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Genetic variants in glutamate cysteine ligase confer protection against type 2 diabetes

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Abstract

Oxidative stress contributes to the pathogenesis of type 2 diabetes (T2D). This study investigated whether single nucleotide polymorphisms (SNPs) at genes encoding glutamate cysteine ligase catalytic (rs12524494, rs17883901, rs606548, rs636933, rs648595, rs761142 at GCLC) and modifier (rs2301022, rs3827715, rs7517826, rs41303970 at GCLM) subunits are associated with susceptibility to type 2 diabetes. 2096 unrelated Russian subjects were enrolled for the study. Genotyping was done with the use of the MassArray System. Plasma levels of reactive oxygen species (ROS) and glutathione in the study subjects were analyzed by fluorometric and colorimetric assays, respectively.The present study found, for the first time, an association of SNP rs41303970 in the GCLM gene with a decreased risk of T2D (P = 0.034, Q = 0.17). Minor alleles such as rs12524494-G GCLC gene (P = 0.026, Q = 0.17) and rs3827715-C GCLM gene (P = 0.03, Q = 0.17) were also associated with reduced risk for T2D. Protective effects of variant alleles such as rs12524494-G at GCLC (P = 0.02, Q = 0.26) and rs41303970-A GCLM (P = 0.013, Q = 0.25) against the risk of T2D were seen solely in nonsmokers. As compared with healthy controls, diabetic patients had markedly increased levels of ROS and decreased levels of total GSH in plasma. Interestingly, fasting blood glucose level positively correlated with oxidized glutathione concentration (rs = 0.208, P = 0.01). Three SNPs rs17883901, rs636933, rs648595 at GCLC and one rs2301022 at GCLM were associated with decreased levels of ROS, while SNPs rs7517826, rs41303970 at GCLM were associated with increased levels of total GSH in plasma. Single nucleotide polymorphisms in genes encoding glutamate cysteine ligase subunits confer protection against type 2 diabetes and their effects are mediated through increased levels of glutathione.

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Acknowledgements

We thank all the T2D patients, healthy volunteers and staff of the Kursk Emergency Hospital. The study was supported by Russian Science Foundation (№20–15-00227).

Funding

The study was supported by Russian Science Foundation (No. 20-15-00227).

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Authors and Affiliations

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

    Iuliia Azarova & Alexander Konoplya

  2. 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 Azarova & Elena Klyosova

  3. Department of Surgical Diseases of Postgraduate Faculty, Kursk State Medical University, 3 Karl Marx Street, Kursk, Russian Federation, 305041

    Victor Lazarenko

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

    Alexey Polonikov

  5. 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 Polonikov

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  1. Iuliia Azarova
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  2. Elena Klyosova
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Contributions

IA: laboratory investigations, database handling, statistical and bioinformatics analysis, interpretation and discussion of study results, writing and revising the paper; EK: laboratory investigations, database handling, data curation; VL: project administration, instructions of clinical, laboratory and instrumental examination of the study patients; AK: instructions of patients enrollment, consultancy; AP: the study conception and design, supervision of the study, interpretation and discussion of the study results, writing and revising the paper. All authors read and approved the final manuscript.

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Correspondence to Iuliia Azarova.

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This study was performed in line with the principles of the Declaration of Helsinki. Approval was granted by the Ethics Committee of Kursk State Medical University (Date: 12.12.2016/No.10).

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Informed consent was obtained from all individual participants included in the study.

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Azarova, I., Klyosova, E., Lazarenko, V. et al. Genetic variants in glutamate cysteine ligase confer protection against type 2 diabetes. Mol Biol Rep 47, 5793–5805 (2020). https://doi.org/10.1007/s11033-020-05647-5

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