Genome-Wide Association Study of Susceptibility to Idiopathic Pulmonary Fibrosis.

Autor: Allen RJ; Department of Health Sciences, University of Leicester, Leicester, United Kingdom., Guillen-Guio B; Unidad de Investigacion, Hospital Universitario Ntra. Sra. de Candelaria and., Oldham JM; Department of Internal Medicine, University of California Davis, Davis, California., Ma SF; Division of Pulmonary and Critical Care Medicine., Dressen A; Genentech, South San Francisco, California., Paynton ML; Department of Health Sciences, University of Leicester, Leicester, United Kingdom., Kraven LM; Department of Health Sciences, University of Leicester, Leicester, United Kingdom., Obeidat M; The University of British Columbia Centre for Heart Lung Innovation, St. Paul's Hospital, Vancouver, British Columbia, Canada., Li X; The University of British Columbia Centre for Heart Lung Innovation, St. Paul's Hospital, Vancouver, British Columbia, Canada., Ng M; Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences., Braybrooke R; Division of Epidemiology and Public Health and.; National Institute for Health Research, Nottingham Biomedical Research Centre and., Molina-Molina M; Servei de Pneumologia, Laboratori de Pneumologia Experimental, Instituto de Investigación Biomédica de Bellvitge (IDIBELL), Barcelona, Spain.; Campus de Bellvitge, Universitat de Barcelona, Barcelona, Spain.; Centro de Investigación Biomédica en Red de Enfermedades Respiratorias, Instituto de Salud Carlos III, Madrid, Spain., Hobbs BD; Channing Division of Network Medicine.; Division of Pulmonary and Critical Care Medicine., Putman RK; Division of Pulmonary and Critical Care Medicine., Sakornsakolpat P; Channing Division of Network Medicine.; Department of Medicine, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, Thailand., Booth HL; Department of Thoracic Medicine, University College London Hospitals NHS Foundation Trust, London, United Kingdom., Fahy WA; Discovery Medicine, GlaxoSmithKline, Stevenage, United Kingdom., Hart SP; Respiratory Research Group, Hull York Medical School, Castle Hill Hospital, Cottingham, United Kingdom., Hill MR; Clinical Trial Service Unit and Epidemiological Studies Unit, Nuffield Department of Population Health., Hirani N; Medical Research Council Centre for Inflammation Research, The University of Edinburgh, Edinburgh, United Kingdom., Hubbard RB; Division of Epidemiology and Public Health and.; National Institute for Health Research, Nottingham Biomedical Research Centre and., McAnulty RJ; UCL Respiratory Centre for Inflammation and Tissue Repair, University College London, London, United Kingdom., Millar AB; Academic Respiratory Unit, School of Clinical Sciences, University of Bristol, Bristol, United Kingdom., Navaratnam V; Division of Epidemiology and Public Health and.; National Institute for Health Research, Nottingham Biomedical Research Centre and., Oballa E; Discovery Medicine, GlaxoSmithKline, Stevenage, United Kingdom., Parfrey H; Cambridge Interstitial Lung Disease Service, Royal Papworth Hospital, Cambridge, United Kingdom., Saini G; Respiratory Medicine, Nottingham University Hospitals NHS Trust, Nottingham, United Kingdom., Whyte MKB; Medical Research Council Centre for Inflammation Research, The University of Edinburgh, Edinburgh, United Kingdom., Zhang Y; Division of Pulmonary, Allergy and Critical Care Medicine and.; Simmons Center for Interstitial Lung Diseases, University of Pittsburgh, Pittsburgh, Pennsylvania., Kaminski N; Section of Pulmonary, Critical Care and Sleep Medicine, Yale School of Medicine, New Haven, Connecticut., Adegunsoye A; Section of Pulmonary and Critical Care, Department of Medicine, The University of Chicago, Chicago, Illinois., Strek ME; Section of Pulmonary and Critical Care, Department of Medicine, The University of Chicago, Chicago, Illinois., Neighbors M; Genentech, South San Francisco, California., Sheng XR; Genentech, South San Francisco, California., Gudmundsson G; Department of Respiratory Medicine, Landspital University Hospital, Reykjavik, Iceland.; Faculty of Medicine University of Iceland, Reykjavik, Iceland., Gudnason V; Faculty of Medicine University of Iceland, Reykjavik, Iceland.; Icelandic Heart Association, Kopavogur, Iceland., Hatabu H; Department of Radiology, and.; Center for Pulmonary Functional Imaging, Brigham and Women's Hospital, Boston, Massachusetts., Lederer DJ; Department of Medicine, College of Physicians and Surgeons and.; Department of Epidemiology, Mailman School of Public Health, Columbia University, New York, New York., Manichaikul A; Center for Public Health Genomics, and.; Department of Public Health Sciences, University of Virginia, Charlottesville, Virginia., Newell JD Jr; Division of Cardiovascular and Pulmonary Imaging, Department of Radiology, University of Iowa Carver College of Medicine, Iowa City, Iowa.; Department of Radiology, University of Washington, Seattle, Washington., O'Connor GT; Department of Medicine, Pulmonary Center, Boston University, Boston, Massachusetts.; NHLBI's Framingham Heart Study, Framingham, Massachusetts., Ortega VE; Center for Precision Medicine, Department of Internal Medicine, Wake Forest School of Medicine, Winston-Salem, North Carolina., Xu H; Department of Biostatistics, Boston University School of Public Health, Boston, Massachusetts., Fingerlin TE; Center for Genes, Environment and Health, National Jewish Health, Denver, Colarado.; Department of Biostatistics and Informatics., Bossé Y; Institut universitaire de cardiologie et de pneumologie de Québec, Université Laval, Québec, Québec, Canada., Hao K; Department of Genetics and Genomic Sciences and.; Icahn Institute for Data Science and Genomic Technology, Icahn School of Medicine at Mount Sinai, New York, New York., Joubert P; Institut universitaire de cardiologie et de pneumologie de Québec, Université Laval, Québec, Québec, Canada., Nickle DC; Merck Research Laboratories, Genetics and Pharmacogenomics, Boston, Massachusetts., Sin DD; The University of British Columbia Centre for Heart Lung Innovation, St. Paul's Hospital, Vancouver, British Columbia, Canada.; Respiratory Division, Department of Medicine, University of British Columbia, Vancouver, British Columbia, Canada., Timens W; University Medical Center Groningen, University of Groningen, Department of Pathology and Medical Biology and.; Groningen Research Institute for Asthma and COPD, Groningen, the Netherlands., Furniss D; Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences., Morris AP; Wellcome Centre for Human Genetics, and.; Department of Biostatistics, University of Liverpool, Liverpool, United Kingdom.; Division of Musculoskeletal and Dermatological Sciences, University of Manchester, Manchester, United Kingdom., Zondervan KT; Wellcome Centre for Human Genetics, and.; Oxford Endometriosis Care and Research Centre, Nuffield Department of Women's and Reproductive Health, University of Oxford, Oxford, United Kingdom., Hall IP; Division of Respiratory Medicine, University of Nottingham, Nottingham, United Kingdom.; National Institute for Health Research, Nottingham Biomedical Research Centre and., Sayers I; Division of Respiratory Medicine, University of Nottingham, Nottingham, United Kingdom.; National Institute for Health Research, Nottingham Biomedical Research Centre and., Tobin MD; Department of Health Sciences, University of Leicester, Leicester, United Kingdom.; National Institute for Health Research, Leicester Respiratory Biomedical Research Centre, Glenfield Hospital, Leicester, United Kingdom., Maher TM; National Institute for Health Research Respiratory Clinical Research Facility, Royal Brompton Hospital, London, United Kingdom.; National Heart and Lung Institute, Imperial College, London, United Kingdom; and., Cho MH; Channing Division of Network Medicine.; Division of Pulmonary and Critical Care Medicine., Hunninghake GM; Division of Pulmonary and Critical Care Medicine.; Center for Pulmonary Functional Imaging, Brigham and Women's Hospital, Boston, Massachusetts., Schwartz DA; Center for Genes, Environment and Health, National Jewish Health, Denver, Colarado.; Department of Medicine, and.; Department of Immunology, University of Colorado Denver, Denver, Colorado., Yaspan BL; Genentech, South San Francisco, California., Molyneaux PL; National Institute for Health Research Respiratory Clinical Research Facility, Royal Brompton Hospital, London, United Kingdom.; National Heart and Lung Institute, Imperial College, London, United Kingdom; and., Flores C; Unidad de Investigacion, Hospital Universitario Ntra. Sra. de Candelaria and.; Instituto de Tecnologías Biomédicas, Universidad de La Laguna, Santa Cruz de Tenerife, Spain.; Centro de Investigación Biomédica en Red de Enfermedades Respiratorias, Instituto de Salud Carlos III, Madrid, Spain.; Instituto Tecnológico y de Energías Renovables, S.A., Santa Cruz de Tenerife, Spain., Noth I; Division of Pulmonary and Critical Care Medicine., Jenkins RG; Division of Respiratory Medicine, University of Nottingham, Nottingham, United Kingdom.; National Institute for Health Research, Nottingham Biomedical Research Centre and., Wain LV; Department of Health Sciences, University of Leicester, Leicester, United Kingdom.; National Institute for Health Research, Leicester Respiratory Biomedical Research Centre, Glenfield Hospital, Leicester, United Kingdom.
Jazyk: angličtina
Zdroj: American journal of respiratory and critical care medicine [Am J Respir Crit Care Med] 2020 Mar 01; Vol. 201 (5), pp. 564-574.
DOI: 10.1164/rccm.201905-1017OC
Abstrakt: Rationale: Idiopathic pulmonary fibrosis (IPF) is a complex lung disease characterized by scarring of the lung that is believed to result from an atypical response to injury of the epithelium. Genome-wide association studies have reported signals of association implicating multiple pathways including host defense, telomere maintenance, signaling, and cell-cell adhesion. Objectives: To improve our understanding of factors that increase IPF susceptibility by identifying previously unreported genetic associations. Methods: We conducted genome-wide analyses across three independent studies and meta-analyzed these results to generate the largest genome-wide association study of IPF to date (2,668 IPF cases and 8,591 controls). We performed replication in two independent studies (1,456 IPF cases and 11,874 controls) and functional analyses (including statistical fine-mapping, investigations into gene expression, and testing for enrichment of IPF susceptibility signals in regulatory regions) to determine putatively causal genes. Polygenic risk scores were used to assess the collective effect of variants not reported as associated with IPF. Measurements and Main Results: We identified and replicated three new genome-wide significant ( P  < 5 × 10 -8 ) signals of association with IPF susceptibility (associated with altered gene expression of KIF15 , MAD1L1 , and DEPTOR ) and confirmed associations at 11 previously reported loci. Polygenic risk score analyses showed that the combined effect of many thousands of as yet unreported IPF susceptibility variants contribute to IPF susceptibility. Conclusions: The observation that decreased DEPTOR expression associates with increased susceptibility to IPF supports recent studies demonstrating the importance of mTOR signaling in lung fibrosis. New signals of association implicating KIF15 and MAD1L1 suggest a possible role of mitotic spindle-assembly genes in IPF susceptibility.
Databáze: MEDLINE