PMID- 32381493 OWN - NLM STAT- MEDLINE DCOM- 20210621 LR - 20210621 IS - 1399-3003 (Electronic) IS - 0903-1936 (Print) IS - 0903-1936 (Linking) VI - 56 IP - 3 DP - 2020 Sep TI - Epigenome-wide association study of DNA methylation and adult asthma in the Agricultural Lung Health Study. LID - 10.1183/13993003.00217-2020 [doi] LID - 2000217 AB - Epigenome-wide studies of methylation in children support a role for epigenetic mechanisms in asthma; however, studies in adults are rare and few have examined non-atopic asthma. We conducted the largest epigenome-wide association study (EWAS) of blood DNA methylation in adults in relation to non-atopic and atopic asthma.We measured DNA methylation in blood using the Illumina MethylationEPIC array among 2286 participants in a case-control study of current adult asthma nested within a United States agricultural cohort. Atopy was defined by serum specific immunoglobulin E (IgE). Participants were categorised as atopy without asthma (n=185), non-atopic asthma (n=673), atopic asthma (n=271), or a reference group of neither atopy nor asthma (n=1157). Analyses were conducted using logistic regression.No associations were observed with atopy without asthma. Numerous cytosine-phosphate-guanine (CpG) sites were differentially methylated in non-atopic asthma (eight at family-wise error rate (FWER) p<9x10(-8), 524 at false discovery rate (FDR) less than 0.05) and implicated 382 novel genes. More CpG sites were identified in atopic asthma (181 at FWER, 1086 at FDR) and implicated 569 novel genes. 104 FDR CpG sites overlapped. 35% of CpG sites in non-atopic asthma and 91% in atopic asthma replicated in studies of whole blood, eosinophils, airway epithelium, or nasal epithelium. Implicated genes were enriched in pathways related to the nervous system or inflammation.We identified numerous, distinct differentially methylated CpG sites in non-atopic and atopic asthma. Many CpG sites from blood replicated in asthma-relevant tissues. These circulating biomarkers reflect risk and sequelae of disease, as well as implicate novel genes associated with non-atopic and atopic asthma. CI - Copyright (c)ERS 2020. FAU - Hoang, Thanh T AU - Hoang TT AUID- ORCID: 0000-0002-8498-0020 AD - Epidemiology Branch, National Institute of Environmental Health Sciences, National Institutes of Health, Dept of Health and Human Services, Research Triangle Park, NC, USA. AD - Joint first authors. FAU - Sikdar, Sinjini AU - Sikdar S AD - Epidemiology Branch, National Institute of Environmental Health Sciences, National Institutes of Health, Dept of Health and Human Services, Research Triangle Park, NC, USA. AD - Dept of Mathematics and Statistics, Old Dominion University, Norfolk, VA, USA. AD - Joint first authors. FAU - Xu, Cheng-Jian AU - Xu CJ AD - Centre for Individualised Infection Medicine (CiiM), Hannover Medical School and the Helmholtz Centre for Infection Research, Hannover, Germany. AD - Centre for Experimental and Clinical Infection Research (TWINCORE), Hannover Medical School and the Helmholtz Centre for Infection Research, Hannover, Germany. AD - Joint first authors. FAU - Lee, Mi Kyeong AU - Lee MK AD - Epidemiology Branch, National Institute of Environmental Health Sciences, National Institutes of Health, Dept of Health and Human Services, Research Triangle Park, NC, USA. FAU - Cardwell, Jonathan AU - Cardwell J AD - Dept of Medicine, University of Colorado Anschutz Medical Campus, Aurora, CO, USA. FAU - Forno, Erick AU - Forno E AUID- ORCID: 0000-0001-6497-9885 AD - Division of Pulmonary Medicine, UPMC Children's Hospital of Pittsburgh, Pittsburgh, PA, USA. AD - Dept of Pediatrics, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA. FAU - Imboden, Medea AU - Imboden M AD - Chronic Disease Epidemiology Unit, Dept of Epidemiology and Public Health, Swiss Tropical and Public Health Institute, Basel, Switzerland. AD - Dept of Public Health, University of Basel, Basel, Switzerland. FAU - Jeong, Ayoung AU - Jeong A AD - Chronic Disease Epidemiology Unit, Dept of Epidemiology and Public Health, Swiss Tropical and Public Health Institute, Basel, Switzerland. AD - Dept of Public Health, University of Basel, Basel, Switzerland. FAU - Madore, Anne-Marie AU - Madore AM AD - Departement des Sciences Fondamentales, Universite du Quebec a Chicoutimi, Saguenay, QC, Canada. FAU - Qi, Cancan AU - Qi C AD - Dept of Pediatric Pulmonology and Pediatric Allergy, University Medical Center Groningen, University of Groningen, Beatrix Children's Hospital and GRIAC Research Institute, Groningen, The Netherlands. FAU - Wang, Tianyuan AU - Wang T AD - Integrative Bioinformatics Support Group, National Institutes of Health, Dept of Health and Human Services, Research Triangle Park, NC, USA. FAU - Bennett, Brian D AU - Bennett BD AD - Integrative Bioinformatics Support Group, National Institutes of Health, Dept of Health and Human Services, Research Triangle Park, NC, USA. FAU - Ward, James M AU - Ward JM AD - Integrative Bioinformatics Support Group, National Institutes of Health, Dept of Health and Human Services, Research Triangle Park, NC, USA. FAU - Parks, Christine G AU - Parks CG AD - Epidemiology Branch, National Institute of Environmental Health Sciences, National Institutes of Health, Dept of Health and Human Services, Research Triangle Park, NC, USA. FAU - Beane-Freeman, Laura E AU - Beane-Freeman LE AD - Occupational and Environmental Epidemiology Branch, National Cancer Institute, Bethesda, MD, USA. FAU - King, Debra AU - King D AD - Clinical Pathology Group, National Institute of Environmental Health Sciences, National Institutes of Health, Dept of Health and Human Services, Research Triangle Park, NC, USA. FAU - Motsinger-Reif, Alison AU - Motsinger-Reif A AD - Biostatistics and Computational Biology Branch, National Institute of Environmental Health Sciences, National Institutes of Health, Dept of Health and Human Services, Research Triangle Park, NC, USA. FAU - Umbach, David M AU - Umbach DM AD - Biostatistics and Computational Biology Branch, National Institute of Environmental Health Sciences, National Institutes of Health, Dept of Health and Human Services, Research Triangle Park, NC, USA. FAU - Wyss, Annah B AU - Wyss AB AD - Epidemiology Branch, National Institute of Environmental Health Sciences, National Institutes of Health, Dept of Health and Human Services, Research Triangle Park, NC, USA. FAU - Schwartz, David A AU - Schwartz DA AD - Dept of Medicine, University of Colorado Anschutz Medical Campus, Aurora, CO, USA. FAU - Celedon, Juan C AU - Celedon JC AD - Division of Pulmonary Medicine, UPMC Children's Hospital of Pittsburgh, Pittsburgh, PA, USA. AD - Dept of Pediatrics, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA. FAU - Laprise, Catherine AU - Laprise C AD - Departement des Sciences Fondamentales, Universite du Quebec a Chicoutimi, Saguenay, QC, Canada. AD - Centre Intersectoriel en Sante Durable, Departement des Sciences Fondamentales, Universite du Quebec a Chicoutimi, Saguenay, QC, Canada. AD - Dept of Pediatrics, Centre Integre Universitaire de Sante et de Services Sociaux du Saguenay-Lac-Saint-Jean, Saguenay, QC, Canada. FAU - Ober, Carole AU - Ober C AUID- ORCID: 0000-0003-4626-9809 AD - Dept of Human Genetics, University of Chicago, Chicago, IL, USA. FAU - Probst-Hensch, Nicole AU - Probst-Hensch N AUID- ORCID: 0000-0001-8561-5976 AD - Chronic Disease Epidemiology Unit, Dept of Epidemiology and Public Health, Swiss Tropical and Public Health Institute, Basel, Switzerland. AD - Dept of Public Health, University of Basel, Basel, Switzerland. FAU - Yang, Ivana V AU - Yang IV AD - Dept of Medicine, University of Colorado Anschutz Medical Campus, Aurora, CO, USA. FAU - Koppelman, Gerard H AU - Koppelman GH AUID- ORCID: 0000-0001-8567-3252 AD - Dept of Pediatric Pulmonology and Pediatric Allergy, University Medical Center Groningen, University of Groningen, Beatrix Children's Hospital and GRIAC Research Institute, Groningen, The Netherlands. FAU - London, Stephanie J AU - London SJ AUID- ORCID: 0000-0003-4911-5290 AD - Epidemiology Branch, National Institute of Environmental Health Sciences, National Institutes of Health, Dept of Health and Human Services, Research Triangle Park, NC, USA london2@niehs.nih.gov. LA - eng GR - Z01 CP010119/ImNIH/Intramural NIH HHS/United States GR - K08 HL125666/HL/NHLBI NIH HHS/United States GR - R38 HL143511/HL/NHLBI NIH HHS/United States GR - R01 HL117191/HL/NHLBI NIH HHS/United States GR - R01 HL129735/HL/NHLBI NIH HHS/United States GR - Z01 ES049030/ImNIH/Intramural NIH HHS/United States GR - U54 MD007587/MD/NIMHD NIH HHS/United States GR - U19 AI095230/AI/NIAID NIH HHS/United States GR - N01ES55546/ES/NIEHS NIH HHS/United States GR - UG3 OD023282/OD/NIH HHS/United States GR - T32 HL007085/HL/NHLBI NIH HHS/United States GR - R01 MD011764/MD/NIMHD NIH HHS/United States GR - WT_/Wellcome Trust/United Kingdom GR - R01 HL149836/HL/NHLBI NIH HHS/United States GR - R01 HL079966/HL/NHLBI NIH HHS/United States GR - UG3 HL151865/HL/NHLBI NIH HHS/United States PT - Journal Article PT - Research Support, N.I.H., Extramural PT - Research Support, U.S. Gov't, Non-P.H.S. DEP - 20200903 PL - England TA - Eur Respir J JT - The European respiratory journal JID - 8803460 SB - IM MH - Adult MH - *Asthma/genetics MH - Case-Control Studies MH - Child MH - CpG Islands MH - DNA Methylation MH - Epigenesis, Genetic MH - *Epigenome MH - Genome-Wide Association Study MH - Humans MH - Lung MH - United States PMC - PMC7469973 COIS- Conflict of interest: T.T. Hoang has nothing to disclose. Conflict of interest: S. Sikdar has nothing to disclose. Conflict of interest: C-J. Xu has nothing to disclose. Conflict of interest: M.K. Lee has nothing to disclose. Conflict of interest: J. Cardwell has nothing to disclose. Conflict of interest: E. Forno has nothing to disclose. Conflict of interest: M. Imboden has nothing to disclose. Conflict of interest: A. Jeong has nothing to disclose. Conflict of interest: A-M. Madore has nothing to disclose. Conflict of interest: C. Qi has nothing to disclose. Conflict of interest: T. Wang has nothing to disclose. Conflict of interest: B.D. Bennett has nothing to disclose. Conflict of interest: J.M. Ward has nothing to disclose. Conflict of interest: C.G. Parks has nothing to disclose. Conflict of interest: L.E. Beane-Freeman has nothing to disclose. Conflict of interest: D. King has nothing to disclose. Conflict of interest: A. Motsinger-Reif reports intramural research funding from the National Institute of Environmental Health Sciences, during the conduct of the study. Conflict of interest: D.M. Umbach has nothing to disclose. Conflict of interest: A.B. Wyss has nothing to disclose. Conflict of interest: D.A. Schwartz reports grants from the National Institutes of Health/National Heart, Lung, and Blood Institute (R38-HL143511, T32-HL007085, UG3/UH3-HL151865 and R01-HL149836) and the Dept of Defense Focused Program (12899593), during the conduct of the study; personal fees for consultancy from Eleven P15 Inc., outside the submitted work; and has a patent "Compositions and methods of treating or preventing fibrotic diseases" pending, a patent "Biomarkers for the diagnosis and treatment of fibrotic lung disease" pending and a patent "Methods and compositions for risk prediction, diagnosis, prognosis, and treatment of pulmonary disorders" issued. Conflict of interest: J.C. Celedon has received research materials from Pharmavite (vitamin D and placebo capsules) and GSK (inhaled steroids), in order to provide medications free of cost to participants in National Institutes of Health funded studies, unrelated to the current work. Conflict of interest: C. Laprise has nothing to disclose. Conflict of interest: C. Ober has nothing to disclose. Conflict of interest: N. Probst-Hensch has nothing to disclose. Conflict of interest: I.V. Yang is a consultant to Eleven P15 Inc., a start-up company that is focused on the early recognition and treatment of pulmonary fibrosis. Conflict of interest: G.H. Koppelman reports grants from the Lung Foundation of the Netherlands, the TETRI Foundation, TEVA the Netherlands, GSK, Vertex and the Ubbo Emmius Foundation, outside the submitted work; and has participated in advisory boards for GSK and PURE IMS, outside the submitted work. Conflict of interest: S.J. London has nothing to disclose. EDAT- 2020/05/10 06:00 MHDA- 2021/06/22 06:00 PMCR- 2020/09/03 CRDT- 2020/05/09 06:00 PHST- 2020/01/31 00:00 [received] PHST- 2020/04/15 00:00 [accepted] PHST- 2020/05/10 06:00 [pubmed] PHST- 2021/06/22 06:00 [medline] PHST- 2020/05/09 06:00 [entrez] PHST- 2020/09/03 00:00 [pmc-release] AID - 13993003.00217-2020 [pii] AID - ERJ-00217-2020 [pii] AID - 10.1183/13993003.00217-2020 [doi] PST - epublish SO - Eur Respir J. 2020 Sep 3;56(3):2000217. doi: 10.1183/13993003.00217-2020. Print 2020 Sep.