DNA methylation and childhood asthma in the inner city
Ivana V Yang, Brent S Pedersen, Andrew Liu, George T O'Connor, Stephen J Teach, Meyer Kattan, Rana Tawil Misiak, Rebecca Gruchalla, Suzanne F Steinbach, Stanley J Szefler, Michelle A Gill, Agustin Calatroni, Gloria David, Corinne E Hennessy, Elizabeth J Davidson, Weiming Zhang, Peter Gergen, Alkis Togias, William W Busse, David A Schwartz, Ivana V Yang, Brent S Pedersen, Andrew Liu, George T O'Connor, Stephen J Teach, Meyer Kattan, Rana Tawil Misiak, Rebecca Gruchalla, Suzanne F Steinbach, Stanley J Szefler, Michelle A Gill, Agustin Calatroni, Gloria David, Corinne E Hennessy, Elizabeth J Davidson, Weiming Zhang, Peter Gergen, Alkis Togias, William W Busse, David A Schwartz
Abstract
Background: Epigenetic marks are heritable, influenced by the environment, direct the maturation of T lymphocytes, and in mice enhance the development of allergic airway disease. Thus it is important to define epigenetic alterations in asthmatic populations.
Objective: We hypothesize that epigenetic alterations in circulating PBMCs are associated with allergic asthma.
Methods: We compared DNA methylation patterns and gene expression in inner-city children with persistent atopic asthma versus healthy control subjects by using DNA and RNA from PBMCs. Results were validated in an independent population of asthmatic patients.
Results: Comparing asthmatic patients (n = 97) with control subjects (n = 97), we identified 81 regions that were differentially methylated. Several immune genes were hypomethylated in asthma, including IL13, RUNX3, and specific genes relevant to T lymphocytes (TIGIT). Among asthmatic patients, 11 differentially methylated regions were associated with higher serum IgE concentrations, and 16 were associated with percent predicted FEV1. Hypomethylated and hypermethylated regions were associated with increased and decreased gene expression, respectively (P < 6 × 10(-12) for asthma and P < .01 for IgE). We further explored the relationship between DNA methylation and gene expression using an integrative analysis and identified additional candidates relevant to asthma (IL4 and ST2). Methylation marks involved in T-cell maturation (RUNX3), TH2 immunity (IL4), and oxidative stress (catalase) were validated in an independent asthmatic cohort of children living in the inner city.
Conclusions: Our results demonstrate that DNA methylation marks in specific gene loci are associated with asthma and suggest that epigenetic changes might play a role in establishing the immune phenotype associated with asthma.
Keywords: DNA methylation; T(H)2 immunity; atopic asthma; epigenetics; inner city.
Conflict of interest statement
Disclosure of potential conflict of interest: I. V. Yang has received research support from the National Institutes of Health (NIH). A. Liu has received payment for lectures from Merck and is on the data safety monitoring committee from GlaxoSmithKline. G. T. O’Connor has received research support from the NIH. S. J. Teach has received research and travel support from the NIH/National Institute of Allergy and Infectious Diseases (NIAID), Patient-Centered Outcome Research Institute, Fight for Children, the DC Department of Health, and the Kellogg Foundation; is employed by Children’s National Health System; and receives royalties from Up-To-Date. M. Kattan has received research support from the NIH and is a member of the Novartis Advisory Board. R. Gruchalla has received research and travel support from the NIAID. S. J. Szefler has received research support from the NIAID and GlaxoSmithKline; has consultant arrangements with Merck, Boehringer Ingelheim, GlaxoSmithKline, and Genentech; has received payment for lectures from Merck; and has submitted a patent for β-adrenengic receptor polymorphism for the National Heart, Lung, and Blood Institute CARE Network. M. A. Gill has received research support from the NIH/ NIAID. A. Calatroni has received research support from the NIH/NIAID. G. David has a contract with the NIH/NIAID. W. W. Busse has received research support from the NIH/NIAID and the National Heart, Lung, and Blood Institute; is a board member for Merck; has consultant arrangements with Novartis, GlaxoSmithKline, Roche, Pfizer, Boston Scientific, Circassia, ICON, AstraZeneca, Sanofi, Amgen, Med-Immune, NeoStem, Takeda, and Boehringer Ingelheim; and has received royalties from Elsevier. D. A. Schwartz has received research support from the NIH and the Veterans Administration; has consultant arrangements with Novartis and Boehringer-Ingelheim; is employed by the University of Colorado Medical School and the Department of Veterans Affairs; has provided expert testimony from Weitz and Luxenberg Law Firm, Brayton and Purcell Law Firm, and Wallace and Graham Law Firm; has patents for TLR2 single nucleotide polymorphism, MUC5b single nucleotide polymorphism, and has patent applications (61/248,505, 61/666,233, 60/ 992,079); and has received royalties from Springer. The rest of the authors declare that they have no relevant conflicts of interest.
Published by Elsevier Inc.
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Source: PubMed