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

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Eighty-eight variants highlight the role of T cell regulation and airway remodeling in asthma pathogenesis.
Nature Communications ( IF 14.7 ) Pub Date : 2020-01-20 , DOI: 10.1038/s41467-019-14144-8
Thorunn A Olafsdottir _{1,

2} , Fannar Theodors ₁ , Kristbjorg Bjarnadottir ₁ , Unnur Steina Bjornsdottir _{3,

4} , Arna B Agustsdottir ₁ , Olafur A Stefansson ₁ , Erna V Ivarsdottir _{1,

5} , Jon K Sigurdsson ₁ , Stefania Benonisdottir ₁ , Gudmundur I Eyjolfsson ₆ , David Gislason _{4,

7} , Thorarinn Gislason _{2,

8} , Steinunn Guðmundsdóttir ₁ , Arnaldur Gylfason ₁ , Bjarni V Halldorsson _{1,

9} , Gisli H Halldorsson ₁ , Thorhildur Juliusdottir ₁ , Anna M Kristinsdottir ₁ , Dora Ludviksdottir _{2,

7} , Bjorn R Ludviksson _{2,

10} , Gisli Masson ₁ , Kristjan Norland ₁ , Pall T Onundarson _{2,

11} , Isleifur Olafsson ₁₂ , Olof Sigurdardottir _{2,

13} , Lilja Stefansdottir ₁ , Gardar Sveinbjornsson ₁ , Vinicius Tragante _{1,

14} , Daniel F Gudbjartsson _{1,

5} , Gudmar Thorleifsson ₁ , Patrick Sulem ₁ , Unnur Thorsteinsdottir _{1,

2} , Gudmundur L Norddahl ₁ , Ingileif Jonsdottir _{1,

2} , Kari Stefansson _{1,

2}

Affiliation

deCODE genetics/Amgen, Inc., Reykjavik, Iceland.
Faculty of Medicine, School of Health Sciences, University of Iceland, Reykjavik, Iceland.
Department of Medicine, Landspitali, The National University Hospital of Iceland, Reykjavik, Iceland.
The Medical Center Mjodd, Reykjavik, Iceland.
School of Engineering and Natural Sciences, University of Iceland, Reykjavik, Iceland.
The Laboratory in Mjodd, RAM, Reykjavik, Iceland.
Department of Respiratory Medicine and Sleep, Landspitali, The National University Hospital of Iceland, Reykjavik, Iceland.
Department of Sleep, Landspitali, The National University Hospital of Iceland, Reykjavik, Iceland.
School of Science and Engineering, Reykjavik University, Reykjavík, Iceland.
Department of Immunology, Landspitali, The National University Hospital of Iceland, Reykjavik, Iceland.
Department of Laboratory Hematology, Landspitali, The National University Hospital of Iceland, Reykjavik, Iceland.
Department of Clinical Biochemistry, Landspitali, The National University Hospital of Iceland, Reykjavik, Iceland.
Department of Clinical Biochemistry, Akureyri Hospital, Akureyri, Iceland.
Department of Cardiology, Division Heart & Lungs, University Medical Center Utrecht, University of Utrecht, Utrecht, The Netherlands.

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.

中文翻译：

88个变体突出了T细胞调节和气道重塑在哮喘发病机理中的作用。

哮喘是影响儿童和成人的最常见的慢性疾病之一。我们报告了来自冰岛和英国生物库的69,189例病例和702,199例对照的全基因组关联荟萃分析。我们在56个基因位点发现了88个哮喘风险变异体，其中19个以前未报道，并评估了它们对其他哮喘和过敏表型的影响。特别令人感兴趣的是与抗哮喘相关的两种低频变异。TNFRSF8中的错义变体和TGFBR1中的3'UTR变体。功能研究表明，TNFRSF8变体降低了细胞表面和可溶形式的TNFRSF8的表达，从而丧失了功能。eQTL分析表明，TGFBR1变体通过功能获得发挥作用，并与下游基因SMAD3中的内含子变体一起发挥作用，指出有缺陷的TGFβR1信号传导是增加哮喘风险的生物扰动之一。我们的结果增加了哮喘变种的数量，并暗示了在哮喘发病机理中的T细胞调节，炎症和气道重塑中具有已知作用的基因。

更新日期：2020-01-22

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