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. A predicted loss-of-function germline mutation in FLT3 causes a reduction in full-length FLT3, with a compensatory increase in the levels of FLT3 ligand, leading to increased risk of autoimmune thyroid disease.

中文翻译：

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FLT3 终止突变增加 FLT3 配体水平和自身免疫性甲状腺疾病的风险

自身免疫性甲状腺疾病是最常见的自身免疫性疾病，具有高度遗传性1。在这里，通过使用来自冰岛和英国生物银行的 30,234 例病例和 725,172 名对照的全基因组关联研究，我们在 93 个基因座上发现了 99 个序列变异，其中 84 个变异以前未报告2-7。FLT3 中的低频 (1.36%) 内含子变异 (rs76428106-C) 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 fms 相关的酪氨酸激酶 3，这是一种调节造血祖细胞和树突细胞的受体。RNA 测序显示 rs76428106-C 产生了一个隐蔽的剪接位点，它在 30% 的转录本中引入了一个终止密码子，这些转录本预计会编码一种缺少酪氨酸激酶结构域的截短蛋白。rs76428106-C 的每个拷贝使 FTL3 配体的血浆水平加倍。激活 FLT3 中的体细胞突变与预后不良的急性髓系白血病 8 相关，rs76428106-C 也使个体易患急性髓系白血病（OR = 1.90，P = 5.40 × 10−3）。因此，预测的 FLT3 功能丧失种系突变导致全长 FLT3 减少，其配体水平补偿性增加和疾病风险增加，类似于功能获得性突变。FLT3 中预测的功能丧失生殖系突变导致全长 FLT3 减少，