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

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 TGF?R1 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.

SUBMITTER: Olafsdottir TA

PROVIDER: S-EPMC6971247 | biostudies-literature | 2020 Jan

REPOSITORIES: biostudies-literature

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

Olafsdottir Thorunn A TA Theodors Fannar F Bjarnadottir Kristbjorg K Bjornsdottir Unnur Steina US Agustsdottir Arna B AB Stefansson Olafur A OA Ivarsdottir Erna V EV Sigurdsson Jon K JK Benonisdottir Stefania S Eyjolfsson Gudmundur I GI Gislason David D Gislason Thorarinn T Guðmundsdóttir Steinunn S Gylfason Arnaldur A Halldorsson Bjarni V BV Halldorsson Gisli H GH Juliusdottir Thorhildur T Kristinsdottir Anna M AM Ludviksdottir Dora D Ludviksson Bjorn R BR Masson Gisli G Norland Kristjan K Onundarson Pall T PT Olafsson Isleifur I Sigurdardottir Olof O Stefansdottir Lilja L Sveinbjornsson Gardar G Tragante Vinicius V Gudbjartsson Daniel F DF Thorleifsson Gudmar G Sulem Patrick P Thorsteinsdottir Unnur U Norddahl Gudmundur L GL Jonsdottir Ingileif I Stefansson Kari K

Nature communications 20200120 1

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. Functio ...[more]

PMID: 31959851

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Project description:BackgroundAngiotensin (Ang)-(1-7) can reduce airway inflammation and airway remodeling in allergic asthma. Autophagy-related 5 (ATG5) has attracted wide attentions in asthma. However, the effects of Ang-(1-7) on ATG5-mediated autophagy in allergic asthma are unclear.MethodsIn this study, human bronchial epithelial cell (BEAS-2B) and human bronchial smooth muscle cell (HBSMC) were treated with different dose of Ang-(1-7) to observe changes of cell viability. Changes of ATG5 protein expression were measured in 10 ng/mL of interleukin (IL)-13-treated cells. Transfection of ATG5 small interference RNA (siRNA) or ATG5 cDNA in cells was used to analyze the effects of ATG5 on secretion of cytokines in the IL-13-treated cells. The effects of Ang-(1-7) were compared to the effects of ATG5 siRNA transfection or ATG5 cDNA transfection in the IL-13-treated cells. In wild-type (WT) mice and ATG5 knockout (ATG5-/-) mice, ovalbumin (OVA)-induced airway inflammation, fibrosis and autophagy were observed. In the OVA-induced WT mice, Ang-(1-7) treatment was performed to observe its effects on airway inflammation, fibrosis and autophagy.ResultsThe results showed that ATG5 protein level was decreased with Ang-(1-7) dose administration in the IL-13-treated BEAS-2B and IL13-treated HBSMC. Ang-(1-7) played similar results to ATG5 siRNA that it suppressed the secretion of IL-25 and IL-13 in the IL-13-treated BEAS-2B cells, and inhibited the expression of transforming growth factor (TGF)-β1 and α-smooth muscle actin (α-SMA) protein in the IL-13-treated HBSMC cells. ATG5 cDNA treatment significantly increased the secretion of IL-25 and IL-13 and expression of TGF-β1 and α-SMA protein in IL-13-treated cells. Ang-(1-7) treatment suppressed the effects of ATG5 cDNA in the IL-13-treated cells. In OVA-induced WT mice, Ang-(1-7) treatment suppressed airway inflammation, remodeling and autophagy. ATG5 knockout also suppressed the airway inflammation, remodeling and autophagy.ConclusionsAng-(1-7) treatment suppressed airway inflammation and remodeling in allergic asthma through inhibiting ATG5, providing an underlying mechanism of Ang-(1-7) for allergic asthma treatment.

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

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

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