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Journal of Allergy and Clinical Immunology

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Nasal DNA methylation profiling of asthma and rhinitis - 08/06/20

Doi : 10.1016/j.jaci.2019.12.911 
Cancan Qi, MSc a, b, ∗, Yale Jiang, MSc c, d, e, ∗, Ivana V. Yang, PhD f, Erick Forno, MD, MPH c, d, Ting Wang, PhD c, d, Judith M. Vonk, PhD b, g, Ulrike Gehring, PhD h, Henriëtte A. Smit, PhD i, Edith B. Milanzi, MSc h, Orestes A. Carpaij, MD b, j, Marijn Berg, BSc b, k, Laura Hesse, MSc b, k, Sharon Brouwer, BSc b, k, Jonathan Cardwell, MSc f, Cornelis J. Vermeulen, PhD b, j, Edna Acosta-Pérez, PhD l, Glorisa Canino, PhD l, Nadia Boutaoui, PhD c, d, Maarten van den Berge, MD, PhD b, j, Sarah A. Teichmann, PhD m, n, Martijn C. Nawijn, PhD b, k, Wei Chen, PhD c, d, Juan C. Celedón, MD, DrPH c, d, ‡, Cheng-Jian Xu, PhD a, b, o, p, ‡, Gerard H. Koppelman, MD, PhD a, b, ⁎, ‡
a Department of Pediatric Pulmonology and Pediatric Allergy, Beatrix Children’s Hospital, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands 
b Gronigen Research Institute for Asthma and COPD, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands 
c Division of Pulmonary Medicine, UPMC Children’s Hospital of Pittsburgh, Pittsburgh, Pa 
d Department of Pediatrics, University of Pittsburgh School of Medicine, Pittsburgh, Pa 
e School of Medicine, Tsinghua University, Beijing, China 
f Department of Medicine, University of Colorado, Aurora, Colo 
g Department of Epidemiology, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands 
h Institute for Risk Assessment Sciences, Utrecht University, Utrecht, The Netherlands 
i Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, Utrecht, The Netherlands 
j Department of Pulmonary Diseases, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands 
k Department of Pathology & Medical Biology, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands 
l Behavioral Sciences Research Institute, University of Puerto Rico, San Juan, Puerto Rico 
m Wellcome Sanger Institute, Wellcome Genome Campus, Hinxton, Cambridge, United Kingdom 
n Theory of Condensed Matter Group, Cavendish Laboratory/Department of Physics, University of Cambridge, Cambridge, United Kingdom 
o 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 
p 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 

∗Corresponding author: Gerard H. Koppelman, MD, PhD, Department of Pediatric Pulmonology and Pediatric Allergology, Beatrix Children’s Hospital, University Medical Center Groningen, PO Box 30.001, 9700 RB Groningen, The Netherlands.Department of Pediatric Pulmonology and Pediatric AllergologyBeatrix Children’s HospitalUniversity Medical Center GroningenPO Box 30.001GroningenThe Netherlands9700 RB

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.

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Key words : Asthma, rhinitis, united airways, epigenetics, environmental exposure

Abbreviations used : ANO1, AsRh, AUC, CISH, CYP27B1, DMR, eQTM, EVA-PR, EWAS, FDR, FBXL7, GJA4, NCF2, NTRK1, PCSK6, PIAMA, QC, scRNAseq, TREM1, ZMYND10


Mappa


 The PIAMA study was supported by The Netherlands Organization for Health Research and Development; The Netherlands Organization for Scientific Research; the Lung Foundation of the Netherlands (with methylation studies supported by AF 4.1.14.001); The Netherlands Ministry of Spatial Planning, Housing, and the Environment; and The Netherlands Ministry of Health, Welfare, and Sport. C.Q. was supported by a grant from the China Scholarship Council. The Epigenetic Variation and Childhood Asthma in Puerto Ricans Study was supported by grants HL079966 and HL117191 from the US National Institutes of Health (NIH). The contributions of J.C.C. and W.C. were additionally supported by grant MD011764 from the NIH, and RNA Sequencing was funded by the Department of Pediatrics of UPMC Children’s Hospital of Pittsburgh. Research infrastructure for the Epigenetic Variation and Childhood Asthma in Puerto Ricans Study was additionally supported by grant U54MD007587 from the NIH. The Inner City Asthma Consortium was supported by contract N01-AI90052 from the NIH.
 Disclosure of potential conflict of interest: G. H. Koppelman reports grants from Lung Foundation of the Netherlands during the conduct of the study and grants from Lung Foundation of the Netherlands, Teva The Netherlands, Vertex, GSK, Ubbo Emmius Foundation, and TETRI Foundation outside the submitted work. M. van den Berge reports grants paid to the University from Astra Zeneca, Teva, GSK, and Chiesi outside the submitted work. J. C. Celedón received research materials from GSK and Merck (inhaled steroids) and Pharmavite (vitamin D and placebo capsules) to provide medications free of cost to participants in NIH-funded studies., outside the submitted work. C. J. Vermeulen reports grants from GSK outside the submitted work. MCN reports grants from GSK and Lung Foundation of the Netherlands outside the submitted work. S. A. Teichmann reports serving as a consultant for Genentech, Roche, and Biogen. The rest of the authors declare that they have no relevant conflict of interests.


© 2020  American Academy of Allergy, Asthma & Immunology. Pubblicato da Elsevier Masson SAS. Tutti i diritti riservati.
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Vol 145 - N° 6

P. 1655-1663 - Giugno 2020 Ritorno al numero
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