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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 r_s=-0.480,P=0.008;位点2.14 r_s=-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 of glucose transporter 4 (GLUT4) gene and obstructive sleep apnea syndrome (OSAS) in hypertensive population. METHODS: The subjects were consecutive hospitalized patients from January to March 2010 in People’s Hospital of Xinjiang Uygur Autonomous Region. 14 Han Chinese men aged 30-50 years old with normal liver and kidney function and high blood pressure and severe OSAS were selected as OSAS group. Sixteen non-OSAS Han Chinese patients with essential hypertension who were matched for age and body mass index (BMI) with OSAS were selected as the control group. MassARRAY methylation quantification of GLUT4 gene. After the methylation difference sites were found, the sample size was increased (66 cases in the moderate and severe OSAS group and 39 cases in the control group), and further massARRAY detection was performed on the CpG island where the locus was located. Further analysis was conducted to explore the methylation sites of GLUT4 gene in OSAS patients . Results The methylation of all CpG units of GLUT4 gene in OSAS group was not significantly different from that in control group. However, in non-diabetic patients, the loci were 2.10 [3.0 (2.0-6.5) vs 0.5 (0-3.0), P = 0.014], locus 2.14 [6.0 (2.0-9.5) vs 1.5 (0-4.0), P = 0.004]. The methylation level in OSAS group was higher than that in control group. Spearman correlation analysis showed that the methylation level at site 2.10 and site 2.14 were negatively correlated with the lowest oxygen saturation index of OSAS hypoxia (locus 2.10 r_s = -0.480, P = 0.008; locus 2.14 r_s = -0.520, P = 0.004). In the moderate and severe OSAS group, the locus 2.10 and locus 2.14 were significantly higher than those in the control group [sites 2.10: 9.0 (4.5-55.0) vs. 4.5 (2.0-23.0), locus 2.14: 13.5 (6.0 ~ 40.3) vs 6.0 (2.0 ~ 24.0), all P <0.05]. Another locus was found 2.3, locus 2.6, locus 2.7, locus 2.9, locus 2.13 and locus 2.17 The methylation level was also high In the control group (all P <0.05). Conclusion In hypertensive patients with OSAS complicated with diabetes, GLUT4 gene is hypermethylated in adult males and is associated with hypoxia induced by OSAS.