Abstract: 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＿18, CpG2＿21.22, CpG2＿23.24, and CpG22＿27; whereas, in the OSAS combined with diabetes mellitus group, high and low methylation sites co-existed（low methylation sites: CpG1＿2, CpG1＿5, CpG2＿6, CPG17, CPG110.11, CPG117, CPG118.19, CPG214, CPG218, CPG225, CPG227, and hypermethylated sites: CpG2-13, CpG2＿15, and CpG2＿20）. Conclusion Compared with essential hypertension, OSAS combined with hypertension has differential methylation sites, which provides a database of differential methylation genes for subsequent methylation studies. The single gene verification of SLC2A4 gene in the type 2 diabetes pathway confirmed that the gene methylation difference was involved in OSAS diabetes comorbidity.