Title: FLT3 stop mutation increases FLT3 ligand level and risk of autoimmune thyroid disease
Author: 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
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 unreported2,3,4,5,6,7. 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 × 1024). rs76428106-C is also associated with systemic lupus erythematosus (OR = 1.90, P = 6.46 × 104), rheumatoid factor and/or anti-CCP-positive rheumatoid arthritis (OR = 1.41, P = 4.31 × 104) and coeliac disease (OR = 1.62, P = 1.20 × 104). 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 × 103). 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.