BackgroundDNA methylation is an epigenetic mechanism for regulating the transcription of many genes and has been linked to the development of various diseases. A promising gene to investigate is methylenetetrahydrofolate reductase (MTHFR), since the enzyme methylenetetrahydrofolate reductase (MTHFR) promotes methyl radical synthesis in the homocysteine cycle and can provide methyl groups for DNA methylation. In addition, several studies have correlated gene polymorphisms of this enzyme with a greater risk of diabetes, but little is known regarding the relationship between epigenetic changes in this gene and diabetes and its complications. The aim of this study was to investigate the relationship between methylation profile in the MTHFR gene promoter and biochemical, inflammatory and oxidative stress markers in individuals with type 2 diabetes (T2DM) who have been diagnosed for 5–10 years with or without diabetic retinopathy (DR) and nephropathy (DN).MethodsSpecific PCR for methylation (MSP) was used to analyze MTHFR methylation profile in leucocytes DNA. Biochemical markers (glycemia, glycated hemoglobin, total cholesterol, LDL, HDL, triglycerides, serum creatinine), inflammatory markers (C-reactive protein and alpha-1 acid glycoprotein) and oxidative stress (total antioxidant and malonaldehyde) were determined in peripheric blood samples and microalbuminuria in 24 h urine samples. The X2 and Mann–Whitney statistical tests were performed and p < 0.05 were considered significant.ResultsThe hypermethylated profile was most frequently observed in individuals with retinopathy (p < 0.01) and was associated with higher total cholesterol and LDL levels (p = 0.0046, 0.0267, respectively). Individuals with DN and hypermethylated profiles had higher levels of alpha-1 acid glycoprotein (p = 0.0080) and total antioxidant capacity (p = 0.0169) compared to subjects without complications.ConclusionsHypermethylation in the promoter of the MTHFR gene is associated with the occurrence of DR and with biochemical, inflammatory and oxidative stress parameters in the context of chronic complications

BackgroundPolymorphisms in the gene encoding methylenetetrahydrofolate reductase (MTHFR) have been investigated as risk factors for microvascular complications of diabetes; however, simultaneous analysis of these polymorphisms and the methylation pattern of the gene has never been conducted. The objective of the present study was to evaluate the simultaneous relationship between MTHFR methylation and MTHFR C6TT7 and A1298C polymorphisms with metabolic, inflammatory and oxidative stress parameters related to microvascular complications, diabetic retinopathy (DR) and diabetic nephropathy (DN) in diabetic patients.MethodsA total of 107 patients who were diagnosed in the previous 5 to 10 years were recruited and divided into groups with complications (DR and/or DN) or without complications. Methylation analysis of the gene promoter was conducted using the MSP technique, and analysis of the A1298C and C677T polymorphisms was conducted using the restriction fragment length polymorphism (RFLP) assay. Microalbuminuria was determined using urine samples, and other analytes of interest were determined in blood samples using commercial kits. The Mann–Whitney and Chi square statistical tests were used with significance considered at p < 0.05.ResultsSubjects with a hypermethylated profile and the 1298AA genotype showed the highest levels of blood glucose (p = 0.03), total cholesterol (p = 0.0001) and LDL cholesterol (p = 0.0006). The same profile was associated with higher levels of HbA1c (p = 0.025), glycemia (p = 0.04) and total cholesterol (0.004) in the control group and total cholesterol (p = 0.005) and LDL cholesterol (p = 0.002) in the complications group. Serum creatinine was higher in subjects in the hypermethylated group with the genotype 677CC only in the control group (p = 0.0020). The methylated profile in presence of 677CC + 1298AA and the 677CT/TT +1298AA haplotypes showed higher levels of total cholesterol (p = 0.0024; 0.0031) and LDL cholesterol (p = 0.0060; 0.0125) than 1298AC/CC carriers. The fasting glycemia was higher in hypermethylated profile in the presence of 677CC/1298AA haplotype (p = 0.0077).ConclusionThe hypermethylated methylation profile associated with the 1298AA genotype appeared to be connected to higher values of glycemia, total cholesterol and LDL cholesterol.

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