Role of cyba gene polymorphisms in pathogenesis of type 2 diabetes mellitus

Impairments of redox homeostasis play a key role in the development of type 2 diabetes mellitus (T2D). The main endogenous source of the superoxide radical is NADPH oxidase, one of the subunits of which is the light chain of cytochrome b-245, CYBA. The aim of the study was to study the associations of cytochrome b-245 alpha chain gene polymorphisms rs7195830 (G>A), rs8854 (C>T), rs9932581 (C>T) and rs4673 (G>A) with a risk of developing T2D. The study included 1022 patients with T2D (average age 61,1 ± 7,2 years) and 1064 sex-and age-matched healthy volunteers. Genotyping of CYBA gene polymorphisms was performed using iPLEX technology on a MassArray Analyzer 4 genome time-of-flight mass spectrometer (Agena Bioscience). The CYBA gene A/A genotype (rs4673, G>A) was associated with an increased risk of developing the disease (OR 1,49, 95%CI 1,11-1,99, P=0,0074, recessive model). The identified association remained significant even after the adjustment for gender, age, and body mass index (ORadj 1,51, 95%CI 1,09-2,09, padj=0,014). Gender-stratified analysis revealed that the established association rs4673 was characteristic only for females (ORadj 1,60, 95% CIadj 1,04-2,46, padj= 0,032). Patients with T2D had a significantly higher level of hydrogen peroxide in blood plasma compared with the control group (p<0,05), regardless of gender, however, the relationship between the A/A genotype rs4673 with the increase in the content of Н2О2 in plasma by 0,77 mmol/L (p = 0,044) was found only in males. The T/T genotype rs9932581 was associated with an increase in glycated hemoglobin level of 2,71% (p = 0,042) in the general group of patients with T2D, as well as with an increase in the same indicator by 4,44% (p = 0,03) among females. The association of the C/T genotype rs9932581 with an increase in the proportion of HbA1c by 0,61% (p = 0,018) and with an increase in blood glucose level by 1,06 mmol/L (p = 0,029) was noted exclusively in males. The association of fasting blood glucose level was also established with genotype A/A rs7195830, in which carriers the glucose concentration was 1.17 mmol/L higher than in homozygotes for the reference allele (P = 0,022).

сахарный диабет 2 типа, НАДФН-оксидаза, цитохром b-245, однонуклеотидный полиморфизм, наследственная предрасположенность, оксидантный стресс, type 2 diabetes mellitus, NADPH oxidase, cytochrome b-245, single nucleotide polymorphism, genetic predisposition, oxidative stress