Eighty-eight variants highlight the role of T cell regulation and airway remodeling in asthma pathogenesis
| Autor: | Bjorn R. Ludviksson, Daniel F. Gudbjartsson, Vinicius Tragante, Pall T. Onundarson, Arnaldur Gylfason, Thorarinn Gislason, Olafur A. Stefansson, Olof Sigurdardottir, Stefania Benonisdottir, Gudmundur L. Norddahl, Arna B Agustsdottir, Fannar Theodors, Bjarni V. Halldorsson, Patrick Sulem, Lilja Stefansdottir, Gardar Sveinbjornsson, Erna V. Ivarsdottir, Thorunn A. Olafsdottir, Unnur Thorsteinsdottir, Gisli Masson, Gudmar Thorleifsson, Gudmundur I. Eyjolfsson, Steinunn Guðmundsdóttir, Thorhildur Juliusdottir, David Gislason, Ingileif Jonsdottir, Jon K. Sigurdsson, Kristjan Norland, Kristbjorg Bjarnadottir, Kari Stefansson, Unnur S. Bjornsdottir, Gisli H. Halldorsson, Anna M. Kristinsdottir, Dora Ludviksdottir, Isleifur Olafsson |
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| Přispěvatelé: | Læknadeild (HÍ), Faculty of Medicine (UI), Verkfræðideild (HR), Department of Engineering (RU), Heilbrigðisvísindasvið (HÍ), School of Health Sciences (UI), Verkfræði- og náttúruvísindasvið (HÍ), School of Engineering and Natural Sciences (UI), Tæknisvið (HR), School of Technology (RU), Háskóli Íslands, University of Iceland, Háskólinn í Reykjavík, Reykjavik University |
| Jazyk: | angličtina |
| Rok vydání: | 2020 |
| Předmět: |
0301 basic medicine
T-Lymphocytes Iceland Receptor Transforming Growth Factor-beta Type I General Physics and Astronomy Genome-wide association study 02 engineering and technology Genome-wide association studies Pathogenesis Leukocyte Count Missense mutation lcsh:Science 3' Untranslated Regions Multidisciplinary Gen 021001 nanoscience & nanotechnology Phenotype Astmi 3. Good health medicine.anatomical_structure Airway Remodeling 0210 nano-technology Erfðarannsóknir T cell Science Quantitative Trait Loci T cells Ki-1 Antigen Polymorphism Single Nucleotide Article General Biochemistry Genetics and Molecular Biology 03 medical and health sciences Immunogenetics medicine Humans Genetic Predisposition to Disease Loss function Asthma business.industry General Chemistry medicine.disease United Kingdom respiratory tract diseases Eosinophils MicroRNAs Meta-analysis Genarannsóknir 030104 developmental biology Expression quantitative trait loci Immunology lcsh:Q Gene expression business Genome-Wide Association Study |
| Zdroj: | Nature Communications, Vol 11, Iss 1, Pp 1-11 (2020) Nature Communications |
| ISSN: | 2041-1723 |
| Popis: | Publisher's version (útgefin grein) Asthma is one of the most common chronic diseases affecting both children and adults. We report a genome-wide association meta-analysis of 69,189 cases and 702,199 controls from Iceland and UK biobank. We find 88 asthma risk variants at 56 loci, 19 previously unreported, and evaluate their effect on other asthma and allergic phenotypes. Of special interest are two low frequency variants associated with protection against asthma; a missense variant in TNFRSF8 and 3‘ UTR variant in TGFBR1. Functional studies show that the TNFRSF8 variant reduces TNFRSF8 expression both on cell surface and in soluble form, acting as loss of function. eQTL analysis suggests that the TGFBR1 variant acts through gain of function and together with an intronic variant in a downstream gene, SMAD3, points to defective TGFβR1 signaling as one of the biological perturbations increasing asthma risk. Our results increase the number of asthma variants and implicate genes with known role in T cell regulation, inflammation and airway remodeling in asthma pathogenesis. We thank the individuals who participated in this study and the staff at the Icelandic Patient Recruitment Center and the deCODE genetics core facilities. Further to all our colleagues who contributed to the data collection and phenotypic characterization of clinical samples as well as to the genotyping and analysis of the whole-genome association data. This research has been conducted using the UK biobank Resource under Application Number ‘24711’. |
| Databáze: | OpenAIRE |
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