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Association between RAC1 gene variation, redox homeostasis and type 2 diabetes mellitus

Iuliia Azarova1,2, Elena Klyosova2, Alexey Polonikov3,4

  • 1Department of Biological Chemistry, Kursk State Medical University, Kursk, Russian Federation.

European Journal of Clinical Investigation
|April 13, 2022
PubMed
Abstract

Insights

Genetic variations in the RAC1 gene are linked to an increased risk of type 2 diabetes (T2D). These RAC1 gene polymorphisms influence glucose metabolism and redox balance, highlighting their role in T2D pathogenesis.

Area of Science:

  • Genetics
  • Metabolic Diseases
  • Biochemistry

Background:

  • Oxidative stress and reactive oxygen species (ROS) are implicated in type 2 diabetes (T2D) pathogenesis.
  • The role of NADPH oxidase enzyme genes in T2D susceptibility is not well understood.

Purpose of the Study:

  • To investigate the association between single-nucleotide polymorphisms (SNPs) in the RAC1 gene and T2D risk.
  • To explore the relationship between RAC1 gene variations, glucose metabolism, and redox homeostasis in T2D.

Main Methods:

  • Genotyping of six common RAC1 SNPs (rs4724800, rs7784465, rs10951982, rs10238136, rs836478, rs9374) in 3206 Russian individuals (1579 T2D patients, 1627 controls).
  • Utilized the MassArray-4 system for SNP genotyping.

Main Results:

  • SNP rs7784465 showed a significant association with increased T2D risk (p=0.0003).
  • RAC1 haplotypes and 17 genotype combinations were significantly associated with T2D risk.
  • Associations were modified by lifestyle factors including sedentary behavior, stress, diet, and carbohydrate intake.
  • RAC1 polymorphisms correlated with elevated glycated hemoglobin, fasting blood glucose, oxidized glutathione, and uric acid levels in T2D patients.
  • A specific RAC1 haplotype was strongly linked to increased hydrogen peroxide levels (p < 0.0001).

Conclusions:

  • Polymorphisms in the RAC1 gene are novel genetic markers for type 2 diabetes.
  • RAC1 gene variations are associated with altered glucose metabolism and redox homeostasis, contributing to T2D pathogenesis.
Keywords:
NADPH oxidaseRac family small GTPase 1glucose metabolismredox homeostasistype 2 diabetes

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