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

  • Toxicogenomics
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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.

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Acknowledgments

The authors thank to the healthy volunteers and patients for participating to the study. This study was partially supported by Turkish Academy of Sciences.

Conflict of interest

We have no conflict of interest whether of a financial or other nature.

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Authors and Affiliations

  1. Biochemistry Graduate Programme and Department of Biological Sciences, Middle East Technical University, Ankara, 06531, Turkey

    Tugba Boyunegmez Tumer & Emel Arinç

  2. Vocational College of Health Services, Canakkale Onsekiz Mart University, Canakkale, Turkey

    Tugba Boyunegmez Tumer

  3. Department of Oncology, Dr. Sami Ulus Children’s Hospital, Ankara, Turkey

    Gurses Sahin

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  1. Tugba Boyunegmez Tumer
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  2. Gurses Sahin
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Correspondence to Emel Arinç.

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Tumer, T.B., Sahin, G. & Arinç, E. Association between polymorphisms of EPHX1 and XRCC1 genes and the risk of childhood acute lymphoblastic leukemia. Arch Toxicol 86, 431–439 (2012). https://doi.org/10.1007/s00204-011-0760-8

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