Association between polymorphisms of EPHX1 and XRCC1 genes and the risk of childhood acute lymphoblastic leukemia

Abstract

Microsomal epoxide hydrolase, EPHX1, plays a central role in the detoxification of potentially genotoxic epoxide intermediates. In this study, we firstly aimed to investigate the relationship between EPHX1 Tyr113His and His139Arg variants, and the risk of incidence of childhood acute lymphoblastic leukemia (ALL) in Turkish population, comprised of 190 healthy controls and 167 ALL patients. In exon 3 Tyr113His polymorphism, 113His/His homozygous mutant genotype with slow activity was 18.6% in ALL patients and 9% in controls, indicating 113His/His slow activity genotype was significantly associated with an increased risk of childhood ALL (OR: 2.3, 95% CI, 1.2-4.4, P = 0.01). No significant association was found between exon 4 His139Arg variant and the risk of ALL. When both exon 3 Tyr113His and exon 4 His139Arg polymorphisms were considered together, only the exon 3 113His/His, homozygous mutant, slow activity genotype with exon 4 wild-type genotype 139His/His was significantly increased the risk of ALL 2.4-fold (OR: 2.4, P = 0.02). We also evaluated whether haplotype analysis for EPHX1 Tyr113His polymorphism together with DNA protein XRCC1 Arg399Gln variant known for its deficient DNA repair capacity would represent more prominent risk factors for the development of childhood ALL. Accordingly, the co-presence of Tyr113His variant of EPHX1 and Arg399Gln variant of XRCC1 in the same individuals significantly increased the risk of childhood ALL up to 2.1-fold (OR = 2.1, P = 0.03). Moreover, homozygous mutant genotype for both genes significantly and considerably increased the risk of childhood ALL 8.5-fold (OR: 8.5, P = 0.03). In conclusion, individuals with EPHX1 113His/His slow activity genotype may not detoxify reactive carcinogenic epoxides efficiently, binding of reactive epoxides to DNA cause DNA damage. With the inadequate polymorphic DNA repair protein, XRCC1, this situation ultimately leads to significantly increased susceptibility for childhood ALL.

The EPHX1 rs1051740 Polymorphism Is Associated with Childhood Acute Lymphoblastic Leukemia in a Korean Population

“…Tumer et al reported that only the very low activity of the 113 His/His and 139 His/His combinations significantly increased the risk of childhood ALL [21]. However, in our study, no associations were found between these combinations and childhood ALL.…”

“…Three studies of childhood ALL risk have also reported no association with His139Arg, while Tyr113His showed a decreased risk [7] in Brazil, an increase [21] in Turkey, and no association [11] in France. Our results are similar to those of Silveira Vda et al [7].…”

“…To our knowledge, only three reported studies have analyzed these polymorphisms in childhood ALL [7] [11] [21], with the results being variable. Additionally, no research on an Asian population has been published.…”

The Association between mrna Expression Levels of Ephx1 and Prognosis of Acute Myeloid Leukemia

“…In addition, the data showed that EPHX1 gene expression in de novo patients is much higher than control group (P=0.0376). However, what many reports shown was that the EPHX1 gene polymorphisms play an important role in both the activation and detoxification of carcinogenic PAHs and aromatic amines [9][10][11]. Chemotherapeutics (daunorubicin, cytarabine, et.al) which are used for cancer patients almostly based on PAHs, which are also carcinogens in essence.…”

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