Nature. Key genes and causes of risk of autoimmune thyroid disease were found.

Autoimmune thyroid disease (AITD) is the most common autoimmune disease. The prevalence rate of AITD in the population is about 5%. The main manifestation of AITD is hypothyroidism, and the production of anti thyroid autoantibodies and infiltration of lymphocytes in thyroid parenchyma. The disease has a high genetic tendency [1,2].most AITD patients are diagnosed and treated only after the immune attack has destroyed the thyroid gland.this is quite different from other autoimmune diseases often associated with AITD, such as rheumatoid arthritis. For rheumatoid arthritis, more than 100 risk gene loci have been found. There are also several effective treatments, and some methods focus on early diagnosis and even prevention [3].and the need for early diagnosis and treatment of AITD also requires us to further understand the causes of AITD.June 24, 2020, from code genetics / Amgen, Iceland, Kari Stefansson of Reykjavik and saedits saevarsdottir, together with several European research institutions, published an article entitled "FLT3 stop mutation increases FLT3 life level and risk of autoimmune thymid disease" in nature Among them, rs76428106-c mutation located in intron FLT3 was highly related to the pathogenesis of AITD, and rs76428106-c mutation caused the early termination of FLT3 transcripts, which made FLT3 lose its function, and the increase of Flt3L content in patients' plasma triggered autoimmunity.first of all, the researchers conducted a comparative study on 4692 AITD cases and 342061 control cases from Iceland and UK Biobank in the UK (25542 AITD cases, 383 cases), The results of GWAS analysis showed that 99 sequence variations at 93 loci were associated with AITD, of which 84 were not previously associated with AITD, and 15 previously reported mutations associated with AITD were repeated by the researchers.further gene annotation showed that these mutations affected the protein expression or mRNA content of 37 candidate genes. Through network analysis of these genes, it was found that 24 genes were directly or indirectly related to CTLA4 – CD86 and IRF3 – IFIH1, while other molecules were related to T cell receptor, CD3 and IFN - α.subsequently, researchers found that a new gene mutation had the greatest effect on the risk of AITD: FLT3 intron variation (rs76428106-c, minor allele frequency (MAF) = 1.36%, or = 1.46, P = 2.4 × 10-24), which was not previously found to be associated with other diseases.FLT3 (also known as CD135) encodes a cell surface receptor for l-kinase, which plays an important role in the development of monocytes and dendritic cells.the rs76428106-c mutation in FLT3 was detected to be associated with systemic lupus erythematosus (or = 1.90, P = 6.46 × 10-4), rheumatoid arthritis (or = 1.41, P = 4.31 × 10-4) and celiac disease (or = 1.62, P = 1.20 × 10-4) in FLT3.rs76428106-c is located in intron 15 of FLT3 gene In the mRNA transcript data, the researchers found that rs76428106-c mutation resulted in the formation of a secret splicing site. If the mRNA was sheared at this shear site, the intron upstream of the splicing site would be retained, and a termination codon was introduced in advance, which resulted in the protein being truncated at 650 amino acid position, resulting in the protein losing most of the kinase domain, thus losing the majority of the kinase domain The function of kinase receptor (Fig.analysis of FLT3 transcripts in the population showed that about 30% of FLT3 transcripts were cut abnormally in carriers of rs76428106-c heterozygotes.further functional analysis showed that rs76428106-c had a significant effect on Flt3 ligand and Flt3L content in plasma. The median plasma Flt3L content of pure and carriers was higher than that of heterozygous carriers or wild-type population (Fig. 1).based on previous studies and data, the researchers believe that the decrease of FLT3 content in normal function leads to the increase of Flt3L content, which will activate plasma cell like dendritic cells to secrete type I interferon, thus triggering the body's autoimmunity.Fig. 1 the mutation of rs76428106-c in FLT3 intron resulted in protein truncation and was associated with high levels of Flt3L in plasma. In conclusion, this study was conducted in UK, Iceland and UK GWAS analysis of biobank population revealed some AITD related mutations. Among them, rs76428106-c could affect the splicing of FLT3 transcripts, resulting in the truncation of FLT3 protein and loss of function, which further increased the level of Flt3L in plasma and caused autoimmunity.it provides guidance for understanding the pathogenesis of atid and early diagnosis and screening. (2): P. 174-80.2. Hwangbo, Y. and Y.J. Park, genome wide association studies of autoimmune thymoid diseases, thymoid function, and thymoid cancer. Endocrinol Metab (Seoul), 2018. 33(2): p. 175-184.3. Cope, A.P., Considerations for Optimal Trial Design for Rheumatoid Arthritis Prevention Studies. Clin Ther, 2019. 41(7): p. 1299-1311.