FLT3终止突变会增加FLT3配体水平和自身免疫性甲状腺疾病的风险-小柯机器人-科学网

FLT3终止突变会增加FLT3配体水平和自身免疫性甲状腺疾病的风险

2020-06-28 14:05

冰岛安进公司Kari Stefansson、Saedis Saevarsdottir等研究人员合作发现，FLT3终止突变会增加FLT3配体水平和自身免疫性甲状腺疾病的风险。这一研究成果于2020年6月24日在线发表在《自然》上。

通过对来自冰岛和英国生物库的30,234例病例和725,172例对照的全基因组关联研究，研究人员在93个基因座上发现了99个序列变体，其中84个变体以前未报道过。FLT3（rs76428106-C）中的一种低频（1.36％）内含子变体对自身免疫性甲状腺疾病的风险影响最大（优势比（OR）=1.46，P=2.37×10^-24）。rs76428106-C还与系统性红斑狼疮（OR=1.90，P=6.46×10⁻⁴）、类风湿因子和/或抗CCP阳性类风湿性关节炎（OR=1.41，P=4.31×10⁻⁴）和乳糜泻（OR=1.62，P=1.20×10⁻⁴）。

FLT3编码与fms相关的酪氨酸激酶3，该受体调节造血祖细胞和树突状细胞。RNA测序显示rs76428106-C产生了一个隐蔽的剪接位点，该位点在30％的转录本中产生了一个终止密码子，这些转录本可能编码截短的蛋白，该蛋白缺少酪氨酸激酶结构域。rs76428106-C的每个拷贝都会使FTL3配体的血浆水平加倍。FLT3中的激活体细胞突变与预后较差的急性髓性白血病有关，而rs76428106-C也使个体易患急性髓性白血病（OR=1.90，P=5.40×10^-3）。因此，与功能获得性突变相似，潜在的FLT3功能丧失性生殖系突变会导致全长FLT3减少，其配体水平得到补偿性增加，进而疾病风险增加。

据悉，自身免疫性甲状腺疾病是最常见的自身免疫性疾病，并且遗传性强。

附：英文原文

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

Issue&Volume: 2020-06-24

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.

DOI: 10.1038/s41586-020-2436-0

Source: https://www.nature.com/articles/s41586-020-2436-0

Nature：《自然》，创刊于1869年。隶属于施普林格·自然出版集团，最新IF：69.504
官方网址：http://www.nature.com/
投稿链接：http://www.nature.com/authors/submit_manuscript.html

本期文章：《自然》：Online/在线发表

分享到: