Abstract
We hypothesized that epigenetics is a link between smoking/allergen exposures and the development of Asthma and chronic obstructive pulmonary disease (ACO). A total of 75 of 228 COPD patients were identified as ACO, which was independently associated with increased exacerbations. Microarray analysis identified 404 differentially methylated loci (DML) in ACO patients, and 6575 DML in those with rapid lung function decline in a discovery cohort. In the validation cohort, ACO patients had hypermethylated PDE9A (+ 30,088)/ZNF323 (− 296), and hypomethylated SEPT8 (− 47) genes as compared with either pure COPD patients or healthy non-smokers. Hypermethylated TIGIT (− 173) gene and hypomethylated CYSLTR1 (+ 348)/CCDC88C (+ 125,722)/ADORA2B (+ 1339) were associated with severe airflow limitation, while hypomethylated IFRD1 (− 515) gene with frequent exacerbation in all the COPD patients. Hypermethylated ZNF323 (− 296) / MPV17L (+ 194) and hypomethylated PTPRN2 (+ 10,000) genes were associated with rapid lung function decline. In vitro cigarette smoke extract and ovalbumin concurrent exposure resulted in specific DNA methylation changes of the MPV17L / ZNF323 genes, while 5-aza-2′-deoxycytidine treatment reversed promoter hypermethylation-mediated MPV17L under-expression accompanied with reduced apoptosis and decreased generation of reactive oxygen species. Aberrant DNA methylations may constitute a determinant for ACO, and provide a biomarker of airflow limitation, exacerbation, and lung function decline.
Highlights
We hypothesized that epigenetics is a link between smoking/allergen exposures and the development of Asthma and chronic obstructive pulmonary disease (ACO)
We hypothesized that gene-specific CpG methylation profiles of peripheral blood mononuclear cells (PBMCs) may contribute to disease susceptibility, severity, and clinical phenotypes in ACO patients, with the goal of identifying novel epigenetic changes related to frequent exacerbation, rapid lung function decline, or severe airflow limitation
A total of 75 of the 228 chronic obstructive pulmonary disease (COPD) patients were identified as ACO, while the others classified as pure COPD (Table 1)
Summary
We hypothesized that epigenetics is a link between smoking/allergen exposures and the development of Asthma and chronic obstructive pulmonary disease (ACO). CCDC88C Coiled-coil domain containing 88C COPD Chronic obstructive pulmonary disease CpG Cytosine guanine dinucleotides CSE Cigarette smoke extract CYSLTR1 Cysteinyl leukotriene receptor 1 DML Differentially methylated locus EWAS Epigenome-wide association study FEV1 Forced expiratory volume in the first second FVC Forced expiratory vital capacity HS Healthy non-smoker IFRD1 Interferon related developmental regulator 1 MPV17L MPV17 mitochondrial inner membrane protein like OVA Ovalbumin PCR Polymerase chain reaction PDE9A Phosphodiesterase 9A PTPRN2 Protein tyrosine phosphatase receptor type N2 SEPT8 Septin 8 SNP Single nucleotide polymorphism TIGIT T cell immunoreceptor with Ig and ITIM domains ZNF323 Zinc finger and SCAN domain containing 31. We hypothesized that gene-specific CpG methylation profiles of peripheral blood mononuclear cells (PBMCs) may contribute to disease susceptibility, severity, and clinical phenotypes in ACO patients, with the goal of identifying novel epigenetic changes related to frequent exacerbation, rapid lung function decline, or severe airflow limitation
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