Dust Mite-Induced Dectin-2 Pathway Triggers IL-33 Generation in Leukotriene C4 Synthase- and CARD9-Independent Manner

Abstract

S U N D A Y 530 DNA Methylation and Childhood Asthma in the Inner-City Ivana Yang, PhD, Andrew H. Liu, MD, FAAAAI, Brent Pedersen, PhD, George T. O’Connor, MD, Stephen J. Teach, MD, Meyer Kattan, MD, Rana T. Misiak, MD, Rebecca S. Gruchalla, MD, PhD, FAAAAI, Suzanne F. Steinbach, MD, Stanley J. Szefler, MD, FAAAAI, Michelle A. Gill, MD PhD, Agustin Calatroni, MA MS, Gloria L. David, PhD, Corinne E. Hennessy, B.S., Elizabeth J. Davidson, BA, Weiming Zhang, PhD, Peter J. Gergen, MD MPH, Alkis Togias, MD, FAAAAI, WilliamW. Busse, MD, FAAAAI, David A. Schwartz, MD; Department of Medicine, University of Colorado Denver, Denver, CO, University of Colorado School of Medicine, Aurora, CO, National Jewish Health, Denver, CO, University of Colorado Denver, Aurora, CO, Boston University School of Medicine, Boston, MA, Children’s National Health System, Washington, DC, NewYork-Presbyterian/Columbia, New York, NY, Henry Ford Health System, Northville, MI, UT Southwestern Medical Center, Dallas, TX, The Breathing Institute, Children’s Hospital Colorado, Aurora, CO, Rho, Inc., Chapel Hill, NC, University of Colorado School of Medicine, Colorado School of Public Health, University of Colorado, AAIB/DAIT/NIH, Bethesda, MD, NIAID/NIH, Bethesda, MD, University of Wisconsin School of Medicine and Public Health, Madison, WI, University of Colorado Denver School of Medicine, Aurora, CO. RATIONALE: Epigeneticmarks, like asthma, are heritable, influenced by the environment, direct the maturation of T lymphocytes, and influence the development of allergic airway disease in mice. We hypothesize that epigenetic marks in circulating immune cells are associated with allergic asthma in humans. METHODS: We compared DNA methylation patterns and gene expression in African American inner city children with persistent atopic asthma versus healthy controls, using DNA and RNA from peripheral blood mononuclear cells (PBMCs). Findings were validated in an independent population of inner city atopic asthmatics. We also examined asthmaassociated methylation changes identified in nasal epithelia from a subset of the same subjects. RESULTS: Comparing asthma subjects (N597) to controls (N597), we identified 81 regions that were differentially methylated. Several immune genes were hypomethylated in asthma, including IL-13, RUNX3, and specific genes relevant to T lymphocytes (TIGIT). Hypoand hypermethylated genes were associated with increased and decreased gene expression respectively (P<0.6x10). We further explored the relationship between DNA methylation and gene expression using an integrative analysis and identified additional candidates relevant to asthma (IL-4 and ST2). Methylation marks on genes involved in T cell maturation (RUNX3), Th2 immunity (IL-4), and oxidative stress (Catalase) replicated in an independent asthma cohort of AfricanAmerican children living in the inner city. 16 of the 81 DMRs are also differentiallymethylated in nasal epithelia of asthmatics (N536) compared to controls (N536) with larger percent methylation changes than PBMCs. CONCLUSIONS: Our results define novel methylation-gene transcription relationships that may prove important in asthma.