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Genetic variation at the catalytic subunit of glutamate cysteine ligase contributes to the susceptibility to sporadic colorectal cancer: a pilot study

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Abstract

Background

Glutathione is a tripeptide detoxifying a variety of exogenous and endogenous free radicals and carcinogens, and a deficiency of glutathione is associated with an increased host susceptibility to oxidative stress, a pathological condition implicated in the development and progression of cancer. The catalytic subunit of glutamate-cysteine ligase (GCLC) is an enzyme responsible for the initial and rate-limiting step of glutathione biosynthesis.

Methods and results

The aim of this pilot study was to investigate whether genetic variation at the GCLC gene contributes to the risk of colorectal cancer (CRC). DNA samples from 681 unrelated Russian individuals (283 patients with CRC and 398 age- and sex-matched healthy controls) were genotyped for six common functional SNPs of the GCLC gene (SNPs) such as rs12524494, rs17883901, rs606548, rs636933, rs648595 and rs761142 of the GCLC gene using the MassARRAY-4 system. We found that genotype rs606548-C/T is significantly associated with increased risk of CRC regardless of sex and age (OR 2.24; 95% CI 1.24–4.03; P = 0.007, FDR = 0.04). Moreover, ten GCLC genotype combinations showed association with the risk of CRC (P < 0.05). Functional SNP annotation enabled establishing the CRC-associated polymorphisms are associated with a decreased GCLC expression that may be attributed to epigenetic effects of histone modifications operating in a colon-specific manner.

Conclusions

The present study was the first to show that genetic variation at the catalytic subunit of glutamate-cysteine ligase may contribute to the risk of colorectal cancer risk. However, further genetic association studies with a larger sample size are required to substantiate the role of GCLC gene polymorphisms in the development of sporadic colorectal cancer.

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Acknowledgements

This study was supported by the TRC GEN+ Genetic Research Foundation of Trans Russian Co (contract no. 474).

Funding

This study was supported by the TRC GEN + Genetic Research Foundation of Trans Russian Co (Contract No. 474).

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Authors and Affiliations

  1. Laboratory of Genomic Research, Research Institute for Genetic and Molecular Epidemiology, Kursk State Medical University, 18 Yamskaya St., Kursk, 305041, Russian Federation

    Marina A. Bykanova & Olga Y. Bushueva

  2. Department of Biology, Medical Genetics and Ecology, Kursk State Medical University, 3 Karl Marx Street, Kursk, Russian Federation, 305041

    Marina A. Bykanova, Maria A. Solodilova, Elena Y. Klyosova, Olga Y. Bushueva, Anna A. Polonikova & Alexey V. Polonikov

  3. Department of Biological Chemistry, Kursk State Medical University, 3 Karl Marx Street, Kursk, Russian Federation, 305041

    Iuliia E. Azarova

  4. Laboratory of Biochemical Genetics and Metabolomics, Research Institute for Genetic and Molecular Epidemiology, Kursk State Medical University, 18 Yamskaya St., Kursk, Russian Federation, 305041

    Iuliia E. Azarova & Elena Y. Klyosova

  5. Department of Medical Biological Disciplines, Belgorod State University, 85 Pobedy Street, Belgorod, Russian Federation, 308015

    Mikhail I. Churnosov

  6. Laboratory of Statistical Genetics and Bioinformatics, Research Institute for Genetic and Molecular Epidemiology, Kursk State Medical University, 18 Yamskaya St., Kursk, Russian Federation, 305041

    Alexey V. Polonikov

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  1. Marina A. Bykanova
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Correspondence to Marina A. Bykanova.

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Bykanova, M.A., Solodilova, M.A., Azarova, I.E. et al. Genetic variation at the catalytic subunit of glutamate cysteine ligase contributes to the susceptibility to sporadic colorectal cancer: a pilot study. Mol Biol Rep 49, 6145–6154 (2022). https://doi.org/10.1007/s11033-022-07406-0

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