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研究生:陳政儀
研究生(外文):Jeng-Yi Chen
論文名稱:HLA基因定型及建構資料庫以從事重症肌無力之遺傳學研究
論文名稱(外文):HLA genotyping and building a database for the genetic study of myasthenia gravis
指導教授:蔡世峰蔡世峰引用關係
指導教授(外文):Shih-Feng Tsai
學位類別:碩士
校院名稱:國立陽明大學
系所名稱:遺傳學研究所
學門:生命科學學門
學類:生物訊息學類
論文種類:學術論文
論文出版年:2004
畢業學年度:92
語文別:中文
論文頁數:110
中文關鍵詞:HLA基因定型重症肌無力資料庫單型定型HLA-DQB1
外文關鍵詞:HLA genotypingmyasthenia gravisdatabasehaplotypingHLA-DQB1
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  重症肌無力為一自體免疫疾病,主要症狀為眼肌或全身性肌肉無力。根據台大醫院的調查,在臺灣重症肌無力的盛行率大約為每十萬人口中有8例。在成因方面,已知大多數病患產生自體免疫抗體,使得運動神經元傳遞之神經訊號無法通過神經肌肉交接處(NMJ)之突觸,影響肌肉運動。眾多免疫學、遺傳學、生化學等的研究顯示出肌無力症可能有多種因子影響,如:基因突變、免疫系統功能障礙甚至感染病毒。由於眾多家族案例的研究指出重症肌無力應有受遺傳因素影響,但遺傳因子佔肌無力症成因之比重目前仍待研究。
  十七世紀已有文獻描述重症肌無力,但直到近期才有較多研究記載重症肌無力與遺傳因子的關係。目前研究影響重症肌無力之遺傳因子的研究朝向基因突變或影響免疫系統的基因。部份研究認為人類第六號染色體的短臂上有一區域與人類白血球組織抗原(HLA)有關的基因群與肌無力症有關,此區域是目前已知的功能基因中最具多態性的基因群之一。重症肌無力的臨床症狀表現出種族及性別的差異。患有重症肌無力的西方人其男女比例為2:3,但在臺灣是女性人數約為男性人數的兩倍。從發病年齡分析,在台灣的病患近七成屬於早發病。西方人眼肌型重症肌無力病患僅10%至15%,在臺灣則將近50%。患有胸腺瘤的男性病患佔全體男性病患比率較女性病患為高。約有三成的病患血液中偵測不出抗乙醯膽鹼受體抗體。分析發病年齡與臨床症狀發現晚發病的病患為廣泛型者增多。分析發病年齡與胸腺狀態發現晚發病的病患且有胸腺瘤者增多。早發病的病患有較多比率屬於血液中偵測不出抗乙醯膽鹼受體抗體。臨床症狀越嚴重者的病患患有胸腺瘤的比率明顯增加。臨床症狀越嚴重者血液中偵測出抗乙醯膽鹼受體抗體的比率明顯增加。本文使用SBT基因型定型法分析臺灣族群的重症肌無力病患其HLA基因型分布。實驗結果發現有顯著差異之HLA-DQ等位基因型與女性、有自體免疫抗體、廣泛型肌無力症及胸腺腫大者有關。而DQB1*0201更與發病年齡較大及患有胸腺瘤有關,且在病患中出現頻率減少;DQB1* 05031則與較早發病及胸腺腫大有關,且在病患中出現頻率遠高於正常人。HLA-DRB與臨床資料分析中,DRB5*01011在女性晚發病的病患中出現頻率增加。而屬於HLA class I的HLA-A及-B則沒有重要的顯著關連。
  本文運用資訊庫記錄臺灣重症肌無力病患之臨床醫療資料及HLA基因型定型資料,並且運用嵌入式程式語言開發分析比對程式,建構研究人員及醫療從業人員均能方便使用的系統。以期能更方便快速瞭解重症肌無力的致病因子。
Myasthenia gravis(MG) is a autoimmune disease, which characteristic feature is fatigue of ocular or skeletal muscle. According to the investigation of NTU hospital, the prevalence of MG (in Taiwan) is 8 cases per hundred thousand. It has been discovered that pathogenesis of MG results from the autoantibody produced by most patients themselves, which would block the signal transmitted by moto neuron, and stop it from passing through synapse in neuromuscular junction (NMJ). The autoantibody affects the motion of muscles. Some immunological, genetic, biochemical research indicates that multiple factors, including mutation, affection of immune system or even virus infection, would cause MG synergistically. With the studies of family cases, it is suggested that the transmission of MG is related to some genetic factors, but further research is required to understand the genetic component of MG.
Myasthenia gravis was first described in 17th century, but the genetic factors are not referred to in literatures until much lately. Recent studies of the genetic factors are aimed to understand the gene mutation or the genes that affect immune system. It is proposed in a number of studies that the HLA gene complex located on the chromosome 6p is a candidate regions, which is one of the highly polymorphic gene clusters ever known. Differences with regard to race and gender have been shown in clinical symptoms of myasthenia gravis. The percentage of the male and female Caucasian patients of MG is 2 : 3, however, the number of the female patients (in Taiwan) is twice the number of the male patients. By onset-age analysis, we found that almost seventy percent MG patients are early onset-age in Taiwan. Furthermore, the rate of Caucasian ocular MG patients is 10% ~ 15% of MG patients, while it rises up to 50% in Taiwan. Male MG patients with thymoma have more percentage than female patients. Almost thirty percent MG patients are SNMG. We found that the percentage of generalized MG patients with late onset-age are increased in onset-age vs. clinical stage analysis. By onset-age vs. thymus status analysis, we found that MG patients with late onset-age and thymoma are increased. MG patients with early onset-age are more SNMG. MG patients with more severe clinical stage and thymoma are increased percentage. MG patients with more severe clinical stage and not SNMG are increased percentage. In this study, the HLA genotypes of MG patients in Taiwan are analyzed with the sequence-based typing method. The HLA alleles with significant frequency differences were revealed in the results to be associated with the sex of female, sero-positive, generalized MG and hyperplasia. DQB1*0201 was also found to be closely related to late onset age and thymoma, and the allele frequency of it is decreased among the patients; DQB1*05031 was connected with early onset age and thymus hyperplasia, and the allele frequency of it is much higher than that among ordinary Chinese people. In HLA-DRB vs. clinical information analysis, the allele frequency of DRB5*01011 is increased in female MG patients with late onset-age. And we also found that HLA-A and -B of HLA class I genes have no significant association.
In this research, a database was built to record the clinical information and HLA genotypes of MG patients in Taiwan, and embedded programming language was utilized to develop a program for the analysis of HLA genotypes and clinical information as well as a helpful system for the studies of MG. It is hoped that it can be used as a faster and more convenient way for a larger scale of HLA genotyping analysis and further understanding of its causes.
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