Ivana V Yang1, Brent S Pedersen2, Andrew Liu3, George T O'Connor4, Stephen J Teach5, Meyer Kattan6, Rana Tawil Misiak7, Rebecca Gruchalla8, Suzanne F Steinbach4, Stanley J Szefler9, Michelle A Gill8, Agustin Calatroni10, Gloria David10, Corinne E Hennessy2, Elizabeth J Davidson2, Weiming Zhang11, Peter Gergen12, Alkis Togias12, William W Busse13, David A Schwartz14. 1. Department of Medicine, University of Colorado, School of Medicine, Aurora, Colo; Departments of Pediatrics and Medicine, National Jewish Health, Denver, Colo. 2. Department of Medicine, University of Colorado, School of Medicine, Aurora, Colo. 3. Departments of Pediatrics and Medicine, National Jewish Health, Denver, Colo. 4. Department of Medicine, Boston University School of Medicine, Boston, Mass. 5. Children's National Health System, Washington, DC. 6. Columbia University Medical Center, New York, NY. 7. Department of Medicine, Henry Ford Hospital, Detroit, Mich. 8. University of Texas, Southwestern Medical Center, Dallas, Tex. 9. Department of Pediatrics, Children's Hospital Colorado and University of Colorado, School of Medicine, Aurora, Colo. 10. Rho Federal Systems Division, Chapel Hill, NC. 11. Department of Biostatistics and Informatics, Colorado School of Public Health, University of Colorado, Aurora, Colo. 12. National Institute of Allergy and Infectious Diseases, Bethesda, Md. 13. Department of Medicine, University of Wisconsin School of Medicine and Public Health, Madison, Wis. 14. Department of Medicine, University of Colorado, School of Medicine, Aurora, Colo; Departments of Pediatrics and Medicine, National Jewish Health, Denver, Colo; Department of Immunology, University of Colorado, Aurora, Colo. Electronic address: david.schwartz@ucdenver.edu.
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. Published by Elsevier Inc.
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. Published by Elsevier Inc.
Entities:
Keywords:
DNA methylation; T(H)2 immunity; atopic asthma; epigenetics; inner city
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