (NFATC2, P = 0.01), rs558550699 (GRIA1, P = 0.02), and rs7803055 (ANSN, P= 0.04), although not significant after correction for multiple testing.
Conclusion
This lack of association with variants reported in populations of European ancestry may be influenced by ethnic specific differences in genetic structure surrounding these variants as exemplified by differences in observed minor allele frequency of the reported NFATC2 rs6021191 and GRIA1 rs4958351 SNPs in Japanese (0.11 and 0.01) and Europeans (< 0.01 and 0.36). Moreover, the type of L-asparaginase, and/or differences in therapeutic protocol may also contribute to inconsistencies with the previous reports. There is indication of an involvement of genetic variation of NFATC2 in L-asparaginase hypersensitivity, but whether the signal is representing the same regions as the previous reports needs to be further examined.

Disclosures
No relevant conflicts of interest to declare.