title: DNA methylation in lung cells is associated with asthma endotypes and genetic risk.
abstract: The epigenome provides a substrate through which environmental exposures can exert their effects on gene expression and disease risk, but the relative importance of epigenetic variation on human disease onset and progression is poorly characterized. Asthma is a heterogeneous disease of the airways, for which both onset and clinical course result from interactions between host genotype and environmental exposures, yet little is known about the molecular mechanisms for these interactions. We assessed genome-wide DNA methylation using the Infinium Human Methylation 450K Bead Chip and characterized the transcriptome by RNA sequencing in primary airway epithelial cells from 74 asthmatic and 41 nonasthmatic adults. Asthma status was based on doctor's diagnosis and current medication use. Genotyping was performed using various Illumina platforms. Our study revealed a regulatory locus on chromosome 17q12-21 associated with asthma risk and epigenetic signatures of specific asthma endotypes and molecular networks. Overall, these data support a central role for DNA methylation in lung cells, which promotes distinct molecular pathways of asthma pathogenesis and modulates the effects of genetic variation on disease risk and clinical heterogeneity.
authors.affiliation: Department of Human Genetics.
authors.forename: Jessie
authors.initials: J
authors.lastname: Nicodemus-Johnson
authors.affiliation: Department of Human Genetics.
authors.forename: Rachel A
authors.initials: RA
authors.lastname: Myers
authors.affiliation: Department of Human Genetics.
authors.forename: Noburu J
authors.initials: NJ
authors.lastname: Sakabe
authors.affiliation: Department of Human Genetics.
authors.forename: Debora R
authors.initials: DR
authors.lastname: Sobreira
authors.affiliation: Department of Medicine, and.
authors.forename: Douglas K
authors.initials: DK
authors.lastname: Hogarth
authors.affiliation: Department of Medicine, and.
authors.forename: Edward T
authors.initials: ET
authors.lastname: Naureckas
authors.affiliation: Department of Medicine, and.
authors.forename: Anne I
authors.initials: AI
authors.lastname: Sperling
authors.affiliation: Department of Medicine, and.
authors.forename: Julian
authors.initials: J
authors.lastname: Solway
authors.affiliation: Department of Medicine, and.
authors.forename: Steven R
authors.initials: SR
authors.lastname: White
authors.affiliation: Department of Human Genetics.
authors.forename: Marcelo A
authors.initials: MA
authors.lastname: Nobrega
authors.affiliation: Department of Human Genetics.|Department of Medicine, and.|Department of Statistics, University of Chicago, Chicago, Illinois, USA.
authors.forename: Dan L
authors.initials: DL
authors.lastname: Nicolae
authors.affiliation: Department of Human Genetics.|Department of Medicine, and.
authors.forename: Yoav
authors.initials: Y
authors.lastname: Gilad
authors.affiliation: Department of Human Genetics.
authors.forename: Carole
authors.initials: C
authors.lastname: Ober
mesh_terms: D000328:Adult; D001249:Asthma / Q000235:genetics*; D016022:Case-Control Studies; D019175:DNA Methylation; D044127:Epigenesis, Genetic; D004847:Epithelial Cells / Q000166:cytology*; D005260:Female; D015870:Gene Expression; D006801:Humans; D008168:Lung / Q000166:cytology; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide; D040641:Quantitative Trait Loci; D059467:Transcriptome