The association of DNA methylation patterns in TCF7L2 and GIPR genes with Type 2 Diabetes

TCF7L2 is the susceptibility gene for Type 2 diabetes (T2D) with the largest effect on disease risk that has been discovered to date. However, the mechanisms by which TCF7L2 contributes to the disease remain largely elusive. In addition, epigenetic mechanisms, such as changes in DNA methylation patterns, might have a role in the pathophysiology of T2D. This study aimed to investigate the differences in terms of DNA methylation profile of TCF7L2 promoter gene between type 2 diabetic patients and ageand Body Mass Index (BMI)matched controls. We included 93 type 2 diabetic patients that were recently diagnosed for T2D and exclusively on diet (without any pharmacological treatment). DNA was extracted from whole blood and DNA methylation was assessed using the Sequenom EpiTYPER system. Type 2 diabetic patients were more insulin resistant than their matched controls (mean HOMA IR 2.6 vs 1.8 in controls, P,0.001) and had a poorer beta-cell function (mean HOMA B 75.7 vs. 113.6 in controls, P,0.001). Results showed that 59% of the CpGs analyzed in TCF7L2 promoter had significant differences between type 2 diabetic patients and matched controls. In addition, fasting glucose, HOMA-B, HOMAIR, total cholesterol and LDL-cholesterol correlated with methylation in specific CpG sites of TCF7L2 promoter. After adjustment by age, BMI, gender, physical inactivity, waist circumference, smoking status and diabetes status uniquely fasting glucose, total cholesterol and LDL-cholesterol remained significant. Taken together, newly diagnosed, drug-naive type 2 diabetic patients display specific epigenetic changes at the TCF7L2 promoter as compared to ageand BMI-matched controls. Methylation in TCF7L2 promoter is further correlated with fasting glucose in peripheral blood DNA, which sheds new light on the role of epigenetic regulation of TCF7L2 in T2D. Citation: Canivell S, Ruano EG, Siso-Almirall A, Kostov B, Gonzalez-de Paz L, et al. (2014) Differential Methylation of TCF7L2 Promoter in Peripheral Blood DNA in Newly Diagnosed, Drug-Naive Patients with Type 2 Diabetes. PLoS ONE 9(6): e99310. doi:10.1371/journal.pone. 0099310 Editor: Arto Mannermaa, University of Eastern Finland, Finland Received December 9, 2013; Accepted May 13, 2014; Published June 10, 2014 Copyright: 2014 Canivell et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Funding: This work was supported by the FIS Grant PI 1000219, the MEDIGENE project, grant agreement number 279171, funded by the EC Seventh Framework Programme theme FP7-HEALTH-2011 and by the Spanish Ministry of Science and Innovation (under the grant agreement number SAF 2010-19527). CIBER de Diabetes y Enfermedades Metabolicas is an initiative of ISCIII (Spanish Ministry of Science and Innovation). Dr. Canivell was awarded with the Rio Hortega Grant from the Spanish Ministry of Science and Innovation. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Competing Interests: The authors have declared that no competing interests exist. * E-mail: ramon.gomis@idibaps.org