Genetic Variation in NFATC2 Associated with Higher Risk of Asparaginase Allergy

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The top inherited genetic loci are likely linked with the development of asparaginase hypersensitivity.
The top inherited genetic loci are likely linked with the development of asparaginase hypersensitivity.

SAN FRANCISCO—The top inherited genetic loci (NFATC2, HLA-DRB1*0701, PPT2) associated with hypersensitivity to asparaginase are directly associated with the human immune response and inherited variations of other genes associated with humoral immunity are likely linked with the development of asparaginase hypersensitivity, according to research (Abstract 63) presented at the 56th American Society of Hematology (ASH) Annual Meeting and Exposition.

Asparaginase hypersensitivity was assessed in 154 children with acute lymphoblastic leukemia (ALL) enrolled on St. Jude Children's Research Hospital protocol Total XIIIA, 498 on Total XV, and 271 on Total XVI, as well as 222 children with ALL on Children's Oncology Group (COG) protocol POG 9906 and 2,163 on COG protocol AALL0232. 

Patients on protocols Total XIIIA, Total XV, and POG 9906 received native E. coli asparaginase while patients on Total XVI and AALL0232 received pegylated E. coli asparaginase.

“The current study is the largest to investigate genetic risk factors asparaginase allergies in a diverse population of ALL patients,” Christian A. Fernandez, PhD, from St. Jude Children's Research Hospital in Memphis, Tennessee, said while presenting at the meeting.

Results of univariate analyses showed that there was a significant positive association between asparaginase hypersensitivity and treatment arm (P<2.2x10-16), particularly Total XV, native E. coli asparaginase (P<2.2x10-16), age less than 10 years (P<3.3x10-4), male gender (P=0.06), and racial ancestry (P<2.1x10-4), particularly African ancestry.

Multivariate analysis demonstrated a significant positive association between asparaginase hypersensitivity and treatment arm (P<2.2x10-16), gender (P=0.04), racial ancestry, and acute lymphoblastic leukemia lineage (P=0.003). “Asparaginase preparation, age, gender, ALL lineage, treatment protocol, and ancestry are associated with asparaginase allergy,” Dr. Fernandez said. 

A multivariate logistic regression model identified various genetic variations associated with asparaginase hypersensitivity. The minor allele rs6021191 in NFATC2 was linked with hypersensitivity at the genome-wide significance threshold (P=2.6x10-8, overall response=3.17) and the frequency for that allele was highest in those with non-European ancestries.

Those with the genetic variant were also found to have a higher expression of NFATC2 versus non-carriers (P=1.0x10-3). “In multivariate analysis treatment, gender and ALL lineage were associated with asparaginase allergy,” Dr. Fernandez said.

Using the Illumina Exome array, HLA-DRB1*0701 was found to have the strongest association with asparaginase hypersensitivity (P=4.0x10-6, overall response=1.65).

A gene-level analysis showed that PPT2 had the strongest association with asparaginase hypersensitivity. Analyses of biological pathways found that 8 genes associated with hypersensitivity are also involved in humoral immunity.

“Our current study expands our previous work by showing that HLA-DRB1*0701 is a risk allele in patients of non-European ancestry,” Dr. Fernandez said.

Asparaginase is a drug used for the treatment of ALL, but hypersensitivity reactions to the drug can lead to suboptimal exposure, thereby increasing the risk of disease recurrence.

Reference
  1. Fernandez, Christian A., PhD, et al. "63 Genetic Variation in NFATC2 Is Associated with a Higher Risk of Asparaginase Allergy." ASH 2014. Oral Presentation. December 7, 2014.

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