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      New genetic signals for lung function highlight pathways and chronic obstructive pulmonary disease associations across multiple ancestries.

      research-article
      1 , 1 , 1 , 1 , 2 , 3 , 4 , 5 , 1 , 1 , 1 , 6 , 4 , 7 , 8 , 9 , 10 , 1 , 11 , 12 , 13 , Understanding Society Scientific Group 14 , 15 , 16 , 17 , 18 , 19 , 20 , 21 , 22 , 23 , 24 , 25 , 26 , 27 , 28 , 29 , 30 , 31 , 32 , 33 , 32 , 34 , 35 , 32 , 36 , 1 , 37 , 38 , 8 , 39 , 40 , 41 , 9 , 42 , 43 , 19 , 44 , 45 , 46 , 4 , 5 , 1 , 47 , 48 , 37 , 49 , 50 , 51 , 52 , 6 , 53 , 15 , 16 , 40 , 54 , 55 , 11 , 56 , 9 , 57 , 58 , 55 , 59 , 60 , 61 , 60 , 62 , 1 , 4 , 1 , 30 , 31 , 4 , 4 , 48 , 60 , 63 , 11 , 64 , 65 , 66 , 67 , 68 , 69 , 70 , 58 , 16 , 71 , 72 , 73 , 6 , 74 , 75 , 76 , 77 , 78 , 79 , 16 , 33 , 16 , 30 , 80 , 28 , 29 , 25 , 27 , 21 , 81 , 82 , 16 , 32 , 47 , 83 , 84 , 85 , 86 , 87 , 13 , 88 , 55 , 4 , 5 , 32 , 18 , 59 , 19 , 46 , 72 , 9 , 8 , 4 , 5 , 89 , 63 , * , 1 , 90 , * , 1 , 90
      Nature genetics
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          There is no author summary for this article yet. Authors can add summaries to their articles on ScienceOpen to make them more accessible to a non-specialist audience.

          Abstract

          Reduced lung function predicts mortality and is key to the diagnosis of chronic obstructive pulmonary disease (COPD). In a genome-wide association study in 400,102 individuals of European ancestry, we define 279 lung function signals, 139 of which are new. In combination, these variants strongly predict COPD in independent patient populations. Furthermore, the combined effect of these variants showed generalizability across smokers and never-smokers, and across ancestral groups. We highlight biological pathways, known and potential drug targets for COPD and, in phenome-wide association studies, autoimmune-related and other pleiotropic effects of lung function associated variants. This new genetic evidence has potential to improve future preventive and therapeutic strategies for COPD.

          Editorial summary:

          A genome-wide association study in over 400,000 individuals identifies 139 new signals for lung function. These variants can predict chronic obstructive pulmonary disease in independent, trans-ethnic cohorts.

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          Most cited references26

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          Chronic obstructive pulmonary disease in non-smokers.

          Chronic obstructive pulmonary disease (COPD) is a leading cause of morbidity and mortality worldwide. Tobacco smoking is established as a major risk factor, but emerging evidence suggests that other risk factors are important, especially in developing countries. An estimated 25-45% of patients with COPD have never smoked; the burden of non-smoking COPD is therefore much higher than previously believed. About 3 billion people, half the worldwide population, are exposed to smoke from biomass fuel compared with 1.01 billion people who smoke tobacco, which suggests that exposure to biomass smoke might be the biggest risk factor for COPD globally. We review the evidence for the association of COPD with biomass fuel, occupational exposure to dusts and gases, history of pulmonary tuberculosis, chronic asthma, respiratory-tract infections during childhood, outdoor air pollution, and poor socioeconomic status.
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            • Record: found
            • Abstract: found
            • Article: not found

            Developing COPD: a 25 year follow up study of the general population.

            Smokers are more prone to develop chronic obstructive pulmonary disease (COPD) than non-smokers, but this finding comes from studies spanning 10 years or less. The aim of this study was to determine the 25 year absolute risk of developing COPD in men and women from the general population. As part of the Copenhagen City Heart Study, 8045 men and women aged 30-60 years with normal lung function at baseline were followed for 25 years. Lung function measurements were collected and mortality from COPD during the 25 year observation period was analysed. The percentage of men with normal lung function ranged from 96% of never smokers to 59% of continuous smokers; for women the proportions were 91% and 69%, respectively. The 25 year incidence of moderate and severe COPD was 20.7% and 3.6%, respectively, with no apparent difference between men and women. Smoking cessation, especially early in the follow up period, decreased the risk of developing COPD substantially compared with continuous smoking. During the follow up period there were 2912 deaths, 109 of which were from COPD. 92% of the COPD deaths occurred in subjects who were current smokers at the beginning of the follow up period. The absolute risk of developing COPD among continuous smokers is at least 25%, which is larger than was previously estimated.
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              • Record: found
              • Abstract: found
              • Article: found
              Is Open Access

              Integrins as Therapeutic Targets: Successes and Cancers

              Integrins are transmembrane receptors that are central to the biology of many human pathologies. Classically mediating cell-extracellular matrix and cell-cell interaction, and with an emerging role as local activators of TGFβ, they influence cancer, fibrosis, thrombosis and inflammation. Their ligand binding and some regulatory sites are extracellular and sensitive to pharmacological intervention, as proven by the clinical success of seven drugs targeting them. The six drugs on the market in 2016 generated revenues of some US$3.5 billion, mainly from inhibitors of α4-series integrins. In this review we examine the current developments in integrin therapeutics, especially in cancer, and comment on the health economic implications of these developments.
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                Author and article information

                Journal
                9216904
                2419
                Nat Genet
                Nat. Genet.
                Nature genetics
                1061-4036
                1546-1718
                30 November 2018
                25 February 2019
                March 2019
                25 August 2019
                : 51
                : 3
                : 481-493
                Affiliations
                [1 ]Department of Health Sciences, University of Leicester, Leicester, LE1 7RH, UK
                [2 ]Population Health and Immunity Division, The Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria, Australia
                [3 ]Department of Medical Biology, University of Melbourne, Parkville, Victoria, Australia
                [4 ]Channing Division of Network Medicine, Brigham and Women’s Hospital, Boston, Massachussetts, USA
                [5 ]Division of Pulmonary and Critical Care Medicine, Brigham and Women’s Hospital, Boston, Massachussetts, USA
                [6 ]Target Sciences, GlaxoSmithKline, Collegeville, Pennsylvania, USA
                [7 ]Department of Medicine, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, Thailand
                [8 ]Division of Genetics, Genomics and Precision Medicine, Department of Medicine, University of Arizona, Tucson, Arizona, USA
                [9 ]Nuffield Department of Population Health, University of Oxford, Oxford, UK
                [10 ]Medical Research Council Population Health Research Unit, University of Oxford, Oxford, UK
                [11 ]The University of British Columbia Centre for Heart Lung Innovation, St Paul’s Hospital, Vancouver, British Columbia, Canada
                [12 ]Cardiovascular Epidemiology Unit, Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK
                [13 ]Department of Epidemiology and Biostatistics, MRC–PHE Centre for Environment & Health, School of Public Health, Imperial College London, London, UK
                [14 ]A list of contributors can be found in the Supplementary Note
                [15 ]Interfaculty Institute for Genetics and Functional Genomics, Department of Functional Genomics, University Medicine Greifswald, Greifswald, Germany
                [16 ]Centre for Global Health Research, Usher Institute for Population Health Sciences and Informatics, University of Edinburgh, Edinburgh, UK
                [17 ]Centre for Cardiovascular Sciences, Queen’s Medical Research Institute, University of Edinburgh, Edinburgh, UK
                [18 ]Department of Biostatistics, University of Liverpool, Liverpool, UK
                [19 ]MRC/BHF Cardiovascular Epidemiology Unit, Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK
                [20 ]Flatiron Institute, Simons Foundation, New York, New York, USA
                [21 ]Busselton Population Medical Research Institute, Sir Charles Gairdner Hospital, Nedlands, Western Australia, Australia
                [22 ]School of Population Health, The University of Western Australia, Crawley, Western Australia Australia
                [23 ]PathWest Laboratory Medicine of WA, Sir Charles Gairdner Hospital, Crawley, Western Australia, Australia
                [24 ]School of Pathology and Laboratory Medicine, The University of Western Australia, Crawley, Western Australia, Australia
                [25 ]Institute of Epidemiology, Helmholtz Zentrum Muenchen – German Research Center for Environmental Health, Neuherberg, Germany
                [26 ]Institute and Outpatient Clinic for Occupational, Social and Environmental Medicine, Ludwig-Maximilians-Universität, Munich, Germany
                [27 ]Comprehensive Pneumology Center Munich (CPC-M), Member of the German Center for Lung Research (DZL), Munich, Germany
                [28 ]Swiss Tropical and Public Health Institute, Basel, Switzerland
                [29 ]University of Basel, Basel, Switzerland
                [30 ]Centre for Cognitive Ageing and Cognitive Epidemiology, University of Edinburgh, Edinburgh, UK
                [31 ]Centre for Genomic and Experimental Medicine, Institute of Genetics & Molecular Medicine, University of Edinburgh, Edinburgh, UK
                [32 ]Medical Research Council Human Genetics Unit, Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh, UK
                [33 ]Department of Immunology, Genetics and Pathology, Science for Life Laboratory, Uppsala Universitet, Uppsala, Sweden
                [34 ]Institute for Molecular Medicine Finland (FIMM), University of Helsinki, Helsinki, Finland
                [35 ]The National Institute for Health and Welfare (THL), Helsinki, Finland
                [36 ]Department of Clinical Chemistry, Fimlab Laboratories, and Finnish Cardiovascular Research Center - Tampere, Faculty of Medicine and Life Sciences, University of Tampere, Tampere, Finland
                [37 ]Department of Clinical Science, University of Bergen, Bergen, Norway
                [38 ]Department of Epidemiology, Johns Hopkins University School of Public Health, Baltimore, Maryland, USA
                [39 ]Department of Molecular Medicine, Laval University, Québec, Canada
                [40 ]Institut Universitaire de Cardiologie et de Pneumologie de Québec, Laval University, Québec, Canada
                [41 ]University of Groningen, University Medical Center Groningen, Department of Pathology and Medical Biology, GRIAC Research Institute, University of Groningen, Groningen, The Netherlands
                [42 ]National Jewish Health, Denver, Colorado, USA
                [43 ]Division of Pulmonary, Critical Care and Sleep Medicine, National Jewish Health, Denver, Colorado, USA
                [44 ]British Heart Foundation Cambridge Centre of Excellence, Division of Cardiovascular Medicine, Addenbrooke’s Hospital, Cambridge, UK
                [45 ]Department of Human Genetics, Wellcome Trust Sanger Institute, Cambridge, UK
                [46 ]NIHR Blood and Transplant Research Unit in Donor Health and Genomics, Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK
                [47 ]Department of Internal Medicine B - Cardiology, Intensive Care, Pulmonary Medicine and Infectious Diseases, University Medicine Greifswald, Greifswald, Germany
                [48 ]Research Unit of Molecular Epidemiology, Institute of Epidemiology, Helmholtz Zentrum Muenchen – German Research Center for Environmental Health, Neuherberg, Germany
                [49 ]Centre for Environmental Health & Sustainability, University of Leicester, Leicester, UK
                [50 ]UK Small Area Health Statistics Unit, MRC-PHE Centre for Environment and Health, School of Public Health, Imperial College London, London, UK
                [51 ]Imperial College Healthcare NHS Trust, St Mary’s Hospital, London, UK
                [52 ]Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, New York, USA
                [53 ]Department of Epidemiology, University of Colorado Anschutz Medical Campus, Aurora, Colorado, USA
                [54 ]Department of Molecular Biology, Medical Biochemistry, and Pathology, Laval University, Québec, Canada
                [55 ]MRC Epidemiology Unit, University of Cambridge School of Clinical Medicine, Cambridge, UK
                [56 ]Department of Epidemiology & Biostatistics, Peking University Health Science Center, Beijing, China
                [57 ]Department of Medical Sciences, Cardiovascular Epidemiology, Uppsala University, Uppsala, Sweden
                [58 ]GSK R&D, Collegeville, Pennsylvania, US
                [59 ]Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK
                [60 ]MRL, Merck & Co., Inc., Kenilworth, New Jersey, USA
                [61 ]The Institute of Medical Sciences, Aberdeen Biomedical Imaging Centre, University of Aberdeen, Aberdeen, UK
                [62 ]Gossamer Bio, San Diego, California, USA
                [63 ]Division of Respiratory Medicine and NIHR-Nottingham Biomedical Research Centre, University of Nottingham, Nottingham, UK
                [64 ]Respiratory Division, Department of Medicine, University of British Columbia, Vancouver, British Columbia, Canada
                [65 ]Division of Population Health and Genomics, Ninewells Hospital and Medical School, University of Dundee, Dundee, UK
                [66 ]Psychiatric Genetics Unit, Group of Psychiatry, Mental Health and Addiction, Vall d’Hebron Research Institute (VHIR), Universitat Autònoma de Barcelona, Barcelona, Spain
                [67 ]Department of Psychiatry, Hospital Universitari Vall d’Hebron, Barcelona, Spain
                [68 ]Biomedical Network Research Centre on Mental Health (CIBERSAM), Instituto de Salud Carlos III, Barcelona, Spain
                [69 ]VA Boston Healthcare System, Boston, Massachusetts, USA
                [70 ]Department of Medicine, Boston University School of Medicine, Boston, Massachusetts, USA
                [71 ]University of Groningen, University Medical Center Groningen, Department of Pulmonology, GRIAC Research Institute, University of Groningen, Groningen, The Netherlands
                [72 ]Target Sciences - R&D, GSK Medicines Research Centre, Stevenage, UK
                [73 ]UCSF Pulmonary, Critical Care, Allergy and Sleep Medicine, University of California San Francisco, California, USA
                [74 ]Department of Computer Science, Princeton University, Princeton, New Jersey, USA
                [75 ]Lewis-Sigler Institute for Integrative Genomics, Princeton University, Princeton, New Jersey, USA
                [76 ]Department of Clinical Physiology and Nuclear Medicine, Turku University Hospital, Turku, Finland
                [77 ]Research Centre of Applied and Preventive Cardiovascular Medicine, University of Turku, Turku, Finland
                [78 ]Department of Clinical Physiology, Tampere University Hospital, and Finnish Cardiovascular Research Center - Tampere, Faculty of Medicine and Life Sciences, University of Tampere, Tampere, Finland
                [79 ]University of Split School of Medicine, Split, Croatia
                [80 ]Department of Psychology, University of Edinburgh, Edinburgh, UK
                [81 ]Department of Pulmonary Physiology and Sleep Medicine, Sir Charles Gairdner Hospital, Nedlands, Western Australia, Australia
                [82 ]School of Medicine and Pharmacology, The University of Western Australia, Crawley, Western Australia, Australia
                [83 ]Wellcome Sanger Institute, Hinxton, UK
                [84 ]Institute of Translational Genomics, Helmholtz Zentrum Muenchen – German Research Center for Environmental Health, Neuherberg, Germany
                [85 ]Center for Life Course Health Research, Faculty of Medicine, University of Oulu, Oulu, Finland
                [86 ]Biocenter Oulu, University of Oulu, Oulu, Finland
                [87 ]Unit of Primary Health Care, Oulu University Hospital, Oulu, Finland
                [88 ]Department of Life Sciences, College of Health and Life Sciences, Brunel University London, Uxbridge, UK
                [89 ]Population Health Research Institute, St George’s, University of London, London, UK
                [90 ]National Institute for Health Research, Leicester Respiratory Biomedical Research Centre, Glenfield Hospital, Leicester, UK
                Author notes

                Author contributions

                All authors critically reviewed the manuscript prior to submission.

                Contributed to the conception and design of the study: K.S., U.S.S.G., S.K., S.M.K., T.L., P.S.B., T.H.B., E.R.B., Y.B., Z.C., J.D.C., J.D., D.L.D., C.G., A.G., K.H., J.D.H., J.E.H., P.J., C.L., L. Li, N.L., J.C.M., H.R., I. Sayers, D.D.S., R.T-S., J.C.W., P.G.W., L.M.Y., O.T.R., M.K., O.P., U.G., I.R., I.J.D., N.M.P., H.S., A.L.J., J.F.W., E.Z., M.J., N.W., A.S.B., R.A.S., D.A.M., M.H.C., D.P.S., I.P.H., M.D.T., L.V.W.

                Undertook data analysis: N.S., A.L.G., A.M.E., V.E.J., B.D.H., C.A.M., C. Batini, K.A.F., K.S., P.S., Xingnan Li, R.B., N.F.R., M.O., J. Zhao, M.W., S.W., K.A.K., J.P.C., B.B.S., J. Zhou, J.H., M.I., S.E.H., J.M., S.E., I. Surakka, V.V., T.L., R.J.A., F.D., J.D.H., P.K.J., Xuan Li, A. Mahajan, J.C.M., D.C.N., M.M.P., D.P., D.Q., R.R., H.R., D.S., P.R.H.J.T., M.V., L.M.Y., O.G.T., N.M.P., N.W., E.K.S., C.H., A.P.M., A.S.B., R.A.S., M.H.C., D.P.S., M.D.T., L.V.W.

                Contributed to data acquisition and/or interpretation: N.S., A.L.G., A.M.E., V.E.J., C.A.M., C. Batini, K.A.F., K.S., P.S., Xingnan Li, N.F.R., M.O., M.W., K.A.K., B.B.S., S.K., M.I., R.J.A., C. Brandsma, J.D., F.D., R.E., C.G., A.G., A.L.H., J.D.H., G.H., P.K.J., C.L., Xuan Li, K.L., L. Lind, J.L., J.C.M., A. Murray, R.P., M.M.P., M.L.P., D.J.P., D.P., D.Q., R.R., H.R., I. Sayers, B.H.S., M.S., L.M.Y., O.G.T., N.M.P., H.S., J.F.W., B.S., M.J., N.W., C.H., A.P.M., A.S.B., R.A.S., R.G.W., M.H.C., D.P.S., I.P.H., M.D.T., L.V.W.

                Drafted the manuscript: N.S., A.L.G., A.M.E., I.P.H., M.D.T., L.V.W.

                [* ]Corresponding Authors. lvw1@ 123456leicester.ac.uk (Louise V Wain), mt47@ 123456leicester.ac.uk (Martin D Tobin)
                Article
                NIHMS1514965
                10.1038/s41588-018-0321-7
                6397078
                30804560
                f89c2fbd-be0f-4fff-b055-50ca04406e55

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