阻塞性睡眠呼吸暂停综合征合并高血压患者全基因组甲基化及葡萄糖转运蛋白4基因的DNA甲基化与并发糖尿病的关系  

Genome wide methylation in patients with obstructive sleep apnea syndrome and hypertension and the relationship between DNA methylation of glucose transporter 4 gene and OASA combined with diabetes mellitus

作　　者：李梅[1] 吴婷[1] 木拉力别克·黑扎提 姚晓光[1] 胡君丽[1] 努尔古丽·买买提[1] 李南方[1] LI Mei;WU Ting;HEIZATI Mulalibieke;YAO Xiaoguang;HU Junli;MAIMAITI Nuerguli;LI Nanfang(Hypertension Center of People's Hospital of Xinjiang Uygur Autonomous Region,Xinjiang Hypertension Institute,National Health Committee Key Laboratory of Hypertension Clinical Research,Key Laboratory of Xinjiang Uygur Autonomous Region"Hypertension Research Laboratory",Xinjiang Clinical Medical Research Center for Hypertension(Cardio-Cerebrovascular)Diseases,Urumqi,Xinjiang 830001,China)

机构地区：[1]新疆维吾尔自治区人民医院高血压中心,新疆高血压研究所,国家卫生健康委高血压诊疗研究重点实验室,新疆维吾尔自治区重点实验室“新疆高血压病研究实验室”,新疆高血压(心脑血管)疾病临床医学研究中心,新疆乌鲁木齐830001

出　　处：《中华高血压杂志（中英文）》2024年第5期453-462,共10页Chinese Journal of Hypertension

基　　金：新疆维吾尔自治区人民医院院内科研项目(20160201)。

摘　　要：目的收集睡眠呼吸暂停综合征(OSAS)合并高血压和原发性高血压(EH)患者进行全基因组甲基化测序寻找差异甲基化位点。在高血压人群,进一步探讨OSAS合并糖尿病与葡萄糖转运蛋白4基因[溶质载体家族2A4(SLC2A4)基因]DNA甲基化的关系。方法全基因组甲基化阶段:从2010年1月至3月,连续招募年龄30~60岁、肾功能和肝功能正常的高血压患者,完善多导睡眠监测,中重度OSAS合并高血压患者作为试验组(12例),年龄、体重指数匹配的非OSAS EH患者作为对照组(12例),通过Microarray高通量基因表达检测外周血甲基化情况。单基因验证阶段:全基因组甲基化检测和京都基因和基因组数据库(KEGG)富集通路发现2型糖尿病通路有四个差异基因,选取其中的SLC2A4基因,进一步扩大样本量在高血压人群收集OSAS合并糖尿病(40例)、OSAS非糖尿病(66例)、非OSAS非糖尿病(39例)三组患者,验证单基因甲基化差异位点。结果全基因组研究中,OSAS合并高血压相比较EH共鉴定出516个差异甲基化位点(低甲基化361个,高甲基化155个),所有选择的差异甲基化位点均存在显著性差异(P<0.05和∣Beta值差异∣>0.14)。通过基因本体(GO)、KEGG富集进行功能学基因富集分析。与非OSAS非糖尿病组相比,OSAS非糖尿病组中SLC2A4基因存在高甲基化位点:CpG2-11、CpG2-13、CpG2_15、CpG1_18、CpG2_21.22、CpG2_23.24和CpG22_27;OSAS合并糖尿病组高低甲基化位点并存,低甲基化位点为CpG1_2、CpG1_5、CpG2_6、CPG17、CPG110.11、CPG117、CPG118.19、CPG214、CPG218、CPG225、CPG227,高甲基化位点为CpG2-13、CpG2_15和CpG2_20。结论OSAS合并高血压较EH,存在差异甲基化位点,为后续甲基化研究提供差异甲基化基因数据库。选取2型糖尿病通路中的SLC2A4基因进行单基因验证,证实该基因甲基化差异参与OSAS糖尿病共病。Objectives Patients with obstructive sleep apnea syndrome(OSAS)combined with hypertension and essential hypertension were collected for genome wide methylation researchto look for differentially methylated sites.In the hypertensive population,the relationship between DNA methylation of glucose transporter 4(GLUT4)[solute carrier family-2A4(SLC2A4)]gene and OASA combined with diabetes mellituswas further explored.Methods In the genome-wide methylation stage,from January to March 2010,consecutive hypertensive patients aged thirty to sixty years with normal renal and hepatic functions were recruited to complete polysomnography monitoring.Among them,12 patients with moderate to severe OSAS combined with hypertension were selected as the experimental group,and 12 patients with age-and body mass index-matched non-OSAS essential hypertension were selected as the control group.The peripheral blood methylation was tested by Microarray high-throughput gene expression assay.In the single-gene validation stage,genome-wide methylation detection and Kyoto Encyclopedia of Genes and Genomes(KEGG)-enriched pathway revealed four differential genes in the type 2 diabetes pathway,in which SLC2A4 was selected,and the sample size was further expanded to collect three groups of patients with OSAS combined with diabetes mellitus(40 cases),OSAS nondiabetics(66 cases),non-OSAS nondiabetics(39 cases)in the hypertension population,to verify the single gene methylation difference.Results Genome-wide study involving OSAS combined with hypertension compared to primary hypertension identified a total of 516 differentially methylated sites(361 hypomethylated and 155 hypermethylated),and all selected differentially methylated sites were significantly different with P<0.05 and∣Beta difference∣>0.14.Functionalistic gene enrichment analysis was performed by Gene Ontology(GO)and KEGG enrichment.Compared with the non-OSAS nondiabetics group,there were hypermethylated sites in SLC2A4 gene in the OSAS nondiabetics group:CpG2-11,CpG2-13,CpG2_15,CpG1_

关 键 词：阻塞性睡眠呼吸暂停综合征 高血压 全基因组甲基化研究 糖尿病 溶质载体家族2A4 葡萄糖转运蛋白4 

分 类 号：R766[医药卫生—耳鼻咽喉科] R544.1[医药卫生—临床医学]