Herman T den Dekker1,2,3,4, Kimberley Burrows5,4, Janine F Felix1,3,6,4, Lucas A Salas7,8,9,10, Ivana Nedeljkovic3, Jin Yao11, Sheryl L Rifas-Shiman12, Carlos Ruiz-Arenas7,9,10, N Amin3, Mariona Bustamante7,9,10,13, Dawn L DeMeo14, A John Henderson5, Caitlin G Howe11, Marie-France Hivert12, M Arfan Ikram3, Johan C de Jongste2, Lies Lahousse3,15, Pooja R Mandaviya16,17, Joyce B van Meurs17, Mariona Pinart7,9,10,18, Gemma C Sharp5, Lisette Stolk17,19, André G Uitterlinden3,17,19, Josep M Anto7,9,10,18, Augusto A Litonjua14, Carrie V Breton11, Guy G Brusselle3,11,20, Jordi Sunyer7,9,10,18, George Davey Smith5, Caroline L Relton5,4, Vincent W V Jaddoe1,3,6,4, Liesbeth Duijts21,22,4. 1. The Generation R Study Group, Erasmus MC, University Medical Center Rotterdam, Rotterdam, The Netherlands. 2. Dept of Pediatrics, Division of Respiratory Medicine and Allergology, Erasmus MC, University Medical Center Rotterdam, Rotterdam, The Netherlands. 3. Dept of Epidemiology, Erasmus MC, University Medical Center Rotterdam, Rotterdam, The Netherlands. 4. These authors contributed equally. 5. MRC Integrative Epidemiology Unit, University of Bristol, UK School of Social and Community Medicine, University of Bristol, Bristol, UK. 6. Dept of Pediatrics, Erasmus MC, University Medical Center Rotterdam, Rotterdam, The Netherlands. 7. ISGLobal, Centre for Research in Environmental Epidemiology (CREAL), Barcelona, Spain. 8. Dept of Epidemiology, Geisel School of Medicine at Dartmouth, Lebanon, NH, USA. 9. Universitat Pompeu Fabra (UPF), Barcelona, Spain. 10. CIBER Epidemiología y Salud Pública (CIBERESP), Barcelona, Spain. 11. Dept of Preventive Medicine, University of Southern California, Los Angeles, CA, USA. 12. Obesity Prevention Program, Dept of Population Medicine, Harvard Medical School and Harvard Pilgrim Health Care Institute, Boston, MA, USA. 13. Centre for Genomic Regulation (CRG), The Barcelona Institute of Science and Technology, Barcelona, Spain. 14. Channing Division of Network Medicine, Brigham and Women's Hospital, Boston, MA, USA. 15. Dept of Respiratory Medicine, Ghent University Hospital, Ghent, Belgium. 16. Dept of Clinical Chemistry, Erasmus MC, University Medical Center Rotterdam, Rotterdam, The Netherlands. 17. Dept of Internal Medicine, Erasmus MC, University Medical Center Rotterdam, Rotterdam, The Netherlands. 18. IMIM (Hospital del Mar Medical Research Institute), Barcelona, Spain. 19. Netherlands Consortium for Healthy Ageing (NCHA), Erasmus MC, University Medical Center Rotterdam, The Netherlands. 20. Dept of Respiratory Medicine, Erasmus MC, University Medical Center Rotterdam, Rotterdam, The Netherlands. 21. Dept of Pediatrics, Division of Respiratory Medicine and Allergology, Erasmus MC, University Medical Center Rotterdam, Rotterdam, The Netherlands l.duijts@erasmusmc.nl. 22. Dept of Pediatrics, Division of Neonatology, Erasmus MC, University Medical Center Rotterdam, Rotterdam, The Netherlands.
Abstract
RATIONALE: We aimed to identify differentially methylated regions (DMRs) in cord blood DNA associated with childhood lung function, asthma and chronic obstructive pulmonary disease (COPD) across the life course. METHODS: We meta-analysed epigenome-wide data of 1688 children from five cohorts to identify cord blood DMRs and their annotated genes, in relation to forced expiratory volume in 1 s (FEV1), FEV1/forced vital capacity (FVC) ratio and forced expiratory flow at 75% of FVC at ages 7-13 years. Identified DMRs were explored for associations with childhood asthma, adult lung function and COPD, gene expression and involvement in biological processes. RESULTS: We identified 59 DMRs associated with childhood lung function, of which 18 were associated with childhood asthma and nine with COPD in adulthood. Genes annotated to the top 10 identified DMRs were HOXA5, PAOX, LINC00602, ABCA7, PER3, CLCA1, VENTX, NUDT12, PTPRN2 and TCL1A. Differential gene expression in blood was observed for 32 DMRs in childhood and 18 in adulthood. Genes related with 16 identified DMRs were associated with respiratory developmental or pathogenic pathways. INTERPRETATION: Our findings suggest that the epigenetic status of the newborn affects respiratory health and disease across the life course.
RATIONALE: We aimed to identify differentially methylated regions (DMRs) in cord blood DNA associated with childhood lung function, asthma and chronic obstructive pulmonary disease (COPD) across the life course. METHODS: We meta-analysed epigenome-wide data of 1688 children from five cohorts to identify cord blood DMRs and their annotated genes, in relation to forced expiratory volume in 1 s (FEV1), FEV1/forced vital capacity (FVC) ratio and forced expiratory flow at 75% of FVC at ages 7-13 years. Identified DMRs were explored for associations with childhood asthma, adult lung function and COPD, gene expression and involvement in biological processes. RESULTS: We identified 59 DMRs associated with childhood lung function, of which 18 were associated with childhood asthma and nine with COPD in adulthood. Genes annotated to the top 10 identified DMRs were HOXA5, PAOX, LINC00602, ABCA7, PER3, CLCA1, VENTX, NUDT12, PTPRN2 and TCL1A. Differential gene expression in blood was observed for 32 DMRs in childhood and 18 in adulthood. Genes related with 16 identified DMRs were associated with respiratory developmental or pathogenic pathways. INTERPRETATION: Our findings suggest that the epigenetic status of the newborn affects respiratory health and disease across the life course.
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