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, 19 (15), 1181-1193

Genetic Risk Factors for VIPN in Childhood Acute Lymphoblastic Leukemia Patients Identified Using Whole-Exome Sequencing

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Genetic Risk Factors for VIPN in Childhood Acute Lymphoblastic Leukemia Patients Identified Using Whole-Exome Sequencing

Rachid Abaji et al. Pharmacogenomics.

Abstract

Aim: To identify genetic markers associated with vincristine-induced peripheral neuropathy (VIPN) in childhood acute lymphoblastic leukemia.

Patients & methods: Whole-exome sequencing data were combined with exome-wide association study to identify predicted-functional germline variants associated with high-grade VIPN. Genotyping was then performed for top-ranked signals (n = 237), followed by validation in independent replication group (n = 405).

Results: Minor alleles of rs2781377/SYNE2 (p = 0.01) and rs10513762/MRPL47 (p = 0.01) showed increased risk, whereas that of rs3803357/BAHD1 had a protective effect (p = 0.007). Using a genetic model based on weighted genetic risk scores, an additive effect of combining these loci was observed (p = 0.003). The addition of rs1135989/ACTG1 further enhanced model performance (p = 0.0001).

Conclusion: Variants in SYNE2, MRPL47 and BAHD1 genes are putative new risk factors for VIPN in childhood acute lymphoblastic leukemia.

Keywords: acute lymphoblastic leukemia; adverse drug reactions; association study; cancer; genetics; pharmacogenetics; polymorphism; vincristine-induced peripheral neuropathy; whole-exome sequencing.

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