Polymorphisms in GRIA1 gene are a risk factor for asparaginase hypersensitivity during the treatment of childhood acute lymphoblastic leukemia

Abstract

l-asparaginase is an effective antineoplastic agent used in chemotherapy of acute lymphoblastic leukemia. The drug effect may be compromised by an elicited immune response, resulting in the production of anti-asparaginase antibodies causing an anaphylactic reaction or silent inactivation of the enzyme. To elucidate possible genetic predisposition for inter-individual differences in asparaginase hypersensitivity, we studied single nucleotide polymorphisms (SNPs) in the GRIA1 gene in 146 pediatric patients treated with l-asparaginase. Allergic reaction to l-asparaginase occurred in 49.3% of patients. We observed a statistically significant association between SNPs in the GRIA1 gene and the occurrence of asparaginase allergy: rs4958351 with p = 0.003, rs4958676 with p = 0.005, rs6889909 with p = 0.005, rs6890057 with p = 0.005 and rs10070447 with p = 0.006. We found a statistically significant correlation between asparaginase allergy and event-free survival (p-value 0.005).

Genetics of glucocorticoid-associated osteonecrosis in children with acute lymphoblastic leukemia

“…33 We have also reported that asparaginase allergy was associated with lower systemic exposure to asparaginase, 34 which in turn was associated with a lower risk of osteonecrosis in the SJ cohort. 35 This prompted us to evaluate asparaginase allergy in the COG AALL0232 discovery cohort (n 5 1845 with follow-up .800 days), and consistent with the SJ cohort, grades 2-4 asparaginase allergy was associated with the risk of osteonecrosis: 206 out of 1647 (12.5%) for those without asparaginase allergies had osteonecrosis compared with 12 out of 198 (6.7%) for those with asparaginase allergies (P 5 .0096).…”

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

“…Notably, five of them (rs4958351, rs10070447, rs6890057, rs4958676 and rs6889909) also remained significant in the validation cohort [41], although no correction for multiple comparisons was applied. In 2015, Rajić et al replicated the association of these last 5 SNPs with native E. coli L-ASP hypersensitivity in a cohort of 146 Caucasian children with ALL [42]. However, the association between rs4958351 and the risk to native E. coli L-ASP hypersensitivity was only replicated by Kutszegi et al specifically in T-ALL subgroup, but with opposite effect.…”

“…In this review, considering all the published data together, we show up that there is growing evidence of the involvement of GRIA1 in L-ASP hypersensitivity, for which SNPs located in this gene were significantly associated in three different studies [34,41,42]. Thus, those SNPs could be new potential predictors of L-ASP hypersensitivity, but further studies are required.…”

“…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).…”