高血压合并阻塞性睡眠呼吸暂停综合征患者中葡萄糖转运蛋白4 DNA高甲基化

DNA hypermethylation of glucose transporters 4 gene in hypertensives with obstructive sleep apnea syndrome

目的 探讨高血压人群中葡萄糖转运蛋白4（GLUT4）基因DNA甲基化与阻塞性睡眠呼吸暂停综合征（OSAS）的关系。方法 研究对象为2010年1-3月新疆维吾尔自治区人民医院高血压科连续入院患者,选取14例年龄30～50岁、肝肾功能正常、诊断高血压合并重度OSAS的汉族男性作为OSAS组。选取16例年龄、体质量指数（BMI）与OSAS组匹配的非OSAS汉族男性原发性高血压患者为对照组。对GLUT4基因进行massARRAY甲基化定量检测。发现甲基化差异位点后,扩大样本量（中重度OSAS组66例和对照组39例）,对该位点所在CpG岛进一步行massARRAY检测,进一步分析探索OSAS患者GLUT4基因甲基化位点。结果 OSAS组GLUT4基因所有CpG单位甲基化与对照组比较,差异无统计学意义,然而在非糖尿病人群中发现,位点2.10[3.0（2.0~6.5）比0.5（0~3.0）,P=0.014]、位点2.14[6.0（2.0~9.5）比1.5（0~4.0）,P=0.004]两个位点OSAS组甲基化水平高于对照组。Spearman相关分析显示位点2.10、位点2.14甲基化水平与OSAS低氧指标最低血氧饱和度呈负相关（位点2.10 rs=-0.480,P=0.008;位点2.14 rs=-0.520,P=0.004）。扩大样本量后发现,中重度OSAS组患者位点2.10、位点2.14甲基化水平高于对照组[位点2.10：9.0（4.5~55.0）比4.5（2.0~23.0）,位点2.14：13.5（6.0~40.3）比6.0（2.0~24.0）;均P〈0.05],另发现位点2.3、位点2.6、位点2.7、位点2.9、位点2.13和位点2.17甲基化水平也高于对照组（均P〈0.05）。结论 在高血压合并OSAS的非糖尿病人群,成年男性患者GLUT4基因存在高甲基化状态,且与OSAS引起的低氧指标相关。

Objective To investigate the relationship between DNA methylation level of glucose transporter 4 （GLUT4} gene and obstructive sleep apnea syndrome （OSAS） in hypertensive patients. Methods All the subjects were consecutively recruited from Hypertension Department, Xinjiang Autonomous Region People＇s Hospital between January and March in 2010. Fourteen Han Chinese male hypertensives complicated with severe OSAS, aged 30--50 years old, with normal liver and kidney function were served as the OSAS group. While 16 age-, body mass index （BMI）-matched Han Chinese male hypertensives without OSAS were selected as the control group. DNA methylation of GLUT4 gene was quantitatively detected. Sample sizes were increased to 66 cases in OSAS group and 39 cases in control group after the detection of aberrant methylation sites. The massARRAY analyses of CpG island at those sites were performed to further analyze DNA methylation levels of GLUT4 gene in OSAS patients. Results DNA methylation level of GLUT4 gene showed no significant differences between OSAS and control group, whereas DNA methylation level of the locus 2.10 and locus 2.14 were significantly higher in OSAS subjects without diabetes than in the control group[loc2.10：3.0 （2.0-6.5） vs 0.5（0-3.0）, P=0. 014; loc2.14： 6.0 （2.0-9.5） vs 1.5 （0-4.0）, P=0. 004]. Spearman correlation analysis showed that the lowest saturation of oxygen was negatively related to the DNA methylation level of the loci 2.10 and 2.14 （rs=-0. 480, P=0. 008 and rs= -0. 520, P=0. 004, respectively）. Further analysis in a larger sample population showed that DNA methylation levels of the loci 2.10 and 2.14 were significantly higher in OSAS group than control group [loc 2.10：9.0 （4.5-55.0） vs 4.5 （2.0-23.0）, loc 2.14： 13.5（6.0-40.3） vs 6.0（2.0-24.01; both P〈0.05], and so were DNA methylation levels of the loc 2.3, loc 2.6, loc 2.7, loc 2.9, loc 2.13 and loc 2.17. Conclusion In the non- diabetic population with hypertension and OSAS, high DNA methylation of GLUT4 gene is found in male adult patients, which is related to hypoxia index induced by OSAS.