title: The nasal methylome and childhood atopic asthma.
abstract: BACKGROUND
  Given the strong environmental influence on both epigenetic marks and allergic asthma in children, the epigenetic alterations in respiratory epithelia might provide insight into allergic asthma.
  
  
  OBJECTIVE
  We sought to identify DNA methylation and gene expression changes associated with childhood allergic persistent asthma.
  
  
  METHODS
  We compared genomic DNA methylation patterns and gene expression in African American children with persistent atopic asthma (n = 36) versus healthy control subjects (n = 36). Results were validated in an independent population of asthmatic children (n = 30) by using a shared healthy control population (n = 36) and in an independent population of white adult atopic asthmatic patients (n = 12) and control subjects (n = 12).
  
  
  RESULTS
  We identified 186 genes with significant methylation changes, differentially methylated regions or differentially methylated probes, after adjustment for age, sex, race/ethnicity, batch effects, inflation, and multiple comparisons. Genes differentially methylated included those with established roles in asthma and atopy and genes related to extracellular matrix, immunity, cell adhesion, epigenetic regulation, and airflow obstruction. The methylation changes were substantial (median, 9.5%; range, 2.6% to 29.5%). Hypomethylated and hypermethylated genes were associated with increased and decreased gene expression, respectively (P < 2.8 × 10-6for differentially methylated regions and P < 7.8 × 10-10for differentially methylated probes). Quantitative analysis in 53 differentially expressed genes demonstrated that 32 (60%) have significant methylation-expression relationships within 5 kb of the gene. Ten loci selected based on the relevance to asthma, magnitude of methylation change, and methylation-expression relationships were validated in an independent cohort of children with atopic asthma. Sixty-seven of 186 genes also have significant asthma-associated methylation changes in nasal epithelia of adult white asthmatic patients.
  
  
  CONCLUSIONS
  Epigenetic marks in respiratory epithelia are associated with allergic asthma and gene expression changes in inner-city children.
authors.affiliation: Department of Medicine and University of Colorado, School of Medicine, Aurora, Colo; National Jewish Health, Denver, Colo; Department of Epidemiology, Colorado School of Public Health, Aurora, Colo. Electronic address: ivana.yang@ucdenver.edu.
authors.forename: Ivana V
authors.initials: IV
authors.lastname: Yang
authors.affiliation: Department of Medicine and University of Colorado, School of Medicine, Aurora, Colo.
authors.forename: Brent S
authors.initials: BS
authors.lastname: Pedersen
authors.affiliation: National Jewish Health, Denver, Colo.
authors.forename: Andrew H
authors.initials: AH
authors.lastname: Liu
authors.affiliation: Department of Medicine, Boston University School of Medicine, Boston, Mass.
authors.forename: George T
authors.initials: GT
authors.lastname: O'Connor
authors.affiliation: Children's National Health System, Washington, DC.
authors.forename: Dinesh
authors.initials: D
authors.lastname: Pillai
authors.affiliation: Columbia University Medical Center, New York, NY.
authors.forename: Meyer
authors.initials: M
authors.lastname: Kattan
authors.affiliation: Department of Medicine, Henry Ford Hospital, Detroit, Mich.
authors.forename: Rana Tawil
authors.initials: RT
authors.lastname: Misiak
authors.affiliation: University of Texas, Southwestern Medical Center, Dallas, Tex.
authors.forename: Rebecca
authors.initials: R
authors.lastname: Gruchalla
authors.affiliation: Department of Pediatrics, Children's Hospital Colorado and University of Colorado, School of Medicine, Aurora, Colo.
authors.forename: Stanley J
authors.initials: SJ
authors.lastname: Szefler
authors.affiliation: Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio.
authors.forename: Gurjit K
authors.initials: GK
authors.lastname: Khurana Hershey
authors.affiliation: Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio.
authors.forename: Carolyn
authors.initials: C
authors.lastname: Kercsmar
authors.affiliation: Department of Medicine and University of Colorado, School of Medicine, Aurora, Colo.
authors.forename: Adam
authors.initials: A
authors.lastname: Richards
authors.affiliation: National Jewish Health, Denver, Colo.
authors.forename: Allen D
authors.initials: AD
authors.lastname: Stevens
authors.affiliation: National Jewish Health, Denver, Colo.
authors.forename: Christena A
authors.initials: CA
authors.lastname: Kolakowski
authors.affiliation: Children's Hospital of Chicago, Chicago, Ill.
authors.forename: Melanie
authors.initials: M
authors.lastname: Makhija
authors.affiliation: Department of Medicine, University of Wisconsin School of Medicine and Public Health, Madison, Wis.
authors.forename: Christine A
authors.initials: CA
authors.lastname: Sorkness
authors.affiliation: Rho Federal Systems Division, Chapel Hill, NC.
authors.forename: Rebecca Z
authors.initials: RZ
authors.lastname: Krouse
authors.affiliation: Rho Federal Systems Division, Chapel Hill, NC.
authors.forename: Cynthia
authors.initials: C
authors.lastname: Visness
authors.affiliation: Department of Medicine and University of Colorado, School of Medicine, Aurora, Colo.
authors.forename: Elizabeth J
authors.initials: EJ
authors.lastname: Davidson
authors.affiliation: Department of Medicine and University of Colorado, School of Medicine, Aurora, Colo.
authors.forename: Corinne E
authors.initials: CE
authors.lastname: Hennessy
authors.affiliation: National Jewish Health, Denver, Colo.
authors.forename: Richard J
authors.initials: RJ
authors.lastname: Martin
authors.affiliation: National Institute of Allergy and Infectious Diseases, Bethesda, Md; and University of Colorado, Aurora, CO.
authors.forename: Alkis
authors.initials: A
authors.lastname: Togias
authors.affiliation: Department of Medicine, University of Wisconsin School of Medicine and Public Health, Madison, Wis.
authors.forename: William W
authors.initials: WW
authors.lastname: Busse
authors.affiliation: Department of Medicine and University of Colorado, School of Medicine, Aurora, Colo; National Jewish Health, Denver, Colo; Department of Immunology, University of Colorado, Aurora, Colo. Electronic address: david.schwartz@ucdenver.edu.
authors.forename: David A
authors.initials: DA
authors.lastname: Schwartz
mesh_terms: D000328:Adult; D001741:Black or African American / Q000235:genetics; D000368:Aged; D000369:Aged, 80 and over; D001249:Asthma / Q000235:genetics*; D002648:Child; D019175:DNA Methylation; D044127:Epigenesis, Genetic; D005260:Female; D005786:Gene Expression Regulation; D006801:Humans; D008297:Male; D008875:Middle Aged; D009297:Nasal Mucosa / Q000378:metabolism*; D044465:White People / Q000235:genetics; D055815:Young Adult
keywords: DNA methylation; atopic asthma; epigenetic regulation; gene expression; inner city; microarray; respiratory epithelia