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      Genome-wide interaction study reveals age-dependent determinants of responsiveness to inhaled corticosteroids in individuals with asthma

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          Abstract

          While genome-wide association studies have identified genes involved in differential treatment responses to inhaled corticosteroids (ICS) in asthma, few studies have evaluated the potential effects of age in this context. A significant proportion of asthmatics experience exacerbations (hospitalizations and emergency department visits) during ICS treatment. We evaluated the interaction of genetic variation and age on ICS response (measured by the occurrence of exacerbations) through a genome-wide interaction study (GWIS) of 1,321 adult and child asthmatic patients of European ancestry. We identified 107 genome-wide suggestive (P<10 −05) age-by-genotype interactions, two of which also met genome-wide significance (P<5x10 -08) (rs34631960 [OR 2.3±1.6–3.3] in thrombospondin type 1 domain-containing protein 4 ( THSD4) and rs2328386 [OR 0.5±0.3–0.7] in human immunodeficiency virus type I enhancer binding protein 2 ( HIVEP2)) by joint analysis of GWIS results from discovery and replication populations. In addition to THSD4 and HIVEP2, age-by-genotype interactions also prioritized genes previously identified as asthma candidate genes, including DPP10, HDAC9, TBXAS1, FBXL7, and GSDMB/ORMDL3, as pharmacogenomic loci as well. This study is the first to link these genes to a pharmacogenetic trait for asthma.

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          Most cited references30

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          The cell biology of thrombospondin-1.

          Thrombospondin-1 (TSP-1) is a matricellular protein that regulates cellular phenotype during tissue genesis and repair. It acts as a molecular facilitator by bringing together cytokines, growth factors, matrix components, membrane receptors and extracellular proteases. TSP-1 binds to a wide variety of integrin and non-integrin cell surface receptors. The binding sites for these receptors on TSP-1 are dispersed throughout the molecule, with most domains binding multiple receptors. In some cases, TSP-1 binds to multiple receptors concurrently, and recent data indicate that there is cross-talk between the receptor systems. Thus, TSP-1 may function to direct the clustering of receptors to specialized domains for adhesion and signal transduction.
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            Deficiency of Schnurri-2, an MHC Enhancer Binding Protein, Induces Mild Chronic Inflammation in the Brain and Confers Molecular, Neuronal, and Behavioral Phenotypes Related to Schizophrenia

            Schnurri-2 (Shn-2), an nuclear factor-κB site-binding protein, tightly binds to the enhancers of major histocompatibility complex class I genes and inflammatory cytokines, which have been shown to harbor common variant single-nucleotide polymorphisms associated with schizophrenia. Although genes related to immunity are implicated in schizophrenia, there has been no study showing that their mutation or knockout (KO) results in schizophrenia. Here, we show that Shn-2 KO mice have behavioral abnormalities that resemble those of schizophrenics. The mutant brain demonstrated multiple schizophrenia-related phenotypes, including transcriptome/proteome changes similar to those of postmortem schizophrenia patients, decreased parvalbumin and GAD67 levels, increased theta power on electroencephalograms, and a thinner cortex. Dentate gyrus granule cells failed to mature in mutants, a previously proposed endophenotype of schizophrenia. Shn-2 KO mice also exhibited mild chronic inflammation of the brain, as evidenced by increased inflammation markers (including GFAP and NADH/NADPH oxidase p22 phox), and genome-wide gene expression patterns similar to various inflammatory conditions. Chronic administration of anti-inflammatory drugs reduced hippocampal GFAP expression, and reversed deficits in working memory and nest-building behaviors in Shn-2 KO mice. These results suggest that genetically induced changes in immune system can be a predisposing factor in schizophrenia.
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              The Childhood Asthma Management Program (CAMP): design, rationale, and methods. Childhood Asthma Management Program Research Group.

              (1999)
              The Childhood Asthma Management Program (CAMP) is a multicenter, randomized, double-masked clinical trial designed to determine the long-term effects of three inhaled treatments for mild to moderate childhood asthma: budesonide (a glucocorticoid used daily) and albuterol (a short-acting beta-agonist bronchodilator used as needed); nedocromil (a nonsteroid anti-inflammatory agent used daily) and albuterol; and placebo and albuterol. One thousand forty-one children (32% from ethnic minority groups), aged 5 to 12 years at screening, are currently participating. The primary outcome measure is lung growth as indicated by postbronchodilator forced expiratory volume in 1 second (FEV1) percent of predicted, observed over 5- to 6-year period. The trial also assesses differences between treatment groups with respect to airway responsiveness, morbidity, physical growth and development, and psychological growth and development. This report describes the design of the trial, the rationale for the design choices made, and the methods used to carry out the trial.
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                Author and article information

                Contributors
                Role: ConceptualizationRole: Formal analysisRole: Writing – original draftRole: Writing – review & editing
                Role: InvestigationRole: Writing – review & editing
                Role: Writing – review & editing
                Role: InvestigationRole: Writing – review & editing
                Role: InvestigationRole: Writing – review & editing
                Role: Formal analysisRole: Writing – review & editing
                Role: InvestigationRole: Writing – review & editing
                Role: ConceptualizationRole: Funding acquisitionRole: InvestigationRole: SupervisionRole: Writing – original draftRole: Writing – review & editing
                Role: Editor
                Journal
                PLoS One
                PLoS ONE
                plos
                plosone
                PLoS ONE
                Public Library of Science (San Francisco, CA USA )
                1932-6203
                2 March 2020
                2020
                : 15
                : 3
                : e0229241
                Affiliations
                [1 ] Channing Division of Network Medicine, Brigham and Women’s Hospital and Harvard Medical School, Boston, Massachusetts, United States of America
                [2 ] Department of Population Medicine, PRecisiOn Medicine Translational Research (PROMoTeR) Center, Harvard Medical School and Harvard Pilgrim Health Care Institute, Boston, Massachusetts, United States of America
                [3 ] Division of Pulmonary and Critical Care Medicine, Brigham and Women’s Hospital, Boston, Massachusetts, United States of America
                Illumina Inc, UNITED STATES
                Author notes

                Competing Interests: The authors have declared that no competing interests exist.

                Author information
                http://orcid.org/0000-0002-4966-1796
                Article
                PONE-D-19-25588
                10.1371/journal.pone.0229241
                7051058
                32119686
                7dae92d1-e8cb-4e4a-9257-ee8d3f175158
                © 2020 Dahlin et al

                This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

                History
                : 11 September 2019
                : 1 February 2020
                Page count
                Figures: 1, Tables: 2, Pages: 12
                Funding
                Funded by: funder-id http://dx.doi.org/10.13039/100000009, Foundation for the National Institutes of Health;
                Award ID: R01HD085993
                Award Recipient :
                Authors received funding from NIH (National Institutes of Health). A.C. Wu received an R01 grant (R01HD085993) and A.D. received grant K01 HL130629. Funders did not play a role in study design, analysis, data collection, decision to publish or manuscript prep. https://www.nih.gov/
                Categories
                Research Article
                Medicine and Health Sciences
                Pulmonology
                Asthma
                Biology and Life Sciences
                Computational Biology
                Genome Analysis
                Genome-Wide Association Studies
                Biology and Life Sciences
                Genetics
                Genomics
                Genome Analysis
                Genome-Wide Association Studies
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                Engineering and Technology
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                Pharmacogenomics
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                Genetic Loci
                Custom metadata
                All genotype files are available from dbgap. https://www.ncbi.nlm.nih.gov/gap/.

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