Hypermethylation in the promoter of the MTHFR gene is associated with diabetic complications and biochemical indicators

Mayara Karla Dos Santos Nunes; Alexandre Sérgio Silva; Isabella Wanderley de Queiroga Evangelista; João Modesto Filho; Cecília Neta Alves Pegado Gomes; Rayner Anderson Ferreira do Nascimento; Rafaella Cristhine Pordeus Luna; Maria José de Carvalho Costa; Naila Francis Paulo de Oliveira; Darlene Camati Persuhn

doi:10.1186/s13098-017-0284-3

Hypermethylation in the promoter of the MTHFR gene is associated with diabetic complications and biochemical indicators

Diabetol Metab Syndr. 2017 Oct 18:9:84. doi: 10.1186/s13098-017-0284-3. eCollection 2017.

Affiliations

¹ Post-Graduation Program in Cellular and Molecular Biology, Federal University of Paraiba, Joao Pessoa, Brazil.
² Physical Education Department, Federal University of Paraiba, Joao Pessoa, Brazil.
³ Ophthalmology Reference Center, Lauro Wanderley University Hospital, Federal University of Paraiba, Joao Pessoa, Brazil.
⁴ Department of Internal Medicine, Federal University of Paraiba, Joao Pessoa, Brazil.
⁵ Nephrology Clinic, Lauro Wanderley University Hospital, Federal University of Paraiba, Joao Pessoa, Brazil.
⁶ Faculty Mauricio of Nassau, Joao Pessoa, Brazil.
⁷ Post-Graduate Program in Nutrition Science, Federal University of Paraiba, Joao Pessoa, Brazil.
⁸ Nutrition Science Department and Post-Graduate Program in Nutrition Science, Federal University of Paraiba, Joao Pessoa, Brazil.
⁹ Department of Molecular Biology, Federal University of Paraiba, Joao Pessoa, Brazil.
¹⁰ Department of Molecular Biology and Post-Graduation Program in Nutrition Science, Federal University of Paraiba, CEP 58051-900 Joao Pessoa, Brazil.

Abstract

Background: DNA 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).

Methods: Specific 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.

Results: The 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.

Conclusions: Hypermethylation 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.