NADPH oxidase 5 is a novel gene for type 2 diabetes susceptibility determined by gene-body mass index and gene-environment interactions

Abstract Due to the role that oxidative stress plays in the pathophysiology of type 2 diabetes (T2D), polymorphic genes that encode enzymes producing reactive oxygen species represent attractive targets for genetic disease susceptibility testing. This pilot study investigated whether single nucleotide polymorphisms (SNP) in the NOX5 gene (NADPH oxidase 5) are associated with the risk of type 2 diabetes. A total of 1579 T2D patients and 1627 age- and sex-matched healthy subjects were recruited for this study. Genotyping of five common SNPs, namely rs35672233, rs3743093, rs2036343, rs311886, and rs438866, was performed using the MassArray-4 system. SNP rs35672233 of the NOX5 gene was strongly associated with an increased risk of T2D (P < 0.0001). The haplotype rs35672233T-rs3743093G-rs2036343A-rs311886C-rs438866C of NOX5 was associated with T2D susceptibility (OR = 1.65, 95% CI 1.27–2.13, FDR = 0.001). Joint effects on disease risk were found for the seven NOX5 diplotypes (FDR < 0.05). However, the impact of the rs35672233 polymorphism on diabetes risk occurred only in subjects with a body mass index greater than 25 kg/m2 (OR = 1.70, 95% CI 1.28–2.25, FDR = 0.006). Furthermore, synergistic effects on T2D risk were observed between the rs35672233 polymorphism and environmental risk factors such as chronic psycho-emotional stress (P = 0.015), physical inactivity (P = 0.0002), and a high-calorie diet (P = 0.019), suggesting that gene-environment interactions play a key role in the disease development. The results of the study show, for the first time, that NOX5 gene polymorphisms are unique susceptibility markers for type 2 diabetes and that their effects on disease risk are influenced by recognized environmental risk factors for diabetes.