The nasal methylome and childhood atopic asthma - 27/09/17
, Brent S. Pedersen, PhD a, ∗, Andrew H. Liu, MD b, ∗, George T. O'Connor, MD d, Dinesh Pillai, MD e, Meyer Kattan, MD f, Rana Tawil Misiak, MD g, Rebecca Gruchalla, MD h, Stanley J. Szefler, MD i, Gurjit K. Khurana Hershey, MD, PhD j, Carolyn Kercsmar, MD j, Adam Richards, PhD a, Allen D. Stevens, BA b, Christena A. Kolakowski, MS b, Melanie Makhija, MD k, Christine A. Sorkness, PharmD l, Rebecca Z. Krouse, MS m, Cynthia Visness, PhD m, Elizabeth J. Davidson, BA a, Corinne E. Hennessy, BS a, Richard J. Martin, MD b, Alkis Togias, MD n, William W. Busse, MD l, David A. Schwartz, MD a, b, o, ⁎ 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 × 10−6 for differentially methylated regions and P < 7.8 × 10−10 for 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.
Le texte complet de cet article est disponible en PDF.Key words : DNA methylation, gene expression, microarray, atopic asthma, respiratory epithelia, epigenetic regulation, inner city
Abbreviations used : ALOX15, CAPN14, DMP, DMR, POSTN
Plan
| Supported by the National Institute of Allergy and Infectious Diseases (N01-AI90052); the National Heart, Lung, and Blood Institute (R01-HL101251); the National Institute for Environmental Health Sciences (P01-ES18181); and the National Center for Advancing Translational Sciences (UL1TR000075). |
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| Disclosure of potential conflict of interest: I. V Yang has received a grant from the National Institutes of Health (NIH). A. H. Liu is a data monitoring committee member for GlaxoSmithKline and has received payment for lectures from Merck. G. T. O'Connor has received a grant from the NIH and has consultant arrangements with AstraZeneca. M. Kattan has received a grant from the NIH and has board memberships with Novartis and Sanofi. S. J. Szefler has received grants from the National Institute of Allergy and Infectious Diseases (NIAID) and GlaxoSmithKline and has consultant arrangements with Roche, AstraZeneca, Aerocrine, Daiichi Sankyo, Boehringer Ingelheim, Merck, Genentech, and Novartis. G. K. Khurana Hershey has received grants from the NIH. C. Kercsmar was chair of a Data Safety Materials Board for GlaxoSmithKline. R. Z. Krouse has received a grant from the NIH/NIAID. C. Visness has received a grant from the NIH/NIAID. E. J. Davidson has received a grant from the University of Colorado Anschutz Medical Campus. R. J. Martin has consultant arrangements with Teva, AstraZeneca, Genentech, Boehringer Ingelheim, and PMD; has received grants from the National Heart, Lung, and Blood Institute and MedImmune; and has received travel support from the Respiratory Effectiveness Group. W. W. Busse has received a grant from the NIH/NIAID; received partial study funding, drug, and placebo from Novartis; is on the Data Safety Monitoring Boards for Boston Scientific and Circassia; is on the Study Oversight Committee for ICON; and has consultant arrangements with Novartis, GlaxoSmithKline, Genentech, Roche, Pfizer, Merck, Boehringer Ingelheim, Sanofi, AstraZeneca, Teva, Tekeda, Aerocrine, and 3M. D. A. Schwartz has received a grant from the NIH (R01-HL101251, N01-AI90052, and P01-ES18181). The rest of the authors declare that they have no relevant conflicts of interest. |
Vol 139 - N° 5
P. 1478-1488 - mai 2017 Retour au numéro
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