〔Abstract〕 Objective To investigate the differences of genomic DNA methylation in peripheral blood between asthmatic patients and healthy controls and its clinical significance. Methods 2 ml peripheral blood were collected from patients with acute exacerbation of asthma and healthy controls. After extracting peripheral blood DNA, the whole genome DNA methylation was detected by Illumina DNA methylation gene chip, and they were intersected with the 96 gene chip data samples in the download GSE56553 data set, then they were performed biological analysis on the functional pathways of different genes. Results There was a statistically significant difference in peripheral blood genomic DNA methylation between patients with asthma and healthy people. 1 493 differential genes were found, of which 923 were methylation-up-regulated genes and 570 were methylation-reduced genes.The differential genes obtained by functional enrichment analysis of GO and KEGG pathways were mainly involved in the processes of the regulation of synaptic signaling, muscle contraction, and cell adhesion. By constructing the gene interaction network, TNF, GNB1, PIK3 R1, CDC5 L, IL-10, CD44 and other 24 key genes were screened. Conclusion Differences in genomic DNA methylation between peripheral blood and healthy controls are statistically significant, and these differences may be the main causes of initiation and progression of asthma. The use of bioinformatics methods to screen out the key genes and signaling pathways in the development of asthma can provide new targets and strategies for asthma treatment.