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      Emerging genetics of COPD

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          Abstract

          Since the discovery of alpha-1 antitrypsin in the early 1960s, several new genes have been suggested to play a role in chronic obstructive pulmonary disease (COPD) pathogenesis. Yet, in spite of those advances, much about the genetic basis of COPD still remains to be discovered. Unbiased approaches, such as genome-wide association (GWA) studies, are critical to identify genes and pathways and to verify suggested genetic variants. Indeed, most of our current understanding about COPD candidate genes originates from GWA studies. Experiments in form of cross-study replications and advanced meta-analyses have propelled the field towards unravelling details about COPD's pathogenesis. Here, we review the discovery of genetic variants in association with COPD phenotypes by discussing the available approaches and current findings. Limitations of current studies are considered and future directions provided.

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          Most cited references 76

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          The future of genetic studies of complex human diseases.

           N Risch,  K Merikangas (1996)
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            Chronic obstructive pulmonary disease

            Summary Chronic obstructive pulmonary disease (COPD) is characterised by progressive airflow obstruction that is only partly reversible, inflammation in the airways, and systemic effects or comorbities. The main cause is smoking tobacco, but other factors have been identified. Several pathobiological processes interact on a complex background of genetic determinants, lung growth, and environmental stimuli. The disease is further aggravated by exacerbations, particularly in patients with severe disease, up to 78% of which are due to bacterial infections, viral infections, or both. Comorbidities include ischaemic heart disease, diabetes, and lung cancer. Bronchodilators constitute the mainstay of treatment: β2 agonists and long-acting anticholinergic agents are frequently used (the former often with inhaled corticosteroids). Besides improving symptoms, these treatments are also thought to lead to some degree of disease modification. Future research should be directed towards the development of agents that notably affect the course of disease.
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              Inhibition of VEGF receptors causes lung cell apoptosis and emphysema.

              Pulmonary emphysema, a significant global health problem, is characterized by a loss of alveolar structures. Because VEGF is a trophic factor required for the survival of endothelial cells and is abundantly expressed in the lung, we hypothesized that chronic blockade of VEGF receptors could induce alveolar cell apoptosis and emphysema. Chronic treatment of rats with the VEGF receptor blocker SU5416 led to enlargement of the air spaces, indicative of emphysema. The VEGF receptor inhibitor SU5416 induced alveolar septal cell apoptosis but did not inhibit lung cell proliferation. Viewed by angiography, SU5416-treated rat lungs showed a pruning of the pulmonary arterial tree, although we observed no lung infiltration by inflammatory cells or fibrosis. SU5416 treatment led to a decrease in lung expression of VEGF receptor 2 (VEGFR-2), phosphorylated VEGFR-2, and Akt-1 in the complex with VEGFR-2. Treatment with the caspase inhibitor Z-Asp-CH(2)-DCB prevented SU5416-induced septal cell apoptosis and emphysema development. These findings suggest that VEGF receptor signaling is required for maintenance of the alveolar structures and, further, that alveolar septal cell apoptosis contributes to the pathogenesis of emphysema.
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                Author and article information

                Journal
                EMBO Mol Med
                EMBO Mol Med
                emmm
                EMBO Molecular Medicine
                WILEY-VCH Verlag (Weinheim )
                1757-4676
                1757-4684
                November 2012
                23 October 2012
                : 4
                : 11
                : 1144-1155
                Affiliations
                Division of Pulmonary, Allergy and Critical Care Medicine, Department of Medicine, University of Pittsburgh Medical Center, University of Pittsburgh School of Medicine Pittsburgh, PA, USA
                Author notes
                *Corresponding author: Tel: +1 412 624 8534; Fax: +1 412 648 2117; E-mail: anb128@ 123456pitt.edu
                Article
                10.1002/emmm.201100627
                3494872
                23090857
                Copyright © 2012 The Authors. Published by John Wiley and Sons, Ltd on behalf of EMBO

                Re-use of this article is permitted in accordance with the Creative Commons Deed, Attribution 2.5, which does not permit commercial exploitation.

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