A partial loss-of-function variant in STAT6 protects against type 2 asthma - 14/11/24

Doi : 10.1016/j.jaci.2024.10.002

Katla Kristjansdottir, PhD ^a,^{^{∗
These authors contributed equally to this work.}}, Gudmundur L. Norddahl, PhD ^a,^{^{∗
These authors contributed equally to this work.}}, Erna V. Ivarsdottir, PhD ^a, Gisli H. Halldorsson, MSc ^a,^b, Gudmundur Einarsson, PhD ^a, Kristbjorg Bjarnadottir, PhD ^a, Gudrun Rutsdottir, PhD ^a, Asgeir O. Arnthorsson, MSc ^a, Christian Erikstrup, MD, PhD ^c,^d, Steinunn Gudmundsdottir, MSc ^a, Kristbjorg Gunnarsdottir, MSc ^a, Maria I. Gunnbjornsdottir, MD, PhD ^e, Bjarni V. Halldorsson, PhD ^a,^f, Hilma Holm, MD ^a, Dora Ludviksdottir, MD, PhD ^e,^g, Bjorn R. Ludviksson, MD, PhD ^h, Søren Brunak, PhD ⁱ, Mie Topholm Bruun, MD ^j, Christina Mikkelsen, MD ^k,^l, Susan Mikkelsen, MD, PhD ^c, Bitten Aagaard Jensen, MD ^m, Erik Sørensen, PhD ^l, Simon Francis Thomsen, MD, PhD ⁿ, Henrik Ullum, MD, PhD ^o, Isleifur Olafsson, MD, PhD ^p, Pall T. Onundarson, MD ^g,^p, Sisse Rye Ostrowski, MD, PhD ^l,^q, Saedis Saevarsdottir, MD, PhD ^a,^g, Olof Sigurdardottir, MD, PhD ^r, Bardur Sigurgeirsson, MD, PhD ^s, Audunn S. Snaebjarnarson, PhD ^a, Gardar Sveinbjornsson, PhD ^a, Gudny E. Thorlacius, PhD ^a, Gudmar Thorleifsson, PhD ^a, Vinicius Tragante, PhD ^a, Brynjar Vidarsson, MD ^t, Celeste Porsbjerg, MD, PhD ^q,^u, Unnur S. Bjornsdottir, MD ^v, Patrick Sulem, MD ^a, Daniel F. Gudbjartsson, PhD ^a,^b, Pall Melsted, PhD ^a,^b, Ole Bv. Pedersen, MD, PhD ^q,^w, Ingileif Jonsdottir, PhD ^a, Thorunn A. Olafsdottir, PhD ^a,^g,^⁎ , Kari Stefansson, MD, PhD ^a,^g,^⁎
^a deCODE genetics/Amgen, Inc, University of Iceland, Reykjavik, Iceland
^b School of Engineering and Natural Sciences, University of Iceland, Reykjavik, Iceland
^c Department of Clinical Immunology, Aarhus University, Aarhus, Denmark
^d Department of Clinical Medicine, Aarhus University, Aarhus, Denmark
^e Allergy Department, Landspitali—The National University Hospital of Iceland, Reykjavik, Iceland
^f School of Technology, Reykjavik University, Reykjavik, Iceland
^g Faculty of Medicine, School of Health Sciences, University of Iceland, Reykjavik, Iceland
^h Department of Immunology, Landspitali—The National University Hospital of Iceland, Reykjavik, Iceland
ⁱ Novo Nordisk Foundation Center for Protein Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
^j Department of Clinical Immunology, Odense University Hospital, Odense, Denmark
^k Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
^l Department of Clinical Immunology, Copenhagen University Hospital, Rigshospitalet, Copenhagen, Denmark
^m Department of Clinical Immunology, Aalborg University Hospital, Aalborg, Denmark
ⁿ Department of Dermatology, Bispebjerg Hospital, University of Copenhagen, Copenhagen, Denmark
^o Statens Serum Institut, Copenhagen, Denmark
^p Department of Clinical Biochemistry, Landspitali—The National University Hospital of Iceland, Reykjavik, Iceland
^q Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
^r Department of Clinical Biochemistry, Akureyri Hospital, Akureyri, Iceland
^s Department of Dermatology, Faculty of Medicine, University of Iceland, Reykjavik, Iceland
^t Icelandic Medical Center (Laeknasetrid) Laboratory in Mjodd (RAM), Reykjavik, Iceland
^u Department of Respiratory Medicine and Infectious Diseases, Bispebjerg Hospital, Copenhagen, Denmark
^v Department of Respiratory Medicine and Sleep, Landspitali—The National University Hospital of Iceland, Reykjavik, Iceland
^w Department of Clinical Immunology, Zealand University Hospital, Køge, Denmark

^∗Corresponding author: Thorunn A. Olafsdottir, PhD, or Kari Stefansson, MD, PhD, deCODE genetics, Sturlugata 8, 102 Reykjavik, Iceland.deCODE genetics/AmgenIncReykjavikIceland

Sous presse. Épreuves corrigées par l'auteur. Disponible en ligne depuis le Thursday 14 November 2024

Abstract

Background

Signal transducer and activator of transcription 6 (STAT6) is central to type 2 (T2) inflammation, and common noncoding variants at the STAT6 locus associate with various T2 inflammatory traits, including diseases, and its pathway is widely targeted in asthma treatment.

Objective

We sought to test the association of a rare missense variant in STAT6, p.L406P, with T2 inflammatory traits, including the risk of asthma and allergic diseases, and to characterize its functional consequences in cell culture.

Methods

The association of p.L406P with plasma protein levels, white blood cell counts, and the risk of asthma and allergic phenotypes was tested. Significant associations in other cohorts were also tested using a burden test. The effects of p.L406P on STAT6 protein function were examined in cell lines and by comparing CD4⁺ T-cell responses from carriers and noncarriers of the variant.

Results

p.L406P associated with reduced plasma levels of STAT6 and IgE as well as with lower eosinophil and basophil counts in blood. It also protected against asthma, mostly driven by severe T2-high asthma. p.L406P led to lower IL-4–induced activation in luciferase reporter assays and lower levels of STAT6 in CD4⁺ T cells. We identified multiple genes with expression that was affected by the p.L406P genotype on IL-4 treatment of CD4⁺ T cells; the effect was consistent with a weaker IL-4 response in carriers than in noncarriers of p.L406P.

Conclusions

A partial loss-of-function variant in STAT6 resulted in dampened IL-4 responses and protection from T2-high asthma, implicating STAT6 as an attractive therapeutic target.

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Key words : STAT6, partial loss of function, variant, protective, asthma, T2 endotype, CD4⁺ T cells, RNA sequencing

Abbreviations used : DEG, DRG, FC, FDR, LOF, OR, pSTAT6, STAT6, T2, WT