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

Abstract

Increased production of reactive oxygen species (ROS) and oxidative stress are known to play a key role in the pathogenesis of type 2 diabetes (T2D); however, the relationship between genes encoding a multi-subunit ROS-generated enzyme NADPH oxidase and disease susceptibility remains unexplored. The present pilot study investigated whether single-nucleotide polymorphisms (SNP) at the RAC1 gene (Rac family small GTPase 1), a molecular switcher of NADPH oxidase, are associated with the risk of T2D, glucose metabolism and redox homeostasis. DNA samples from 3206 unrelated Russian subjects (1579 T2D patients and 1627 controls) were genotyped for six common SNPs rs4724800, rs7784465, rs10951982, rs10238136, rs836478 and rs9374 of RAC1 using the MassArray-4 system. SNP rs7784465 was associated with an increased risk of T2D (p=.0003), and significant differences in the RAC1 haplotypes occurred between the cases and controls (p=.005). Seventeen combinations of RAC1 genotypes showed significant associations with T2D risk (FDR <0.05). Associations of RAC1 polymorphisms with T2D were modified by environmental factors such as sedentary lifestyle, psychological stresses, a dietary deficit of fresh fruits/vegetables and increased carbohydrate intake. RAC1 polymorphisms were associated with biochemical parameters in diabetics: rs7784465 (p=.015) and rs836478 (p=.028) with increased glycated haemoglobin, rs836478 (p=.005) with increased fasting blood glucose, oxidized glutathione (p=.012) and uric acid (p=.034). Haplotype rs4724800A-rs7784465C-rs10951982G-rs10238136A-rs836478C-rs9374G was strongly associated with increased levels of hydrogen peroxide (p<.0001). Thus, polymorphisms in the RAC1 gene represent novel genetic markers of type 2 diabetes, and their link with glucose metabolism and disease pathogenesis is associated with the changes in redox homeostasis.