Canivell Silvia, Ruano Elena G, Sisó-Almirall Antoni, Kostov Belchin, González-de Paz Luis, Fernandez-Rebollo Eduardo, Hanzu Felicia A, Párrizas Marcelina, Novials Anna, Gomis Ramon
Department of Endocrinology and Nutrition, Hospital Clinic, Barcelona, Spain; Les Corts Primary Health Care Centre, PHC Research Group, IDIBAPS, Barcelona, Spain; Diabetes and Obesity Laboratory, IDIBAPS, Barcelona, Spain.
Diabetes and Obesity Laboratory, IDIBAPS, Barcelona, Spain; CIBERDEM, Barcelona, Spain.
PLoS One. 2014 Jun 10;9(6):e99310. doi: 10.1371/journal.pone.0099310. eCollection 2014.
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 age- and 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, HOMA-IR, 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-naïve type 2 diabetic patients display specific epigenetic changes at the TCF7L2 promoter as compared to age- and 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.
TCF7L2是2型糖尿病（T2D）的易感基因，是迄今为止发现的对疾病风险影响最大的基因。然而，TCF7L2导致该疾病的机制在很大程度上仍不清楚。此外，表观遗传机制，如DNA甲基化模式的变化，可能在T2D的病理生理学中起作用。本研究旨在调查2型糖尿病患者与年龄和体重指数（BMI）匹配的对照组之间TCF7L2启动子基因DNA甲基化谱的差异。我们纳入了93名最近被诊断为T2D且仅接受饮食治疗（未接受任何药物治疗）的2型糖尿病患者。从全血中提取DNA，并使用Sequenom EpiTYPER系统评估DNA甲基化。2型糖尿病患者比其匹配的对照组胰岛素抵抗更强（平均稳态模型评估胰岛素抵抗指数[HOMA IR]：患者为2.6，对照组为1.8，P<0.001），且β细胞功能更差（平均稳态模型评估β细胞功能指数[HOMA B]：患者为75.7，对照组为113.6，P<0.001）。结果显示，在TCF7L2启动子中分析的59%的CpG在2型糖尿病患者和匹配的对照组之间存在显著差异。此外，空腹血糖、HOMA-B、HOMA-IR、总胆固醇和低密度脂蛋白胆固醇与TCF7L2启动子特定CpG位点的甲基化相关。在按年龄、BMI、性别、缺乏身体活动、腰围、吸烟状况和糖尿病状态进行调整后，仅空腹血糖、总胆固醇和低密度脂蛋白胆固醇仍具有显著性。综上所述，与年龄和BMI匹配的对照组相比，新诊断的、未接受药物治疗的2型糖尿病患者在TCF7L2启动子处表现出特定的表观遗传变化。TCF7L2启动子中的甲基化与外周血DNA中的空腹血糖进一步相关，这为TCF7L2的表观遗传调控在T2D中的作用提供了新的线索。
