Liu Yuwei, Shen Yu, Guo Tao, Parnell Laurence D, Westerman Kenneth E, Smith Caren E, Ordovas Jose M, Lai Chao-Qiang
School of Public Health, Fudan University, Shanghai, China.
Nutrition and Genomics Laboratory, JM-USDA Human Nutrition Research Center on Aging at Tufts University, Boston, MA, United States.
Front Genet. 2020 Jun 16;11:622. doi: 10.3389/fgene.2020.00622. eCollection 2020.
Statin is the medication most widely prescribed to reduce plasma cholesterol levels. Yet, how the medication contributes to diabetes risk and impaired glucose metabolism is not clear. This study aims to examine the epigenetic mechanisms of through which statin use associates with risk of type 2 diabetes. We determined the association between the statin use, DNA methylation at and type 2 diabetes/glycemic traits in the Framingham Heart Study Offspring (FHS, = 2741), with validation in the Women's Health Initiative Study (WHI, = 2020). The causal effect of statin use on the risk of type 2 diabetes was examined using a two-step Mendelian randomization approach. Next, based on transcriptome analysis, we determined the links between the medication-associated epigenetic status of and biological pathways on the pathogenesis of type 2 diabetes. Our results showed that DNA methylation levels at cg06500161 of were positively associated with the use of statin, type 2 diabetes and related traits (fasting glucose and insulin) in FHS and WHI. Two-step Mendelian randomization suggested a causal effect of statin use on type 2 diabetes and related traits through epigenetic mechanisms, specifically, DNA methylation at cg06500161. Our results highlighted that gene expression of and , involved in both cholesterol metabolism and glycemic pathways, was inversely associated with statin use, CpG methylation, and diabetic signatures. We concluded that DNA methylation site cg06500161 at is a mediator of the association between statins and risk of type 2 diabetes.
他汀类药物是最广泛用于降低血浆胆固醇水平的药物。然而，该药物如何导致糖尿病风险和葡萄糖代谢受损尚不清楚。本研究旨在探讨他汀类药物使用与2型糖尿病风险相关的表观遗传机制。我们在弗雷明汉心脏研究后代队列（FHS，n = 2741）中确定了他汀类药物使用、某基因位点的DNA甲基化与2型糖尿病/血糖特征之间的关联，并在妇女健康倡议研究（WHI，n = 2020）中进行了验证。使用两步孟德尔随机化方法研究了他汀类药物使用对2型糖尿病风险的因果效应。接下来，基于转录组分析，我们确定了该基因位点与药物相关的表观遗传状态和2型糖尿病发病机制中的生物学途径之间的联系。我们的结果表明，在FHS和WHI中，某基因位点的cg06500161处的DNA甲基化水平与他汀类药物的使用、2型糖尿病及相关特征（空腹血糖和胰岛素）呈正相关。两步孟德尔随机化表明，他汀类药物使用通过表观遗传机制，特别是cg06500161处的DNA甲基化，对2型糖尿病及相关特征有因果效应。我们的结果强调，参与胆固醇代谢和血糖途径的某基因和另一基因的表达与他汀类药物使用、CpG甲基化和糖尿病特征呈负相关。我们得出结论，某基因位点的DNA甲基化位点cg06500161是他汀类药物与2型糖尿病风险之间关联的一个中介因素。
