ABSTRACT

Obesity is a major risk factor for cardiovascular disease. Blood-detected epigenetic profiles may serve as non-invasive clinically relevant biomarkers. Therefore, we investigated DNA methylation of genes involved in inflammation in peripheral blood of obese subjects and lean controls and their correlation with cardiometabolic measurements. We obtained blood and adipose tissue (AT) samples from bariatric patients (n = 24) and control adults (n = 24). AT-isolated arterioles were tested for flow-induced dilation (FID) and production of nitric oxide (NO) and reactive oxygen species (ROS). Brachial artery flow-mediated dilation (FMD) was measured via doppler ultrasound. Promoter methylation of 94 genes involved in inflammation and autoimmunity were analysed in whole-blood DNA in relation to vascular function and cardiometabolic risk factors. 77 genes had ahigher methylated fraction in the controls compare obese subjects and 28 proinflammatory genes were significantly hypomethylated in the obese individuals; on top of these genes are CXCL1, CXCL12, CXCL6, IGF2BP2, HDAC4, IL12A, and IL17RA. Fifteen of these genes had significantly higher mRNA in obese subjects compared to controls; on top of these genes are CXCL6, TLR5, IL6ST, EGR1, IL15RA, and HDAC4. Methylation % inversely correlated with BMI, total fat %, visceral fat%, blood pressure, fasting plasma insulin, serum IL6 and C-reactive protein, arteriolar ROS, and alcohol consumption and positive correlations with lean %, HDL, plasma folate and vitamin B12, arteriolar FID and NO production, and brachial FMD. Our results suggest that vascular dysfunction in obese adults may be attributed to asystemic hypomethylation and over expression of the immune-related genes.

摘要

肥胖是心血管疾病的主要危险因素。血液检测到的表观遗传谱可作为非侵入性临床相关生物标志物。因此，我们研究了肥胖受试者和瘦对照者外周血炎症相关基因的 DNA 甲基化及其与心脏代谢测量的相关性。我们从肥胖患者 (n = 24) 和对照成人 (n = 24) 获得血液和脂肪组织 (AT) 样本。测试了 AT 分离的小动脉的流动诱导扩张 (FID) 和一氧化氮 (NO) 和活性氧 (ROS) 的产生。通过多普勒超声测量肱动脉血流介导的扩张 (FMD)。在与血管功能和心脏代谢危险因素相关的全血 DNA 中分析了 94 个与炎症和自身免疫有关的基因的启动子甲基化。与肥胖受试者相比，对照组中有 77 个基因甲基化程度较高，肥胖个体中有 28 个促炎基因显着低甲基化；在这些基因之上是CXCL1、CXCL12、CXCL6、IGF2BP2、HDAC4、IL12A和IL17RA。与对照组相比，其中 15 个基因在肥胖受试者中的 mRNA 显着升高；在这些基因之上是CXCL6、TLR5、IL6ST、EGR1、IL15RA和HDAC4。甲基化百分比与 BMI、总脂肪百分比、内脏脂肪百分比、血压、空腹血浆胰岛素、血清 IL6 和 C 反应蛋白、小动脉 ROS 和饮酒量呈负相关，与瘦肉百分比、HDL、血浆叶酸和维生素 B12 呈正相关，小动脉 FID 和 NO 产生，以及肱 FMD。我们的研究结果表明，肥胖成人的血管功能障碍可能归因于全身性低甲基化和免疫相关基因的过度表达。