Introduction: The role of DNA methylation in metabolic dysregulation is emerging. However, the functional role of methylation in obesity and metabolic dysregulation is poorly understood. Aim: The aim of this study was to compare DNA methyltransferase-3A (DNMT3A) and ten-eleven translocase-2 (TET2) levels in children and adolescents with obesity to normal-weighed children and adolescents and to correlate them to various metabolic parameters. Methods: Fifty children and adolescents with obesity were compared to 50 matched normal-weighed children and adolescents. Participants underwent assessment for anthropometric measurements, Tanner staging, acanthosis nigricans, and mean blood pressure percentile on three different occasions. TET2, DNMT3A, fasting lipids, and insulin were measured with calculation of the homeostatic model assessment insulin resistance (HOMA-IR). Results: The median BMI SDS of the studied children and adolescents with obesity was 3.40, their mean TET2 was 178.40 ng/mL, and their mean DNMT3A was 2.18 ng/mL. TET2 is significantly lower (p = 0.009), while DNMT3A is significantly higher (p < 0.001) in children and adolescents with obesity than controls. Children and adolescents with obesity and insulin resistance have significantly lower TET2 (p = 0.012) and significantly higher DNMT3A (p = 0.013) than those without insulin resistance. Diastolic blood pressure percentile and HOMA-IR are positively correlated to DNMT3A (p < 0.001) and negatively correlated to TET-2 (p < 0.001). Multivariate logistic regression analysis revealed that TET2 and DNMT3A are independently associated with diastolic blood pressure percentile (p = 0.03 and p = 0.014, respectively) and HOMA-IR (p = 0.003 and p = 0.001, respectively). Conclusions: Children and adolescents with obesity have significantly higher DNMT3A and significantly lower TET2 than controls. This is more evident in those having insulin resistance than those without. DNMT3A and TET2 are independently associated with systemic hypertension and insulin resistance in children with obesity.

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