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

Author

Listed:
  • Thorunn A. Olafsdottir

    (deCODE genetics/Amgen, Inc.
    University of Iceland)

  • Fannar Theodors

    (deCODE genetics/Amgen, Inc.)

  • Kristbjorg Bjarnadottir

    (deCODE genetics/Amgen, Inc.)

  • Unnur Steina Bjornsdottir

    (The National University Hospital of Iceland
    The Medical Center Mjodd)

  • Arna B. Agustsdottir

    (deCODE genetics/Amgen, Inc.)

  • Olafur A. Stefansson

    (deCODE genetics/Amgen, Inc.)

  • Erna V. Ivarsdottir

    (deCODE genetics/Amgen, Inc.
    University of Iceland)

  • Jon K. Sigurdsson

    (deCODE genetics/Amgen, Inc.)

  • Stefania Benonisdottir

    (deCODE genetics/Amgen, Inc.)

  • Gudmundur I. Eyjolfsson

    (The Laboratory in Mjodd, RAM)

  • David Gislason

    (The Medical Center Mjodd
    The National University Hospital of Iceland)

  • Thorarinn Gislason

    (University of Iceland
    The National University Hospital of Iceland)

  • Steinunn Guðmundsdóttir

    (deCODE genetics/Amgen, Inc.)

  • Arnaldur Gylfason

    (deCODE genetics/Amgen, Inc.)

  • Bjarni V. Halldorsson

    (deCODE genetics/Amgen, Inc.
    Reykjavik University)

  • Gisli H. Halldorsson

    (deCODE genetics/Amgen, Inc.)

  • Thorhildur Juliusdottir

    (deCODE genetics/Amgen, Inc.)

  • Anna M. Kristinsdottir

    (deCODE genetics/Amgen, Inc.)

  • Dora Ludviksdottir

    (University of Iceland
    The National University Hospital of Iceland)

  • Bjorn R. Ludviksson

    (University of Iceland
    The National University Hospital of Iceland)

  • Gisli Masson

    (deCODE genetics/Amgen, Inc.)

  • Kristjan Norland

    (deCODE genetics/Amgen, Inc.)

  • Pall T. Onundarson

    (University of Iceland
    The National University Hospital of Iceland)

  • Isleifur Olafsson

    (The National University Hospital of Iceland)

  • Olof Sigurdardottir

    (University of Iceland
    Akureyri Hospital)

  • Lilja Stefansdottir

    (deCODE genetics/Amgen, Inc.)

  • Gardar Sveinbjornsson

    (deCODE genetics/Amgen, Inc.)

  • Vinicius Tragante

    (deCODE genetics/Amgen, Inc.
    University Medical Center Utrecht, University of Utrecht)

  • Daniel F. Gudbjartsson

    (deCODE genetics/Amgen, Inc.
    University of Iceland)

  • Gudmar Thorleifsson

    (deCODE genetics/Amgen, Inc.)

  • Patrick Sulem

    (deCODE genetics/Amgen, Inc.)

  • Unnur Thorsteinsdottir

    (deCODE genetics/Amgen, Inc.
    University of Iceland)

  • Gudmundur L. Norddahl

    (deCODE genetics/Amgen, Inc.)

  • Ingileif Jonsdottir

    (deCODE genetics/Amgen, Inc.
    University of Iceland)

  • Kari Stefansson

    (deCODE genetics/Amgen, Inc.
    University of Iceland)

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.

Suggested Citation

  • Thorunn A. Olafsdottir & Fannar Theodors & Kristbjorg Bjarnadottir & Unnur Steina Bjornsdottir & Arna B. Agustsdottir & Olafur A. Stefansson & Erna V. Ivarsdottir & Jon K. Sigurdsson & Stefania Benoni, 2020. "Eighty-eight variants highlight the role of T cell regulation and airway remodeling in asthma pathogenesis," Nature Communications, Nature, vol. 11(1), pages 1-11, December.
    • Handle: RePEc:nat:natcom:v:11:y:2020:i:1:d:10.1038_s41467-019-14144-8
    DOI: 10.1038/s41467-019-14144-8
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    Cited by:

    1. Tomoko Nakanishi & Julian Willett & Yossi Farjoun & Richard J. Allen & Beatriz Guillen-Guio & Darin Adra & Sirui Zhou & J. Brent Richards, 2023. "Alternative splicing in lung influences COVID-19 severity and respiratory diseases," Nature Communications, Nature, vol. 14(1), pages 1-12, December.

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