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.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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3',5'-Cyclic-AMP Phosphodiesterases / genetics
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3',5'-Cyclic-AMP Phosphodiesterases / metabolism
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Aged
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Aged, 80 and over
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Allergens / adverse effects
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Asthma / complications
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Asthma / etiology
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Asthma / genetics*
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Asthma / metabolism
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Cohort Studies
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DNA Methylation*
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DNA-Binding Proteins / genetics
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DNA-Binding Proteins / metabolism
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Epigenesis, Genetic*
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Female
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Genome-Wide Association Study
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Humans
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Immediate-Early Proteins / genetics
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Immediate-Early Proteins / metabolism
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Intracellular Signaling Peptides and Proteins / genetics
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Intracellular Signaling Peptides and Proteins / metabolism
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Lung / drug effects
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Lung / metabolism
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Lung / pathology
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Male
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Membrane Proteins / genetics
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Membrane Proteins / metabolism
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Microarray Analysis
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Microfilament Proteins / genetics
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Microfilament Proteins / metabolism
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Middle Aged
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Phenotype
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Pulmonary Disease, Chronic Obstructive / complications
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Pulmonary Disease, Chronic Obstructive / etiology
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Pulmonary Disease, Chronic Obstructive / genetics*
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Pulmonary Disease, Chronic Obstructive / metabolism
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Reactive Oxygen Species / metabolism
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Receptor, Adenosine A2B / genetics
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Receptor, Adenosine A2B / metabolism
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Receptor-Like Protein Tyrosine Phosphatases, Class 8 / genetics
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Receptor-Like Protein Tyrosine Phosphatases, Class 8 / metabolism
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Receptors, Immunologic / genetics
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Receptors, Immunologic / metabolism
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Receptors, Leukotriene / genetics
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Receptors, Leukotriene / metabolism
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Respiratory Function Tests
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Septins / genetics
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Septins / metabolism
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Smoking / adverse effects*
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Transcription Factors / genetics
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Transcription Factors / metabolism
Substances
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ADORA2B protein, human
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Allergens
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CCDC88C protein, human
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DNA-Binding Proteins
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IFRD1 protein, human
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Immediate-Early Proteins
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Intracellular Signaling Peptides and Proteins
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MPV17L protein, human
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Membrane Proteins
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Microfilament Proteins
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Reactive Oxygen Species
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Receptor, Adenosine A2B
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Receptors, Immunologic
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Receptors, Leukotriene
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TIGIT protein, human
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Transcription Factors
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ZSCAN31 protein, human
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PTPRN2 protein, human
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Receptor-Like Protein Tyrosine Phosphatases, Class 8
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3',5'-Cyclic-AMP Phosphodiesterases
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PDE9A protein, human
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SEPTIN8 protein, human
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Septins
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leukotriene D4 receptor