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

Sædís Sævarsdóttir; Þórunn A. Ólafsdóttir; Erna V. Ívarsdóttir; Gísli H. Halldórsson; Kristbjörg Gunnarsdóttir; Ásgeir Sigurðsson; Ari J Jóhannesson; Jón K. Sigurðsson; Þórhildur Júlíusdóttir; Sigrún H. Lund; Ásgeir O. Arnþórsson; Edda L. Styrmisdóttir; Júlíus Guðmundsson; Gerður María Gröndal; Kristján Steinsson; Lars Alfredsson; Johan Askling; Rafn Benediktsson; Ragnar Grímur Bjarnason; Árni Jón Geirsson; Björn Guðbjörnsson; Hallgrímur Guðjónsson; Haukur Hjaltason; Ástráður Benedikt Hreiðarsson; Lars Klareskog; Ingrid Kockum; Helga Kristjánsdóttir; Þorvarður Jón Löve; Björn Rúnar Lúðvíksson; Tomas Olsson; Páll Torfi Önundarson; Kjartan B. Örvar; Leonid Padyukov; Bárður Sigurgeirsson; Vinicius Tragante; Kristbjörg Bjarnadóttir; Þórunn Rafnar; Gísli Másson; Patrick Sulem; Daníel Fannar Guðbjartsson; Páll Melsted; Guðmar Þorleifsson; Guðmundur L. Norddahl; Unnur Thorsteinsdottir; Ingileif Jónsdóttir; Kári Stefánsson

doi:10.1038/s41586-020-2436-0

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

Sædís Sævarsdóttir, Þórunn A. Ólafsdóttir, Erna V. Ívarsdóttir, Gísli H. Halldórsson, Kristbjörg Gunnarsdóttir, Ásgeir Sigurðsson, Ari J Jóhannesson, Jón K. Sigurðsson, Þórhildur Júlíusdóttir, Sigrún H. Lund, Ásgeir O. Arnþórsson, Edda L. Styrmisdóttir, Júlíus Guðmundsson, Gerður María Gröndal, Kristján Steinsson, Lars Alfredsson, Johan Askling, Rafn Benediktsson, Ragnar Grímur Bjarnason, Árni Jón GeirssonBjörn Guðbjörnsson, Hallgrímur Guðjónsson, Haukur Hjaltason, Ástráður Benedikt Hreiðarsson, Lars Klareskog, Ingrid Kockum, Helga Kristjánsdóttir, Þorvarður Jón Löve, Björn Rúnar Lúðvíksson, Tomas Olsson, Páll Torfi Önundarson, Kjartan B. Örvar, Leonid Padyukov, Bárður Sigurgeirsson, Vinicius Tragante, Kristbjörg Bjarnadóttir, Þórunn Rafnar, Gísli Másson, Patrick Sulem, Daníel Fannar Guðbjartsson, Páll Melsted, Guðmar Þorleifsson, Guðmundur L. Norddahl, Unnur Thorsteinsdottir, Ingileif Jónsdóttir, Kári Stefánsson

Landspitali, University of Iceland

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

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 unreported^2–7. 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.

Original language	English
Pages (from-to)	619-623
Number of pages	5
Journal	Nature
Volume	584
Issue number	7822
DOIs	https://doi.org/10.1038/s41586-020-2436-0
Publication status	Published - 27 Aug 2020

Bibliographical note

Other keywords

Autoimmune diseases
Genome-wide association studies
Risk factors

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1038/s41586-020-2436-0

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Sævarsdóttir, S., Ólafsdóttir, Þ. A., Ívarsdóttir, E. V., Halldórsson, G. H., Gunnarsdóttir, K., Sigurðsson, Á., Jóhannesson, A. J., Sigurðsson, J. K., Júlíusdóttir, Þ., Lund, S. H., Arnþórsson, Á. O., Styrmisdóttir, E. L., Guðmundsson, J., Gröndal, G. M., Steinsson, K., Alfredsson, L., Askling, J., Benediktsson, R., Bjarnason, R. G., ... Stefánsson, K. (2020). FLT3 stop mutation increases FLT3 ligand level and risk of autoimmune thyroid disease. Nature, 584(7822), 619-623. https://doi.org/10.1038/s41586-020-2436-0

@article{66bd15b4fc7e4304be40ece1c1dbbf0f,

title = "FLT3 stop mutation increases FLT3 ligand level and risk of autoimmune thyroid disease",

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.",

keywords = "Autoimmune diseases, Genome-wide association studies, Risk factors",

author = "S{\ae}d{\'i}s S{\ae}varsd{\'o}ttir and {\'O}lafsd{\'o}ttir, \{{\TH}{\'o}runn A.\} and {\'I}varsd{\'o}ttir, \{Erna V.\} and Halld{\'o}rsson, \{G{\'i}sli H.\} and Kristbj{\"o}rg Gunnarsd{\'o}ttir and {\'A}sgeir Sigur{\dh}sson and J{\'o}hannesson, \{Ari J\} and Sigur{\dh}sson, \{J{\'o}n K.\} and {\TH}{\'o}rhildur J{\'u}l{\'i}usd{\'o}ttir and Lund, \{Sigr{\'u}n H.\} and Arn{\th}{\'o}rsson, \{{\'A}sgeir O.\} and Styrmisd{\'o}ttir, \{Edda L.\} and J{\'u}l{\'i}us Gu{\dh}mundsson and Gr{\"o}ndal, \{Ger{\dh}ur Mar{\'i}a\} and Kristj{\'a}n Steinsson and Lars Alfredsson and Johan Askling and Rafn Benediktsson and Bjarnason, \{Ragnar Gr{\'i}mur\} and Geirsson, \{{\'A}rni J{\'o}n\} and Bj{\"o}rn Gu{\dh}bj{\"o}rnsson and Hallgr{\'i}mur Gu{\dh}j{\'o}nsson and Haukur Hjaltason and Hrei{\dh}arsson, \{{\'A}str{\'a}{\dh}ur Benedikt\} and Lars Klareskog and Ingrid Kockum and Helga Kristj{\'a}nsd{\'o}ttir and L{\"o}ve, \{{\TH}orvar{\dh}ur J{\'o}n\} and L{\'u}{\dh}v{\'i}ksson, \{Bj{\"o}rn R{\'u}nar\} and Tomas Olsson and {\"O}nundarson, \{P{\'a}ll Torfi\} and {\"O}rvar, \{Kjartan B.\} and Leonid Padyukov and B{\'a}r{\dh}ur Sigurgeirsson and Vinicius Tragante and Kristbj{\"o}rg Bjarnad{\'o}ttir and {\TH}{\'o}runn Rafnar and G{\'i}sli M{\'a}sson and Patrick Sulem and Gu{\dh}bjartsson, \{Dan{\'i}el Fannar\} and P{\'a}ll Melsted and Gu{\dh}mar {\TH}orleifsson and Norddahl, \{Gu{\dh}mundur L.\} and Unnur Thorsteinsdottir and Ingileif J{\'o}nsd{\'o}ttir and K{\'a}ri Stef{\'a}nsson",

note = "Publisher Copyright: {\textcopyright} 2020, The Author(s), under exclusive licence to Springer Nature Limited.",

year = "2020",

month = aug,

day = "27",

doi = "10.1038/s41586-020-2436-0",

language = "English",

volume = "584",

pages = "619--623",

journal = "Nature",

issn = "0028-0836",

publisher = "Nature Research",

number = "7822",

}

Sævarsdóttir, S , Ólafsdóttir, ÞA, Ívarsdóttir, EV, Halldórsson, GH, Gunnarsdóttir, K, Sigurðsson, Á, Jóhannesson, AJ, Sigurðsson, JK, Júlíusdóttir, Þ, Lund, SH, Arnþórsson, ÁO, Styrmisdóttir, EL, Guðmundsson, J, Gröndal, GM, Steinsson, K, Alfredsson, L, Askling, J, Benediktsson, R , Bjarnason, RG , Geirsson, ÁJ , Guðbjörnsson, B, Guðjónsson, H, Hjaltason, H, Hreiðarsson, ÁB, Klareskog, L, Kockum, I, Kristjánsdóttir, H , Löve, ÞJ , Lúðvíksson, BR, Olsson, T, Önundarson, PT , Örvar, KB, Padyukov, L, Sigurgeirsson, B, Tragante, V, Bjarnadóttir, K, Rafnar, Þ, Másson, G, Sulem, P, Guðbjartsson, DF, Melsted, P, Þorleifsson, G, Norddahl, GL, Thorsteinsdottir, U , Jónsdóttir, I & Stefánsson, K 2020, 'FLT3 stop mutation increases FLT3 ligand level and risk of autoimmune thyroid disease', Nature, vol. 584, no. 7822, pp. 619-623. https://doi.org/10.1038/s41586-020-2436-0

TY - JOUR

T1 - FLT3 stop mutation increases FLT3 ligand level and risk of autoimmune thyroid disease

AU - Sævarsdóttir, Sædís

AU - Ólafsdóttir, Þórunn A.

AU - Ívarsdóttir, Erna V.

AU - Halldórsson, Gísli H.

AU - Gunnarsdóttir, Kristbjörg

AU - Sigurðsson, Ásgeir

AU - Jóhannesson, Ari J

AU - Sigurðsson, Jón K.

AU - Júlíusdóttir, Þórhildur

AU - Lund, Sigrún H.

AU - Arnþórsson, Ásgeir O.

AU - Styrmisdóttir, Edda L.

AU - Guðmundsson, Júlíus

AU - Gröndal, Gerður María

AU - Steinsson, Kristján

AU - Alfredsson, Lars

AU - Askling, Johan

AU - Benediktsson, Rafn

AU - Bjarnason, Ragnar Grímur

AU - Geirsson, Árni Jón

AU - Guðbjörnsson, Björn

AU - Guðjónsson, Hallgrímur

AU - Hjaltason, Haukur

AU - Hreiðarsson, Ástráður Benedikt

AU - Klareskog, Lars

AU - Kockum, Ingrid

AU - Kristjánsdóttir, Helga

AU - Löve, Þorvarður Jón

AU - Lúðvíksson, Björn Rúnar

AU - Olsson, Tomas

AU - Önundarson, Páll Torfi

AU - Örvar, Kjartan B.

AU - Padyukov, Leonid

AU - Sigurgeirsson, Bárður

AU - Tragante, Vinicius

AU - Bjarnadóttir, Kristbjörg

AU - Rafnar, Þórunn

AU - Másson, Gísli

AU - Sulem, Patrick

AU - Guðbjartsson, Daníel Fannar

AU - Melsted, Páll

AU - Þorleifsson, Guðmar

AU - Norddahl, Guðmundur L.

AU - Thorsteinsdottir, Unnur

AU - Jónsdóttir, Ingileif

AU - Stefánsson, Kári

PY - 2020/8/27

Y1 - 2020/8/27

N2 - 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.

AB - 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.

KW - Autoimmune diseases

KW - Genome-wide association studies

KW - Risk factors

UR - https://www.scopus.com/pages/publications/85086773553

U2 - 10.1038/s41586-020-2436-0

DO - 10.1038/s41586-020-2436-0

M3 - Article

C2 - 32581359

SN - 0028-0836

VL - 584

SP - 619

EP - 623

JO - Nature

JF - Nature

IS - 7822

ER -

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

Abstract

Bibliographical note

Other keywords

UN SDGs

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