2011-05-012024-05-14https://scholars.lib.ntu.edu.tw/handle/123456789/657642摘要：葛瑞夫茲氏症（MIM 27500)是全球最重要導致曱狀腺機能亢進以及曱狀腺眼病變的原 因。本疾病是一種常見的器官專一性自體免疫疾病，在臨床上以及基礎研究上都非常 重要。本疾病的致病基因在不同的人種中，可以發現有相當的歧異性。人類白血球抗 原（HLA)是一群非常重要的基因，掌管免疫功能，並且跟許多免疫相關疾病有關，然 而，對於HLA的基因型定型非常昂貴而且技術上不容易，導致說實務上的應用相當困 難。根據基因型來預估疾病發病風險是遺傳研究非常想要達成的目標，然而，對大多 數的常見疾病來說，此一目標仍然遙不可及。在本計晝中，我們將要製作出基因型定 型晶片，用以來預估葛瑞夫茲氏症的罹病風險以及人類白血球抗原的基因型，為達成 此終極目標，我們設定以下六個步驟：第一：我們將完成葛瑞夫茲氏症的全基因體相 關研究，第二 ：我們要完成一個總共兩千人的完整HLA基因型定型計晝，第三：我們 要將HLA的訊息納入全基因體相關研究中協同來分析，第四：我們將設立使用SNP來 預測HLA基因型的預測模型，第五：我們將建立預測葛瑞夫茲氏症發病機率的預測模 型，第六：我們會將以上兩種預測模型做成基因定型晶片，這會有廣大的市場。我們 的團隊之所以能夠執行這樣大規模高難度的計晝，是因為我們已經在葛瑞夫茲氏症遺 傳研究領域投入超過十年的時間，而且我們團隊内除了葛瑞夫茲氏症以及遺傳學的專 長之外，還有HLA以及遺傳統計學的專家。我們的病人數目是全球最多，而且我們也 發現了在華人族群中，我們的葛瑞夫茲氏症致病HLA基因和白人完全不同。像這樣子 跨人種的HLA極端不同以及本疾病致病基因的歧異性，會導致說類似的基因定型產品 只適用於同一種族之中，也因此西方國家未來即使有類似產品也無法適用於華人。所 以說此一基因定型晶片很有潛力來獨佔十億華人市場。此外，此產品相當具有彈性， 經過少許修改之後，未來也可適用到其他免疫相關疾病。<br> Abstract: Graves disease (GD, MIM 27500), the worldwide leading cause of hyperthyroidism and thyroid eye disease, is a common organ-specific autoimmune disorder with both clinical and scientific importance. The etiology of GD is generally accepted to be multifactorial with several lines of evidence showing significant genetic influence. Susceptibility genes of GD showed high locus heterogeneity and allelic heterogeneity. Classical human leukocyte antigen (HLA) genes are very important for many immune-related clinical conditions, including GD; however, it is quite expensive and technically challenging to direct genotype HLA, which prevents its practical usefulness. Disease risk prediction based on genetic information is one of the dreams for genetic study; however, for most complex diseases, the dream is not fulfilled yet. In this project, we proposed to develop a single nucleotide polymorphism (SNP) genotyping chip, which can predict the genotypes of classical HLA genes and the risk of GD. There are 6 specific aims/steps to achieve the final goal, including: (A). Fine mapping and functional analysis of our genome-wide association study, (B). Completion of a “1,000 GD cases-1,000 controls” HLA genotyping project, (C). Integration of classical HLA genotypes into the GWAS analysis and gene-gene interaction assessment, (D). Prediction of classical HLA alleles using nearby SNPs, (E). GD disease risk prediction, and (F) A final product of flexible genotyping chip for both HLA allele prediction and GD risk prediction. Our team can perform such a challenging task because we have been working in genetic study of GD for more than 10 years, and because our team, in addition to being good at GD and genetics, has experts in HLA and statistical genetics. Our GD collection is the largest in the world, and we have recruited both unrelated GD cases and family samples. We identified a whole spectrum of HLA alleles associated with GD in our population, which was totally different from the spectrum in Caucasians. The high inter-population heterogeneity of GD risk genes/alleles and HLA prediction SNPs set a barrier for any possible future competing products from western countries, which gives our genotyping chips a very good chance to dominate the ethnic Chinese Hans market (a population of more than 1,000,000,000 people). The flexibility of this platform makes it possible to extend its applications to other important immune-related clinical conditions.葛瑞夫茲氏症人類白血球抗原相關研究疾病風險預估基因定型晶片Graves diseaseHuman leukocyte antigen (HLA)association studyrisk predictiongenotyping chip