FLT3 stop mutation increases FLT3 ligand level and risk of autoimmune thyroid disease

Saedis Saevarsdottir (), Thorunn A. Olafsdottir, Erna V. Ivarsdottir, Gisli H. Halldorsson, Kristbjorg Gunnarsdottir, Asgeir Sigurdsson, Ari Johannesson, Jon K. Sigurdsson, Thorhildur Juliusdottir, Sigrun H. Lund, Asgeir O. Arnthorsson, Edda L. Styrmisdottir, Julius Gudmundsson, Gerdur M. Grondal, Kristjan Steinsson, Lars Alfredsson, Johan Askling, Rafn Benediktsson, Ragnar Bjarnason, Arni J. Geirsson, Bjorn Gudbjornsson, Hallgrimur Gudjonsson, Haukur Hjaltason, Astradur B. Hreidarsson, Lars Klareskog, Ingrid Kockum, Helga Kristjansdottir, Thorvardur J. Love, Bjorn R. Ludviksson, Tomas Olsson, Pall T. Onundarson, Kjartan B. Orvar, Leonid Padyukov, Bardur Sigurgeirsson, Vinicius Tragante, Kristbjorg Bjarnadottir, Thorunn Rafnar, Gisli Masson, Patrick Sulem, Daniel F. Gudbjartsson, Pall Melsted, Gudmar Thorleifsson, Gudmundur L. Norddahl, Unnur Thorsteinsdottir, Ingileif Jonsdottir and Kari Stefansson ()
Additional contact information
Saedis Saevarsdottir: deCODE genetics/Amgen
Thorunn A. Olafsdottir: deCODE genetics/Amgen
Erna V. Ivarsdottir: deCODE genetics/Amgen
Gisli H. Halldorsson: deCODE genetics/Amgen
Kristbjorg Gunnarsdottir: deCODE genetics/Amgen
Asgeir Sigurdsson: deCODE genetics/Amgen
Ari Johannesson: The National University Hospital of Iceland
Jon K. Sigurdsson: deCODE genetics/Amgen
Thorhildur Juliusdottir: deCODE genetics/Amgen
Sigrun H. Lund: deCODE genetics/Amgen
Asgeir O. Arnthorsson: deCODE genetics/Amgen
Edda L. Styrmisdottir: deCODE genetics/Amgen
Julius Gudmundsson: deCODE genetics/Amgen
Gerdur M. Grondal: University of Iceland
Kristjan Steinsson: University of Iceland
Lars Alfredsson: Karolinska Institutet
Johan Askling: Solna, Karolinska Institutet
Rafn Benediktsson: University of Iceland
Ragnar Bjarnason: University of Iceland
Arni J. Geirsson: University of Iceland
Bjorn Gudbjornsson: University of Iceland
Hallgrimur Gudjonsson: University of Iceland
Haukur Hjaltason: University of Iceland
Astradur B. Hreidarsson: University of Iceland
Lars Klareskog: Solna, Karolinska Institutet
Ingrid Kockum: Center for Molecular Medicine, Karolinska Institutet
Helga Kristjansdottir: Landspitali, The National University Hospital of Iceland
Thorvardur J. Love: University of Iceland
Bjorn R. Ludviksson: University of Iceland
Tomas Olsson: Center for Molecular Medicine, Karolinska Institutet
Pall T. Onundarson: University of Iceland
Kjartan B. Orvar: University of Iceland
Leonid Padyukov: Solna, Karolinska Institutet
Bardur Sigurgeirsson: University of Iceland
Vinicius Tragante: deCODE genetics/Amgen
Kristbjorg Bjarnadottir: deCODE genetics/Amgen
Thorunn Rafnar: deCODE genetics/Amgen
Gisli Masson: deCODE genetics/Amgen
Patrick Sulem: deCODE genetics/Amgen
Daniel F. Gudbjartsson: deCODE genetics/Amgen
Pall Melsted: deCODE genetics/Amgen
Gudmar Thorleifsson: deCODE genetics/Amgen
Gudmundur L. Norddahl: deCODE genetics/Amgen
Unnur Thorsteinsdottir: deCODE genetics/Amgen
Ingileif Jonsdottir: deCODE genetics/Amgen
Kari Stefansson: deCODE genetics/Amgen

Nature, 2020, vol. 584, issue 7822, 619-623

Abstract: Abstract Autoimmune thyroid disease is the most common autoimmune disease and is highly heritable1. Here, by using a genome-wide association study of 30,234 cases and 725,172 controls from Iceland and the UK Biobank, we find 99 sequence variants at 93 loci, of which 84 variants are previously unreported2–7. A low-frequency (1.36%) intronic variant in FLT3 (rs76428106-C) has the largest effect on risk of autoimmune thyroid disease (odds ratio (OR) = 1.46, P = 2.37 × 10−24). rs76428106-C is also associated with systemic lupus erythematosus (OR = 1.90, P = 6.46 × 10−4), rheumatoid factor and/or anti-CCP-positive rheumatoid arthritis (OR = 1.41, P = 4.31 × 10−4) and coeliac disease (OR = 1.62, P = 1.20 × 10−4). FLT3 encodes fms-related tyrosine kinase 3, a receptor that regulates haematopoietic progenitor and dendritic cells. RNA sequencing revealed that rs76428106-C generates a cryptic splice site, which introduces a stop codon in 30% of transcripts that are predicted to encode a truncated protein, which lacks its tyrosine kinase domains. Each copy of rs76428106-C doubles the plasma levels of the FTL3 ligand. Activating somatic mutations in FLT3 are associated with acute myeloid leukaemia8 with a poor prognosis and rs76428106-C also predisposes individuals to acute myeloid leukaemia (OR = 1.90, P = 5.40 × 10−3). Thus, a predicted loss-of-function germline mutation in FLT3 causes a reduction in full-length FLT3, with a compensatory increase in the levels of its ligand and an increased disease risk, similar to that of a gain-of-function mutation.

Date: 2020
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DOI: 10.1038/s41586-020-2436-0

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