人類甲狀腺球蛋白基因之多型性與葛瑞夫茲氏病停藥後復發的關係

Association of the thyroglobulin gene polymorphyism with relapse of Graves’ hyperthyroidism after Antithyroid withdrawal

蕭政岳(Jeng-Yueh Hsiao)

指導教授 ： 林綉茹

高雄醫學大學/醫學院/醫學研究所/碩士(2007年)

https://doi.org/10.6832/KMU.2007.00058

摘要

葛瑞夫茲氏病是一種與基因相關的自體免疫疾病，甲狀腺球蛋白是葛瑞夫茲氏病的一種主要自體抗原，甲狀腺球蛋白基因是位於人類第八對基因上，最近被報導和基因上第10、12、33外基因上的單一核甘酸多型性〈Single nucleotide polymorphism; SNP〉變化有關。葛瑞夫茲氏病是一種可以和甲狀腺球蛋白來進行細胞性和體液性免疫反應，因此甲狀腺蛋白基因是葛瑞夫茲氏病的一種強力候選基因，尋找這方面的易感基因和發現高危險性病人對於葛瑞夫茲氏病發作的預防是重要的。基於上述的發現，我們將設計下列研究方法來偵測台灣葛瑞夫茲氏病的甲狀腺球蛋白單一核酸多型性變化。本研究檢體是由高雄醫學大學附設醫院新陳代謝內科門診評選出來的葛瑞夫茲氏病病患共計215人及正常對照組141人。我們對台灣葛瑞夫茲氏病病患研究三個已知的甲狀腺球蛋白基因的單一核甘酸多型性變化，甲狀腺球蛋白之基因以聚合酵素連鎖反應〈Polymerase chain reaction, PCR〉進行DNA增幅，接著進行限制片段長度多型性〈Restriction Fragment Length polymorphism, RFLP〉分析技術作為基因多型性檢查。我們也分析這些單一核甘酸多型性〈Single nucleotide polymorphism; SNP〉和臨床相關資料之間的相關性，更加以驗證了葛瑞夫茲氏病的強基因易感性。本研究結果發現，甲狀腺球蛋白基因的第33外基因的T/T基因型中可見葛瑞夫茲氏病組有較高的發生率〈P<0.001〉，然後把215位葛瑞夫茲氏病病患依三個不同的停藥後復發時間，分別為9個月，9個月到3年，大於3年分成三組，結果發現三組和三種SNP的基因型分布及疾病相關因子之分析結果並無統計上的差異。除此之外，我們發現甲狀腺球蛋白基因的第33外基因的C/C基因型與葛瑞夫茲氏病的高復發率及有較高頻率發現在抽菸及眼病變病人有相關。基因因子在葛瑞夫茲氏病扮演一個相當重要的角色，單一核甘酸多型性〈SNP〉基因分析提供一種對對此疾病基因的分析，分析葛瑞夫茲氏病可選擇一種較好的方法來治療疾病及預防高危險性病人的疾病發生。在我們的研究中，甲狀腺球蛋白基因分析可提供治療前去評估及決定治療方法的一種有價值的參數。

關鍵字

葛瑞夫茲氏病 ； 甲狀腺球蛋白基因 ； 單一核甘酸多型性

並列摘要

Graves’ disease(GD) is an autoimmune disorder with genetic predisposition. GD is characterized by cellular and humoral immune responses to Tg. The thyroglobulin(Tg) is a major autoantigen for GD. Thus, the Tg gene is a strong positional candidate gene for GD. The Tg gene has been mapped to chromosome 8q24, which has recently been linked to GD in exon 10,12 and 33. Searching the susceptive genes and finding high risk person are important for prevention of the onset of GD. Therefore, we will design the following study to determine Tg gene polymorphisms are associated with GD in Taiwanese population. We can elucidate the susceptive genes for GD which are highly likely polygenic. This is very important for predication of prognosis and selection of treatment type of GD. Case control association studies were performed for the 3 discovered Tg SNPs(E10,E12,E33) in 215 GD patients and 141 controls. The three SNPs(single nucleotide polymorphism) were identified within the Tg gene. These SNPs were analyzed by a fluorescent-based restriction fragment length polymorphism method(RFLP) and PCR. We then analyze interactions between these SNPs and examined whether certain combinations stronger susceptibility for GD. There was a significant statistical difference in the T/T genotype of E33SNP and G/G genotype of E12SNP compared with control group.(P <0.001). Furthermore, we found the E33SNP T/T genotype was positively associated with Graves’ disease, whereas E12SNP G/G genotype protects against it. The 215 patients were divided into three groups according to their time of relapse after drug withdrawal. The cutoff points of 9m, 9m-3years, and more than 3 yr. There was no statistical significant difference of genotypic distribution and associated risk factor among the three groups. Additionally, we also found the E33SNP C/C genotype of the Tg gene were strongly associated with a subgroup of GD patients who were likely to have higher relapse rate, as they had significantly higher levels in persisting TSH-receptor antibody(i.e. TBII) at the end of treatment, and higher frequency in smoking and were ophthalmopathy patients(P <0.05). Genetic factor play an important role in GD. SNP genotyping offers a good way to identify the genes of GD. Identifying the genes of GD can select a best way to treat disease and high patient to prevent disease. In our study, the Tg genotypes provide a more valuable parameter to assess and decide clinical management before treatment starts.

並列關鍵字

Graves’ disease ； thyroglobulin gene ； Single nucleotide polymorphism

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