Genetic and biochemical investigation of the gamma-glutamylcyclotransferase role in predisposition to type 2 diabetes mellitus

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Abstract


Background. Imbalance in the system of redox homeostasis is an important link in the pathogenesis of type 2 diabetes (T2D). Gamma-glutamyl cyclotransferase is an antioxidant defense enzyme directly involved in the metabolism of glutathione, an endogenous antioxidant.

The aim of the study was to examine the association of single nucleotide polymorphisms (SNP) rs38420 (G > A), rs4270 (T > C), rs6462210 (C > T) and rs28679 (G > A) in GGCT gene with the risk of developing T2D.

Materials and Methods. The study included 1022 T2D patients and 1064 healthy volunteers. Genotyping of GGCT gene loci was performed using iPLEX technology on a MassARRAY Analyzer 4 genome time-of-flight mass spectrometer (Agena Bioscience).

Results. As a result, we identified for the first time the association of SNP rs4270 in the GGCT gene with the risk of T2D in the Russian population. We have also established genetic and environmental interactions associated with predisposition to the disease: protective effect of gamma-glutamyl cyclotransferase gene was observed only in non-smokers under condition of daily consumption of fresh vegetables and fruits, whereas in persons with insufficient consumption of plant foods, as well as in all smoking patients protective effect of GGCT was not observed. In patients with T2D, the level of hydrogen peroxide and glutathione monomer was sharply increased compared to the controls. SNP rs4270 was also found to be associated with elevated levels of reduced glutathione in the plasma of type 2 diabetics.

Conclusion. Thus, for the first time it was established that polymorphic locus rs4270 in the GGCT gene is associated with a predisposition to T2D, but its relationship with the disease is modulated by smoking and fresh plant foods consumption.


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About the authors

Iuliia E. Azarova

Kursk State Medical University

Author for correspondence.
Email: azzzzar@yandex.ru
ORCID iD: 0000-0001-8098-8052
SPIN-code: 9173-3698
Scopus Author ID: 57200117409
ResearcherId: S-7266-2018
Mendeley Profile: https://www.mendeley.com/profiles/iuliia-azarova/

Russian Federation, Kursk

MD, PhD, Associate Professor of Department of Biological Chemistry of KSMU, Head of Laboratory of Biochemical Genetics and Metabolomics of Research Institute for Genetic and Molecular Epidemiology

Elena Yu. Klyosova

Kursk State Medical University

Email: ecless@yandex.ru
ORCID iD: 0000-0002-1543-9230
SPIN-code: 5121-7160

Russian Federation, Kursk

Biotechnologist of the Laboratory of Biochemical Genetics and Metabolomics of Research Institute of Genetic and Molecular Epidemiology of KSMU

Mikhail I. Churilin

Kursk State Medical University

Email: mpmi2@yandex.ru
ORCID iD: 0000-0002-6064-986X
SPIN-code: 7728-6220
ResearcherId: 779606

Russian Federation, Kursk

Assistant Lecturer of Department of Infectious Diseases

Tatiana A. Samgina

Kursk State Medical University

Email: tass@list.ru
ORCID iD: 0000-0002-7781-3793
SPIN-code: 9973-9738

Russian Federation, Kursk

MD, PhD, Associate Professor, Associate Professor of Department of Surgical Diseases No. 2

Alexander I. Konoplya

Kursk State Medical University

Email: konoplya51@mail.ru
ORCID iD: 0000-0003-4748-8405
SPIN-code: 9631-2390
Scopus Author ID: 6602518934
ResearcherId: H-2197-2013
Mendeley Profile: https://www.mendeley.com/profiles/alexander-konoplya/

Russian Federation, Kursk

MD, PhD, Professor, Professor of Department of Biological Chemistry

Alexey V. Polonikov

Kursk State Medical University

Email: polonikov@rambler.ru
ORCID iD: 0000-0001-6280-247X
SPIN-code: 6373-6556
Scopus Author ID: 6506508435
ResearcherId: R-7537-2016

Russian Federation, Kursk

MD, PhD, Professor, Professor of Department of Biology, Medical Genetics and Ecology, Head of Laboratory of Statistical Genetics and Bioinformatics of Research Institute for Genetic and Molecular Epidemiology

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Supplementary files

Supplementary Files Action
1.
A network of proteins formed by gamma-glutamylcyclotransferase. GGCT - gamma-glutamylcyclotransferase; OPLAH - 5-oxoprolinase; GGACT - gamma-glutamylamine cyclotransferase; GCLC - glutamate cysteine ligase, catalytic subunit; GCLM - glutamate cysteine ligase modifying subunit; GSS - glutathione synthetase; ANPEP - aminopeptidase N; GGT1 - gamma-glutamyltransferase 1; GGT5 - gamma-glutamyltransferase 5; GGT6 - gamma-glutamyltransferase 6; GGT7 - gamma-glutamyltransferase 7

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Copyright (c) 2020 Azarova I.E., Klyosova E.Y., Churilin M.I., Samgina T.A., Konoplya A.I., Polonikov A.V.

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