2012-08-012024-05-14https://scholars.lib.ntu.edu.tw/handle/123456789/658190摘要：葛瑞夫茲氏症是世界造成甲狀腺機能亢進最重要原因，也是內分泌領域中僅次 於糖尿病的常見疾病。Thionamides 是治療的藥物的首選，這類藥物發生的最嚴重 副作用是顆粒性白血球缺乏症(agranulocytosis)，機率大約是 0.1% - 0.4 %。一旦發 生 agranulocytosis，病人容易有嚴重感染，會造成醫療資源極度耗損，更重要的是 可能導致死亡，死亡率約為 18.2%。引起 agranulocytosis 的原因不明，可能與免疫反應有關。迄今為止，尚未能預測誰可能會發生 agranulocytosis。本研究之目的在 尋找抗甲狀腺藥物引起 agranulocytosis 之 致病基因。 人類白血球表面抗原基因（HLA）理所當然地是很可能的候選基因，但是我們同時也要分析全基因體上的其 他可能基因。我們將納入 30 位產生 agranulocytosis 之病人，以及 499 位未發生 agranulocytosis 之對照組，來進行 HLA 基因分析，根據計算，此實驗設計及人數具 有非常高的統計檢力。我們同時將對六位病人利用次世代定序來檢測他們的所有其 他基因變異。本團隊非常適合來進行這樣複雜而精細之藥物基因體學研究，因為我 們長期以來就投入在 GD 病人檢體收集以及表現型分析，有非常好的 GD 遺傳學研 究，並且在 HLA 基因定型以及次世代定序平台著墨甚深。找出造成 agranulocytosis 的致病基因，不但能夠因而建立用藥前的基因檢測平台，還能夠了解致病機轉幫助 對其他藥物副作用之研究。<br> Abstract: Graves’ disease [GD (MIM 27500)] is the leading cause of hyperthyroidism worldwide. According to the epidemiologic survey, the prevalence of Graves’ disease is about 2.7% in women, which is only next to diabetes mellitus in endocrine diseases. Thionamides, including methimazole, carbimazole, propylthiouracil, are the major anti-thyroid drugs, and are the treatment of choice for GD. The most serious side effect of thionamides is agranulocytosis (severe drop of neutrophil count to < 500/mm3), which occurs in 0.1% - 0.4% of the patients. Agranulocytosis inevitably compromises the immune system of the patients, making them at high risk of severe infection. Patients with the complication of agranulocytosis need to be hospitalized for expensive medications and close monitoring. In addition to the medical cost, the fatal rate can be as high as 18.2%. The underlying mechanism is unclear, and to date it has been impossible to predict who will develop agranulocytosis. An immune phenomenon may be involved because the anti-granulocyte antibodies or lymphocyte sensitized to anti-thyroid drugs can be found in these patients. The ultimate goal of this project is to identify the possible genetic variants causing agranulocytosis induced by anti-thyroid drugs. We consider the human leukocyte antigen (HLA) genes to be very good candidates for the idiosyncratic adverse effect; however, we also plan to investigate the possible role of other genes beyond the HLA loci. We will include 30 GD agranulocytosis “cases” and 499 GD non-agranulocytosis “controls” for comprehensive 6-locus HLA genotype analyses. According to the power calculation, this study design has very high statistic power (mostly greater than 99%) to detect the association signal if any of the HLA genes is the causative gene. At the same time, we will perform whole exome sequencing using the next-generation sequencing (NGS) approach on 6 cases to identify any possible risk gene outside the HLA loci. Our team has strong foundation to perform such a complicated pharmacogenomics study because of our long-term devotion in GD patient enrollment and phenotype characterization, our well-established GD genetic study basis, and our expertise in HLA genotyping and NGS experiments. Identification of genetic determinant(s) for anti-thyroid drugs-related agranulocytosis will have paramount clinical and academic importance. It may lead to an efficient genetic test, which can be used before the launch of thionamides to prevent expensive medical cost related to agranulocytosis and to save valuable lives. Furthermore, such breakthrough can also shed light on the pathogenesis, and might facilitate the search of genes responsible fordrug-related agranulocytosis by other medications.葛瑞夫茲氏症硫代酰胺顆粒性白血球缺乏症人類白血球表面抗原次世代定序藥物基因醫學藥物基因體學Graves diseasethionamideagranulocytosishuman leukocyte antigen (HLA)next-generation sequencing (NGS)pharmacogeneticspharmacogenomics