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Eighty-eight variants highlight the role of T cell regulation and airway remodeling in asthma pathogenesis

Eighty-eight variants highlight the role of T cell regulation and airway remodeling in asthma pathogenesis


Title: Eighty-eight variants highlight the role of T cell regulation and airway remodeling in asthma pathogenesis
Author: Ólafsdóttir, Þórunn Ásta
Theódórs, Fannar
Bjarnadóttir, Kristbjörg
Björnsdóttir, Unnur Steina
Agustsdottir, Arna B.
Stefánsson, Ólafur A.
Ivarsdottir, Erna   orcid.org/0000-0002-2069-0681
Sigurðsson, Jón K.
Benónísdóttir, Stefanía
Eyjólfsson, Guðmundur I.
... 25 more authors Show all authors
Date: 2020-01-20
Language: English
Scope: 393
University/Institute: Háskóli Íslands
University of Iceland
Háskólinn í Reykjavík
Reykjavik University
School: Heilbrigðisvísindasvið (HÍ)
School of Health Sciences (UI)
Verkfræði- og náttúruvísindasvið (HÍ)
School of Engineering and Natural Sciences (UI)
Tæknisvið (HR)
School of Technology (RU)
Department: Læknadeild (HÍ)
Faculty of Medicine (UI)
Series: Nature Communications;11(1)
ISSN: 2041-1723
DOI: 10.1038/s41467-019-14144-8
Subject: Asthma; Gene expression; Meta-analysis; Astmi; Genarannsóknir; Gen; Erfðarannsóknir
URI: https://hdl.handle.net/20.500.11815/2447

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Citation:

Olafsdottir, T.A., Theodors, F., Bjarnadottir, K. et al. Eighty-eight variants highlight the role of T cell regulation and airway remodeling in asthma pathogenesis. Nature Communications 11, 393 (2020). https://doi.org/10.1038/s41467-019-14144-8

Abstract:

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.

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Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.

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