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Genome-wide association analyses for lung function and chronic obstructive pulmonary disease identify new loci and potential druggable targets.
Wain, Louise V; Shrine, Nick; Artigas, María Soler; Erzurumluoglu, A Mesut; Noyvert, Boris; Bossini-Castillo, Lara; Obeidat, Ma'en; Henry, Amanda P; Portelli, Michael A; Hall, Robert J; Billington, Charlotte K; Rimington, Tracy L; Fenech, Anthony G; John, Catherine; Blake, Tineka; Jackson, Victoria E; Allen, Richard J; Prins, Bram P; Campbell, Archie; Porteous, David J; Jarvelin, Marjo-Riitta; Wielscher, Matthias; James, Alan L; Hui, Jennie; Wareham, Nicholas J; Zhao, Jing Hua; Wilson, James F; Joshi, Peter K; Stubbe, Beate; Rawal, Rajesh; Schulz, Holger; Imboden, Medea; Probst-Hensch, Nicole M; Karrasch, Stefan; Gieger, Christian; Deary, Ian J; Harris, Sarah E; Marten, Jonathan; Rudan, Igor; Enroth, Stefan; Gyllensten, Ulf; Kerr, Shona M; Polasek, Ozren; Kähönen, Mika; Surakka, Ida; Vitart, Veronique; Hayward, Caroline; Lehtimäki, Terho; Raitakari, Olli T; Evans, David M.
Affiliation
  • Wain LV; Department of Health Sciences, University of Leicester, Leicester, UK.
  • Shrine N; National Institute for Health Research, Leicester Respiratory Biomedical Research Unit, Glenfield Hospital, Leicester, UK.
  • Artigas MS; Department of Health Sciences, University of Leicester, Leicester, UK.
  • Erzurumluoglu AM; Department of Health Sciences, University of Leicester, Leicester, UK.
  • Noyvert B; Department of Health Sciences, University of Leicester, Leicester, UK.
  • Bossini-Castillo L; Department of Health Sciences, University of Leicester, Leicester, UK.
  • Obeidat M; Wellcome Trust Sanger Institute, Hinxton, UK.
  • Henry AP; University of British Columbia Centre for Heart Lung Innovation, St Paul's Hospital, Vancouver, British Columbia, Canada.
  • Portelli MA; Division of Respiratory Medicine, University of Nottingham, Nottingham, UK.
  • Hall RJ; Division of Respiratory Medicine, University of Nottingham, Nottingham, UK.
  • Billington CK; Division of Respiratory Medicine, University of Nottingham, Nottingham, UK.
  • Rimington TL; Division of Respiratory Medicine, University of Nottingham, Nottingham, UK.
  • Fenech AG; Division of Respiratory Medicine, University of Nottingham, Nottingham, UK.
  • John C; Department of Clinical Pharmacology and Therapeutics, University of Malta, Msida, Malta.
  • Blake T; Department of Health Sciences, University of Leicester, Leicester, UK.
  • Jackson VE; Department of Health Sciences, University of Leicester, Leicester, UK.
  • Allen RJ; Department of Health Sciences, University of Leicester, Leicester, UK.
  • Prins BP; Department of Health Sciences, University of Leicester, Leicester, UK.
  • Porteous DJ; Medical Genetics Section, Centre for Genomic and Experimental Medicine, Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh, UK.
  • Jarvelin MR; Generation Scotland, Centre for Genomic and Experimental Medicine, University of Edinburgh, Edinburgh, UK.
  • Wielscher M; Medical Genetics Section, Centre for Genomic and Experimental Medicine, Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh, UK.
  • James AL; Generation Scotland, Centre for Genomic and Experimental Medicine, University of Edinburgh, Edinburgh, UK.
  • Hui J; Department of Epidemiology and Biostatistics, MRC-PHE Centre for Environment and Health, School of Public Health, Imperial College London, London, UK.
  • Wareham NJ; Faculty of Medicine, Center for Life Course Health Research, University of Oulu, Oulu, Finland.
  • Zhao JH; Biocenter Oulu, University of Oulu, Oulu, Finland.
  • Wilson JF; Unit of Primary Care, Oulu University Hospital, Oulu, Finland.
  • Joshi PK; Department of Epidemiology and Biostatistics, MRC-PHE Centre for Environment and Health, School of Public Health, Imperial College London, London, UK.
  • Stubbe B; Busselton Population Medical Research Institute, Sir Charles Gairdner Hospital, Nedlands, Western Australia, Australia.
  • Rawal R; Department of Pulmonary Physiology and Sleep Medicine, Sir Charles Gairdner Hospital, Nedlands, Western Australia, Australia.
  • Schulz H; School of Medicine and Pharmacology, University of Western Australia, Crawley, Western Australia, Australia.
  • Imboden M; Busselton Population Medical Research Institute, Sir Charles Gairdner Hospital, Nedlands, Western Australia, Australia.
  • Probst-Hensch NM; School of Population Health, University of Western Australia, Crawley, Western Australia, Australia.
  • Karrasch S; PathWest Laboratory Medicine of Western Australia, Sir Charles Gairdner Hospital, Crawley, Western Australia, Australia.
  • Gieger C; School of Pathology and Laboratory Medicine, University of Western Australia, Crawley, Western Australia, Australia.
  • Deary IJ; MRC Epidemiology Unit, University of Cambridge School of Clinical Medicine, Institute of Metabolic Science, Cambridge Biomedical Campus, Cambridge, UK.
  • Harris SE; MRC Epidemiology Unit, University of Cambridge School of Clinical Medicine, Institute of Metabolic Science, Cambridge Biomedical Campus, Cambridge, UK.
  • Marten J; Centre for Global Health Research, Usher Institute for Population Health Sciences and Informatics, University of Edinburgh, Edinburgh, UK.
  • Rudan I; Medical Research Council Human Genetics Unit, Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh, UK.
  • Enroth S; Centre for Global Health Research, Usher Institute for Population Health Sciences and Informatics, University of Edinburgh, Edinburgh, UK.
  • Gyllensten U; Department of Internal Medicine B-Cardiology, Intensive Care, Pulmonary Medicine and Infectious Diseases, University Medicine Greifswald, Greifswald, Germany.
  • Kerr SM; Research Unit of Molecular Epidemiology, Institute of Epidemiology II, Helmholtz Zentrum München-German Research Center for Environmental Health, Neuherberg, Germany.
  • Polasek O; Institute of Epidemiology I, Helmholtz Zentrum München-German Research Center for Environmental Health, Neuherberg, Germany.
  • Kähönen M; Comprehensive Pneumology Center Munich (CPC-M), Member of the German Center for Lung Research, Neuherberg, Germany.
  • Surakka I; Swiss Tropical and Public Health Institute, Basel, Switzerland.
  • Vitart V; University of Basel, Basel, Switzerland.
  • Hayward C; Swiss Tropical and Public Health Institute, Basel, Switzerland.
  • Lehtimäki T; University of Basel, Basel, Switzerland.
  • Raitakari OT; Institute of Epidemiology I, Helmholtz Zentrum München-German Research Center for Environmental Health, Neuherberg, Germany.
  • Evans DM; Institute and Outpatient Clinic for Occupational, Social and Environmental Medicine, Ludwig-Maximilians-Universität, Munich, Germany.
Nat Genet ; 49(3): 416-425, 2017 Mar.
Article in En | MEDLINE | ID: mdl-28166213
ABSTRACT
Chronic obstructive pulmonary disease (COPD) is characterized by reduced lung function and is the third leading cause of death globally. Through genome-wide association discovery in 48,943 individuals, selected from extremes of the lung function distribution in UK Biobank, and follow-up in 95,375 individuals, we increased the yield of independent signals for lung function from 54 to 97. A genetic risk score was associated with COPD susceptibility (odds ratio per 1 s.d. of the risk score (∼6 alleles) (95% confidence interval) = 1.24 (1.20-1.27), P = 5.05 × 10-49), and we observed a 3.7-fold difference in COPD risk between individuals in the highest and lowest genetic risk score deciles in UK Biobank. The 97 signals show enrichment in genes for development, elastic fibers and epigenetic regulation pathways. We highlight targets for drugs and compounds in development for COPD and asthma (genes in the inositol phosphate metabolism pathway and CHRM3) and describe targets for potential drug repositioning from other clinical indications.
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Full text: 1 Collection: 01-internacional Database: MEDLINE Main subject: Genetic Predisposition to Disease / Pulmonary Disease, Chronic Obstructive / Genetic Loci / Lung Type of study: Etiology_studies / Prognostic_studies / Risk_factors_studies Limits: Adult / Aged / Aged80 / Female / Humans / Male / Middle aged Language: En Journal: Nat Genet Journal subject: GENETICA MEDICA Year: 2017 Type: Article Affiliation country: United kingdom
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Full text: 1 Collection: 01-internacional Database: MEDLINE Main subject: Genetic Predisposition to Disease / Pulmonary Disease, Chronic Obstructive / Genetic Loci / Lung Type of study: Etiology_studies / Prognostic_studies / Risk_factors_studies Limits: Adult / Aged / Aged80 / Female / Humans / Male / Middle aged Language: En Journal: Nat Genet Journal subject: GENETICA MEDICA Year: 2017 Type: Article Affiliation country: United kingdom