Cancan Qi1, Yale Jiang2, Ivana V Yang3, Erick Forno4, Ting Wang4, Judith M Vonk5, Ulrike Gehring6, Henriëtte A Smit7, Edith B Milanzi6, Orestes A Carpaij8, Marijn Berg9, Laura Hesse9, Sharon Brouwer9, Jonathan Cardwell3, Cornelis J Vermeulen8, Edna Acosta-Pérez10, Glorisa Canino10, Nadia Boutaoui4, Maarten van den Berge8, Sarah A Teichmann11, Martijn C Nawijn9, Wei Chen4, Juan C Celedón4, Cheng-Jian Xu12, Gerard H Koppelman13. 1. Department of Pediatric Pulmonology and Pediatric Allergy, Beatrix Children's Hospital, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands; Gronigen Research Institute for Asthma and COPD, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands. 2. Division of Pulmonary Medicine, UPMC Children's Hospital of Pittsburgh, Pittsburgh, Pa; Department of Pediatrics, University of Pittsburgh School of Medicine, Pittsburgh, Pa; School of Medicine, Tsinghua University, Beijing, China. 3. Department of Medicine, University of Colorado, Aurora, Colo. 4. Division of Pulmonary Medicine, UPMC Children's Hospital of Pittsburgh, Pittsburgh, Pa; Department of Pediatrics, University of Pittsburgh School of Medicine, Pittsburgh, Pa. 5. Gronigen Research Institute for Asthma and COPD, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands; Department of Epidemiology, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands. 6. Institute for Risk Assessment Sciences, Utrecht University, Utrecht, The Netherlands. 7. Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, Utrecht, The Netherlands. 8. Gronigen Research Institute for Asthma and COPD, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands; Department of Pulmonary Diseases, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands. 9. Gronigen Research Institute for Asthma and COPD, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands; Department of Pathology & Medical Biology, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands. 10. Behavioral Sciences Research Institute, University of Puerto Rico, San Juan, Puerto Rico. 11. Wellcome Sanger Institute, Wellcome Genome Campus, Hinxton, Cambridge, United Kingdom; Theory of Condensed Matter Group, Cavendish Laboratory/Department of Physics, University of Cambridge, Cambridge, United Kingdom. 12. Department of Pediatric Pulmonology and Pediatric Allergy, Beatrix Children's Hospital, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands; Gronigen Research Institute for Asthma and COPD, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands; Department of Gastroenterology, Hepatology and Endocrinology, Centre for Individualised Infection Medicine, CiiM, a joint venture between the Hannover Medical School and the Helmholtz Centre for Infection Research, Hannover, Germany; TWINCORE, Centre for Experimental and Clinical Infection Research, a joint venture between the Hannover Medical School and the Helmholtz Centre for Infection Research, Hannover, Germany. 13. Department of Pediatric Pulmonology and Pediatric Allergy, Beatrix Children's Hospital, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands; Gronigen Research Institute for Asthma and COPD, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands. Electronic address: g.h.koppelman@umcg.nl.
Abstract
BACKGROUND: Epigenetic signatures in the nasal epithelium, which is a primary interface with the environment and an accessible proxy for the bronchial epithelium, might provide insights into mechanisms of allergic disease. OBJECTIVE: We aimed to identify and interpret methylation signatures in nasal epithelial brushes associated with rhinitis and asthma. METHODS: Nasal epithelial brushes were obtained from 455 children at the 16-year follow-up of the Dutch Prevention and Incidence of Asthma and Mite Allergy birth cohort study. Epigenome-wide association studies were performed on children with asthma, rhinitis, and asthma and/or rhinitis (AsRh) by using logistic regression, and the top results were replicated in 2 independent cohorts of African American and Puerto Rican children. Significant CpG sites were related to environmental exposures (pets, active and passive smoking, and molds) during secondary school and were correlated with gene expression by RNA-sequencing (n = 244). RESULTS: The epigenome-wide association studies identified CpG sites significantly associated with rhinitis (n = 81) and AsRh (n = 75), but not with asthma. We significantly replicated 62 of 81 CpG sites with rhinitis and 60 of 75 with AsRh, as well as 1 CpG site with asthma. Methylation of cg03565274 was negatively associated with AsRh and positively associated with exposure to pets during secondary school. DNA methylation signals associated with AsRh were mainly driven by specific IgE-positive subjects. DNA methylation related to gene transcripts that were enriched for immune pathways and expressed in immune and epithelial cells. Nasal CpG sites performed well in predicting AsRh. CONCLUSIONS: We identified replicable DNA methylation profiles of asthma and rhinitis in nasal brushes. Exposure to pets may affect nasal epithelial methylation in relation to asthma and rhinitis.
BACKGROUND: Epigenetic signatures in the nasal epithelium, which is a primary interface with the environment and an accessible proxy for the bronchial epithelium, might provide insights into mechanisms of allergic disease. OBJECTIVE: We aimed to identify and interpret methylation signatures in nasal epithelial brushes associated with rhinitis and asthma. METHODS: Nasal epithelial brushes were obtained from 455 children at the 16-year follow-up of the Dutch Prevention and Incidence of Asthma and Mite Allergy birth cohort study. Epigenome-wide association studies were performed on children with asthma, rhinitis, and asthma and/or rhinitis (AsRh) by using logistic regression, and the top results were replicated in 2 independent cohorts of African American and Puerto Rican children. Significant CpG sites were related to environmental exposures (pets, active and passive smoking, and molds) during secondary school and were correlated with gene expression by RNA-sequencing (n = 244). RESULTS: The epigenome-wide association studies identified CpG sites significantly associated with rhinitis (n = 81) and AsRh (n = 75), but not with asthma. We significantly replicated 62 of 81 CpG sites with rhinitis and 60 of 75 with AsRh, as well as 1 CpG site with asthma. Methylation of cg03565274 was negatively associated with AsRh and positively associated with exposure to pets during secondary school. DNA methylation signals associated with AsRh were mainly driven by specific IgE-positive subjects. DNA methylation related to gene transcripts that were enriched for immune pathways and expressed in immune and epithelial cells. Nasal CpG sites performed well in predicting AsRh. CONCLUSIONS: We identified replicable DNA methylation profiles of asthma and rhinitis in nasal brushes. Exposure to pets may affect nasal epithelial methylation in relation to asthma and rhinitis.
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