A partial loss-of-function variant in STAT6 protects against type 2 asthma

Katla Kristjansdottir; Guðmundur L Norddahl; Erna V Ivarsdottir; Gisli H Halldorsson; Gudmundur Einarsson; Kristbjörg Bjarnadóttir; Gudrun Rutsdottir; Asgeir O Arnthorsson; Christian Erikstrup; Steinunn Gudmundsdottir; Kristbjorg Gunnarsdottir; María I Gunnbjornsdottir; Bjarni V Halldorsson; Hilma Holm; Dora Ludviksdottir; Bjorn R Ludviksson; Søren Brunak; Mie Topholm Bruun; Christina Mikkelsen; Susan Mikkelsen; Bitten Aagaard Jensen; Erik Sørensen; Simon Francis Thomsen; Henrik Ullum; Isleifur Olafsson; Pall T Onundarson; Sisse Rye Ostrowski; Saedis Saevarsdottir; Olof Sigurdardottir; Bardur Sigurgeirsson; Audunn S Snaebjarnarson; Gardar Sveinbjornsson; Gudny E Thorlacius; Gudmar Thorleifsson; Vinicius Tragante; Brynjar Vidarsson; Celeste Porsbjerg; Unnur S Bjornsdottir; Patrick Sulem; Daniel F Gudbjartsson; Pall Melsted; Ole Bv Pedersen; Ingileif Jonsdóttir; Thorunn A Olafsdottir; Kari Stefansson

doi:10.1016/j.jaci.2024.10.002

A partial loss-of-function variant in STAT6 protects against type 2 asthma

Katla Kristjansdottir
, Guðmundur L Norddahl
, Erna V Ivarsdottir
, Gisli H Halldorsson
, Gudmundur Einarsson
, Kristbjörg Bjarnadóttir
, Gudrun Rutsdottir
, Asgeir O Arnthorsson
, Christian Erikstrup
, Steinunn Gudmundsdottir
, Kristbjorg Gunnarsdottir
, María I Gunnbjornsdottir
, Bjarni V Halldorsson
, Hilma Holm
, Dora Ludviksdottir
, Bjorn R Ludviksson
, Søren Brunak
, Mie Topholm Bruun
, Christina Mikkelsen
, Susan Mikkelsen

Bitten Aagaard Jensen, Erik Sørensen, Simon Francis Thomsen, Henrik Ullum, Isleifur Olafsson, Pall T Onundarson, Sisse Rye Ostrowski, Saedis Saevarsdottir, Olof Sigurdardottir, Bardur Sigurgeirsson, Audunn S Snaebjarnarson, Gardar Sveinbjornsson, Gudny E Thorlacius, Gudmar Thorleifsson, Vinicius Tragante, Brynjar Vidarsson, Celeste Porsbjerg, Unnur S Bjornsdottir, Patrick Sulem, Daniel F Gudbjartsson, Pall Melsted, Ole Bv Pedersen, Ingileif Jonsdóttir, Thorunn A Olafsdottir^*, Kari Stefansson^*

^*Corresponding author for this work

Clinical Immunology

Research output: Contribution to journal › Article › Research › peer-review

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.

Original language	English
Pages (from-to)	228-235
Number of pages	8
Journal	Journal of Allergy and Clinical Immunology
Volume	155
Issue number	1
Early online date	16 Oct 2024
DOIs	https://doi.org/10.1016/j.jaci.2024.10.002
Publication status	Published - Jan 2025

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10.1016/j.jaci.2024.10.002

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Kristjansdottir, K., Norddahl, G. L., Ivarsdottir, E. V., Halldorsson, G. H., Einarsson, G., Bjarnadóttir, K., Rutsdottir, G., Arnthorsson, A. O., Erikstrup, C., Gudmundsdottir, S., Gunnarsdottir, K., Gunnbjornsdottir, M. I., Halldorsson, B. V., Holm, H., Ludviksdottir, D., Ludviksson, B. R., Brunak, S., Bruun, M. T., Mikkelsen, C., ... Stefansson, K. (2025). A partial loss-of-function variant in STAT6 protects against type 2 asthma. Journal of Allergy and Clinical Immunology, 155(1), 228-235. https://doi.org/10.1016/j.jaci.2024.10.002

@article{c35e16c0de2e41b3ade562e04fb37817,

title = "A partial loss-of-function variant in STAT6 protects against type 2 asthma",

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.",

author = "Katla Kristjansdottir and Norddahl, \{Gu{\dh}mundur L\} and Ivarsdottir, \{Erna V\} and Halldorsson, \{Gisli H\} and Gudmundur Einarsson and Kristbj{\"o}rg Bjarnad{\'o}ttir and Gudrun Rutsdottir and Arnthorsson, \{Asgeir O\} and Christian Erikstrup and Steinunn Gudmundsdottir and Kristbjorg Gunnarsdottir and Gunnbjornsdottir, \{Mar{\'i}a I\} and Halldorsson, \{Bjarni V\} and Hilma Holm and Dora Ludviksdottir and Ludviksson, \{Bjorn R\} and S{\o}ren Brunak and Bruun, \{Mie Topholm\} and Christina Mikkelsen and Susan Mikkelsen and Jensen, \{Bitten Aagaard\} and Erik S{\o}rensen and Thomsen, \{Simon Francis\} and Henrik Ullum and Isleifur Olafsson and Onundarson, \{Pall T\} and Ostrowski, \{Sisse Rye\} and Saedis Saevarsdottir and Olof Sigurdardottir and Bardur Sigurgeirsson and Snaebjarnarson, \{Audunn S\} and Gardar Sveinbjornsson and Thorlacius, \{Gudny E\} and Gudmar Thorleifsson and Vinicius Tragante and Brynjar Vidarsson and Celeste Porsbjerg and Bjornsdottir, \{Unnur S\} and Patrick Sulem and Gudbjartsson, \{Daniel F\} and Pall Melsted and Pedersen, \{Ole Bv\} and Ingileif Jonsd{\'o}ttir and Olafsdottir, \{Thorunn A\} and Kari Stefansson",

year = "2025",

month = jan,

doi = "10.1016/j.jaci.2024.10.002",

language = "English",

volume = "155",

pages = "228--235",

journal = "Journal of Allergy and Clinical Immunology",

issn = "0091-6749",

publisher = "Elsevier",

number = "1",

}

Kristjansdottir, K, Norddahl, GL, Ivarsdottir, EV, Halldorsson, GH, Einarsson, G, Bjarnadóttir, K, Rutsdottir, G, Arnthorsson, AO, Erikstrup, C, Gudmundsdottir, S, Gunnarsdottir, K, Gunnbjornsdottir, MI, Halldorsson, BV, Holm, H, Ludviksdottir, D, Ludviksson, BR, Brunak, S, Bruun, MT, Mikkelsen, C, Mikkelsen, S, Jensen, BA, Sørensen, E, Thomsen, SF, Ullum, H, Olafsson, I, Onundarson, PT, Ostrowski, SR, Saevarsdottir, S, Sigurdardottir, O, Sigurgeirsson, B, Snaebjarnarson, AS, Sveinbjornsson, G, Thorlacius, GE, Thorleifsson, G, Tragante, V, Vidarsson, B, Porsbjerg, C, Bjornsdottir, US, Sulem, P, Gudbjartsson, DF, Melsted, P, Pedersen, OB, Jonsdóttir, I, Olafsdottir, TA & Stefansson, K 2025, 'A partial loss-of-function variant in STAT6 protects against type 2 asthma', Journal of Allergy and Clinical Immunology, vol. 155, no. 1, pp. 228-235. https://doi.org/10.1016/j.jaci.2024.10.002

TY - JOUR

T1 - A partial loss-of-function variant in STAT6 protects against type 2 asthma

AU - Kristjansdottir, Katla

AU - Norddahl, Guðmundur L

AU - Ivarsdottir, Erna V

AU - Halldorsson, Gisli H

AU - Einarsson, Gudmundur

AU - Bjarnadóttir, Kristbjörg

AU - Rutsdottir, Gudrun

AU - Arnthorsson, Asgeir O

AU - Erikstrup, Christian

AU - Gudmundsdottir, Steinunn

AU - Gunnarsdottir, Kristbjorg

AU - Gunnbjornsdottir, María I

AU - Halldorsson, Bjarni V

AU - Holm, Hilma

AU - Ludviksdottir, Dora

AU - Ludviksson, Bjorn R

AU - Brunak, Søren

AU - Bruun, Mie Topholm

AU - Mikkelsen, Christina

AU - Mikkelsen, Susan

AU - Jensen, Bitten Aagaard

AU - Sørensen, Erik

AU - Thomsen, Simon Francis

AU - Ullum, Henrik

AU - Olafsson, Isleifur

AU - Onundarson, Pall T

AU - Ostrowski, Sisse Rye

AU - Saevarsdottir, Saedis

AU - Sigurdardottir, Olof

AU - Sigurgeirsson, Bardur

AU - Snaebjarnarson, Audunn S

AU - Sveinbjornsson, Gardar

AU - Thorlacius, Gudny E

AU - Thorleifsson, Gudmar

AU - Tragante, Vinicius

AU - Vidarsson, Brynjar

AU - Porsbjerg, Celeste

AU - Bjornsdottir, Unnur S

AU - Sulem, Patrick

AU - Gudbjartsson, Daniel F

AU - Melsted, Pall

AU - Pedersen, Ole Bv

AU - Jonsdóttir, Ingileif

AU - Olafsdottir, Thorunn A

AU - Stefansson, Kari

PY - 2025/1

Y1 - 2025/1

N2 - 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.

AB - 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.

U2 - 10.1016/j.jaci.2024.10.002

DO - 10.1016/j.jaci.2024.10.002

M3 - Article

C2 - 39423878

SN - 0091-6749

VL - 155

SP - 228

EP - 235

JO - Journal of Allergy and Clinical Immunology

JF - Journal of Allergy and Clinical Immunology

IS - 1

ER -

A partial loss-of-function variant in STAT6 protects against type 2 asthma

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