The MTHFR promoter hypermethylation pattern associated with the A1298C polymorphism influences lipid parameters and glycemic control in diabetic patients

Abstract

Polymorphisms 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. A 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. Subjects 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). The hypermethylated methylation profile associated with the 1298AA genotype appeared to be connected to higher values of glycemia, total cholesterol and LDL cholesterol.