Genome-wide analysis links NFATC2 with asparaginase hypersensitivity

Abstract

Key Points The rs6021191 variant in NFATC2 is associated with an increased risk of asparaginase hypersensitivity and is an expression quantitative trait locus associated with expression of NFATC2. Exome interrogation confirms the importance of the HLA-DRB1*07:01 allele in asparaginase hypersensitivity.

Current perspective on pediatric pharmacogenomics

“…human leukocyte antigen HLA-DRB1). [15,16] It can be anticipated that the combination of the two pathways can explain a larger portion of the risk for asparaginase allergy, but further studies are needed to confirm this hypothesis. Another well-studied example in the HLA region is carbamazepine-induced hypersensitivity reactions which are linked to the HLA-B*15:02 and HLA-A*31:01 haplotypes.…”

“…[13,14] Another example of the childhood ALL pharmacogenomics, currently at the discovery level, is the allergic reaction in response to therapy with asparaginase. [15,16] Hypersensitivity to asparaginase can lead to dose reduction, suboptimal drug exposure, and subsequent treatment failure. [15,16] Pharmacogenomics studies identified genetic variants affecting the expression of the asparagine synthetase (ASNS) gene and variants in the genes that regulate the immune responses (i.e.…”

“…[15,16] Hypersensitivity to asparaginase can lead to dose reduction, suboptimal drug exposure, and subsequent treatment failure. [15,16] Pharmacogenomics studies identified genetic variants affecting the expression of the asparagine synthetase (ASNS) gene and variants in the genes that regulate the immune responses (i.e. human leukocyte antigen HLA-DRB1).…”

Review of pharmacogenetics studies of L-asparaginase hypersensitivity in acute lymphoblastic leukemia points to variants in the GRIA1 gene

“…To date, only 10 pharmacogenetics studies analyzing L-ASP have been performed in pediatric ALL [34,[41][42][43][44][45][46][47][48][49]. Among them, six specifically focused on the analysis of the risk to L-ASP hypersensitivity, finding the most remarkable results with 15 polymorphisms located at GRIA1, HLA-DRB1, NFATC2 and ASNS (Table 1) [34,[41][42][43][44]49].…”

“…Among them, six specifically focused on the analysis of the risk to L-ASP hypersensitivity, finding the most remarkable results with 15 polymorphisms located at GRIA1, HLA-DRB1, NFATC2 and ASNS (Table 1) [34,[41][42][43][44]49]. Interestingly, out of these 15 significant polymorphisms, 11 were located in the GRIA1 gene (glutamate receptor, ionotropic, AMPA 1).…”