title: Characteristic DNA methylation profiles in peripheral blood monocytes are associated with inflammatory phenotypes of asthma.
abstract: Epigenetic changes including DNA methylation caused by environmental exposures may contribute to the heterogeneous inflammatory response in asthma. Here we investigate alterations in DNA methylation of purified blood monocytes that are associated with inflammatory phenotypes of asthma. Peripheral blood was collected from adults with eosinophilic asthma (EA; n = 21), paucigranulocytic asthma (PGA; n = 22), neutrophilic asthma (NA; n = 9), and healthy controls (n = 10). Blood monocytes were isolated using ficoll density gradient and immuno-magnetic cell separation. Bisulfite converted genomic DNA was hybridized to Illumina Infinium Methylation27 arrays and analyzed for differential methylation using R/Bioconductor packages; networks of gene interactions were identified using the STRING database. Compared with healthy controls, differentially methylated CpG loci were identified in EA (n = 413), PGA (n = 495), and NA (n = 89). We found that 223, 237, and 72 loci were significantly hypermethylated in EA, PGA, and NA, respectively. Nine genes were common to all three phenotypes and showed increased methylation in asthma. Three pathway networks were identified in EA, involved in purine metabolism, calcium signaling, and ECM-receptor interaction. In PGA, two networks were identified, involved in neuroactive ligand-receptor interaction and ubiquitin mediated proteolysis. In NA, one network was identified involving sFRP1 as a key node, over representing the Wnt signaling pathway. We have identified characteristic alterations in DNA methylation that are associated with inflammatory phenotypes of asthma and may contribute to the disease mechanisms. This network-based characterization may help in the development of epigenetic biomarkers and therapeutic targets for asthma.
authors.affiliation: Priority Research Centre for Asthma and Respiratory Disease; Hunter Medical Research Institute; The University of Newcastle; Newcastle, NSW Australia; Department of Respiratory & Sleep Medicine; HMRI; John Hunter Hospital; New Lambton, NSW Australia.
authors.forename: Lakshitha P
authors.initials: LP
authors.lastname: Gunawardhana
authors.affiliation: Priority Research Centre for Asthma and Respiratory Disease; Hunter Medical Research Institute; The University of Newcastle; Newcastle, NSW Australia; Department of Respiratory & Sleep Medicine; HMRI; John Hunter Hospital; New Lambton, NSW Australia.
authors.forename: Peter G
authors.initials: PG
authors.lastname: Gibson
authors.affiliation: Priority Research Centre for Asthma and Respiratory Disease; Hunter Medical Research Institute; The University of Newcastle; Newcastle, NSW Australia; Department of Respiratory & Sleep Medicine; HMRI; John Hunter Hospital; New Lambton, NSW Australia.
authors.forename: Jodie L
authors.initials: JL
authors.lastname: Simpson
authors.affiliation: Genomics Research Centre; Institute of Health and Biomedical Innovation; Queensland Institute of Technology; Brisbane, QLD Australia.
authors.forename: Miles C
authors.initials: MC
authors.lastname: Benton
authors.affiliation: Genomics Research Centre; Institute of Health and Biomedical Innovation; Queensland Institute of Technology; Brisbane, QLD Australia.
authors.forename: Rodney A
authors.initials: RA
authors.lastname: Lea
authors.affiliation: Priority Research Centre for Asthma and Respiratory Disease; Hunter Medical Research Institute; The University of Newcastle; Newcastle, NSW Australia; Department of Respiratory & Sleep Medicine; HMRI; John Hunter Hospital; New Lambton, NSW Australia.
authors.forename: Katherine J
authors.initials: KJ
authors.lastname: Baines
mesh_terms: D000328:Adult; D000368:Aged; D001249:Asthma / Q000097:blood*; D064007:Ataxia Telangiectasia Mutated Proteins / Q000378:metabolism; D016022:Case-Control Studies; D018899:CpG Islands; D019175:DNA Methylation; D005260:Female; D006801:Humans; D007249:Inflammation / Q000097:blood; D008297:Male; D008875:Middle Aged; D009000:Monocytes / Q000378:metabolism*; D010641:Phenotype
chemical_list: C576597:ATR protein, human; D064007:Ataxia Telangiectasia Mutated Proteins
keywords: DNA methylation; Illumina infinium; asthma; inflammatory phenotypes; monocytes; sputum