Ivana V Yang1, Brent S Pedersen2, Andrew H Liu3, George T O'Connor4, Dinesh Pillai5, Meyer Kattan6, Rana Tawil Misiak7, Rebecca Gruchalla8, Stanley J Szefler9, Gurjit K Khurana Hershey10, Carolyn Kercsmar10, Adam Richards2, Allen D Stevens3, Christena A Kolakowski3, Melanie Makhija11, Christine A Sorkness12, Rebecca Z Krouse13, Cynthia Visness13, Elizabeth J Davidson2, Corinne E Hennessy2, Richard J Martin3, Alkis Togias14, William W Busse12, David A Schwartz15. 1. 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. 2. Department of Medicine and University of Colorado, School of Medicine, Aurora, Colo. 3. 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. Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio. 11. Children's Hospital of Chicago, Chicago, Ill. 12. Department of Medicine, University of Wisconsin School of Medicine and Public Health, Madison, Wis. 13. Rho Federal Systems Division, Chapel Hill, NC. 14. National Institute of Allergy and Infectious Diseases, Bethesda, Md; and University of Colorado, Aurora, CO. 15. 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.
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.
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 asthmaticpatients. CONCLUSIONS: Epigenetic marks in respiratory epithelia are associated with allergic asthma and gene expression changes in inner-city children.
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