| Title: | FLT3 stop mutation increases FLT3 ligand level and risk of autoimmune thyroid disease |
| Journal: | Nature |
| Published: | 24 Jun 2020 |
| Pubmed: | https://pubmed.ncbi.nlm.nih.gov/32581359/ |
| DOI: | https://doi.org/10.1038/s41586-020-2436-0 |
| Citations: | 96 (46 in last 2 years) as of 8 Aug 2024 |
Publication 4860
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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.</p>
46 Authors
- 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
- Kari Stefansson
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