Association of DNMT3A Polymorphism, Oxidative Stress, and Global DNA Methylation in Type 2 Diabetes Mellitus Patients

BACKGROUND/AIMS: DNA methylation is a critical epigenetic mechanism involved in the regulation of gene expression, including genes implicated in glucose metabolism. Despite growing evidence indicating that epigenetic mechanisms are involved in the pathogenesis and progression of type 2 diabetes mellitus (T2DM), available data remain limited. This study analyzed the genetic association of two single-nucleotide polymorphisms (SNPs) in the DNA methyltransferase 3A (DNMT3A) gene, rs11683424 and rs1550117, with T2DM susceptibility and investigated their potential associations with global DNA methylation. METHODS: Total antioxidant status (TAS) and total oxidant status (TOS) were evaluated, the oxidative stress index (OSI) was calculated, and diabetes-related parameters were assessed in T2DM patients and healthy controls, including HbA1c, fasting blood glucose (FBG), insulin, insulin sensitivity (IS), and insulin resistance (IR). Global DNA methylation was determined, and rs11683424 and rs1550117 were genotyped. Associations between metabolic and oxidative stress parameters, global DNA methylation, DNMT3A genotypes, and T2DM status were statistically analyzed. RESULTS: T2DM patients exhibited significantly higher HbA1c, FBG, insulin, and IR levels than healthy controls (p=0.001), whereas IS was significantly lower (p=0.001). TAS, TOS, and OSI were significantly increased in T2DM patients compared with controls (p=0.001), as was global DNA methylation (p=0.001). In patients, a weak but statistically significant inverse correlation was observed between 5mC levels and BMI. Global methylation showed weak inverse associations with TAS and TOS; however, these associations did not reach statistical significance. No significant associations (p>0.05) were observed between 5mC levels and the other studied biomarkers. Neither regression model for predictors of global DNA methylation was statistically significant in T2DM patients (F(5,94)=0.852, p=0.516) or healthy controls (F(4,95)=0.592, p=0.669), and all variance inflation factor (VIF) values were <2.0. For rs11683424, the CT genotype was detected in 15.6% of T2DM patients compared with 2.6% of controls (OR=6.81, 95% CI=1.50-31.25, χ²=7.902, p=0.005). The T allele was present at frequencies of 7.8% and 1.3%, respectively (χ²=7.502, p=0.006). In contrast, rs1550117 was not significantly associated with T2DM. Linkage disequilibrium analysis indicated incomplete or moderate linkage disequilibrium between the two SNPs. The CG haplotype was the most common in both groups, whereas the TG and TA haplotypes were enriched among patients and showed increased disease odds, particularly TG (OR=7.89); however, neither association reached statistical significance. Genotype-phenotype analyses revealed only limited differences in global DNA methylation among the investigated genotypes. CONCLUSION: T2DM was associated with altered oxidative stress parameters and increased global DNA methylation. The findings further indicate a potential association between DNMT3A rs11683424 and T2DM susceptibility, whereas rs1550117 was not significantly associated with disease status. However, the data do not establish a direct relationship between the investigated DNMT3A variants, oxidative stress, and global DNA methylation. These findings warrant validation in larger, multi-ethnic cohorts.