Polymorphic Variants of the Neutrophil Cytosolic Factor 2 Gene: Associations with Susceptibility to Type 2 Diabetes Mellitus and Cardiovascular Autonomic Neuropathy

We examined 3206 unrelated individuals of Slavic origin (1579 T2DM patients, including 535 patients with cardiovascular autonomic neuropathy, and 1627 healthy volunteers). SNPs were genotyped with the use of a MassArray Analyzer 4 genomic time-of-flight mass spectrometer. Statistical analysis of the obtained data was performed using the SNPStats software program. The genotype rs17849502-G/T NCF2 was found to be associated with the increased risk of T2DM (OR = 1.42, 95% CI = 1.08-1.87, P = 0.043). Analysis of the NCF2 genotype frequencies stratified by body mass index (BMI) showed that the rs17849502-G/T genotype was statistically significantly more frequent only in patients who were overweight and obese (OR = 1.34, 95% CI = 1.01-1.77, P = 0.012). In addition, the rs789180-A/T (OR = 1.46, 95% CI = 1.11-1.92, P = 0.015) and rs10911363-G/T (OR = 0.77, 95% CI = 0.61-0.97, P = 0.046) genotypes were found to be associated with cardiovascular autonomic neuropathy in T2DM regardless of sex, age, and BMI of the patients. Analysis of the effect of NCF2 polymorphism on the blood plasma biochemical parameters showed that, in the carriers of the H5 rs796860A-rs789180T-rs17849502G-rs2274064C-rs10911363G-rs147415774C-rs2274065A-rs3754515C haplotype, the glycated hemoglobin level was 4.81% higher (95% CI = 2.63-6.98, P < 0.0001) compared to that in the carriers of the reference haplotype H1 rs796860A-rs789180A-rs17849502G-rs2274064T-rs10911363G-rs147415774C-rs2274065A-rs3754515C. Thus, in this study, associations of the NCF2 rs17849502 with the risk of T2DM, as well as associations of rs789180 and rs10911363 with cardiovascular autonomic neuropathy, were demonstrated for the first time. The data obtained point to considerable contribution of the NCF2 polymorphism to the pathogenesis of T2DM and lay the groundwork for further studies of genetic and biochemical alterations of the redox homeostasis system in type 2 diabetes mellitus.