https://scholars.lib.ntu.edu.tw/handle/123456789/194452
標題: | 腸病毒整合性生物資訊計畫-功能基因體學,宿主易感基因之研究與應用─腸病毒71型宿主基因分析-找尋易感染或抗感染之基因(子計畫五) | 作者: | 張鑾英 | 關鍵字: | 腸病毒71 型;宿主因素;基因變異;敏感基因;症狀嚴重程度;EV71;host factor;genetic var iants;clinical outcome | 公開日期: | 2003 | 出版社: | 臺北市:國立臺灣大學醫學院小兒科 | 摘要: | 1998 年台灣腸病毒71 型流行造成78 位孩童先有手足口病繼而快速死於肺水腫或 肺出血。而2000 年及2001 年則分別有41 位及47 位孩童因感染腸病毒而死亡。但感染 相同腸病毒71 型後引起之症狀差異很大,從毫無症狀(約有71%) 至死亡(0.05%)。造成 腸病毒71 型嚴重程度之差異,其真正機轉仍未明。雖然我們已經作了部分腸病毒71 型之基因分析,但並未找到有關腸病毒71 型之毒性基因,而不同基因型之腸病毒71 型之嚴重度亦無差別。因此是否因宿主本身之基因差異,因而造成感染相同腸病毒71 型後症狀嚴重程度之差異是很值得探究的。故本計劃希望能找到易感染腸病毒71 型之 敏感基因及與嚴重程度相關之基因變異型。 我們將收集嚴重程度不同之腸病毒71 型個案,及其父母和兄弟姐妹及正常之小 孩當對照組(case-parental trio design, sibship design, case-control design)。粹取其DNA, 利用聚合酵素鏈反應法(PCR)、限制脢(restriction enzymes)及DNA 序列分析等,將 研究兩組基因變異型(polymorphism)及其與腸病毒71 型之感染及與嚴重程度之相關 性。因為我們發現腸病毒71 型死亡個案之發炎細胞激素(TNF-a, IL-1 b, and IL-6)明顯 升高,故第壹組基因變異型分析將包括免疫相關之基因,如TNF-a promoter, IL-1 b promoter, IL-6 promoter, CD40-ligand promoter, CTLA-4 and HLA genotyping。第貳組基 因變異型分析將包含受腸病毒71 型感染後有明顯表現不同之基因、其調控基因及腸病 毒71 型受體基因。最後將利用基因統計分析,以個案對照研究法、父母對照(TDT, transmission distortion test )及兄弟姐妹對照研究法(STDT),找出易感染腸病毒71 型之 敏感基因及與嚴重程度相關之基因變異型。 我們已收集了150 個EV71 的個案,及100 個正常孩子當對照組,這150 EV71 個 案,有38%(57/150)是輕症;44%(66/150)在中樞神經併發症,如無菌性腦膜炎、腦炎、 類小兒麻痺症候群等;有18%(27/150)在中樞神經受侵犯後發生心肺衰竭(肺水腫)。經 過治療,最後有7%(11/150)死亡,有24%(36/150)有後遺症。 經過PCR, 及限制 , 自動化基因定序等方法,我們將研究免疫調節基因之多型 性與臨床嚴重度或會不會感染EV71 作相關的研究統計。結果發現,感染EV71 的個案 其TNF-a promoter type II 的比率為26%,而正常孩童TNF-a promoter type II 的比率為 14%(P=0.045),顯示TNF-a promoter type II 可能與容不容易感染EV71 有正相關性。然 而TNF-a promoter type II 與EV71 感染後之嚴重程度及預後並無相關。另一個基因,IL-6 promoter 對容不容易感染EV71,或感染EV71 後之臨床嚴重度及預後並不影響。 未來我們將持續收集EV71 的個案,並繼續研究宿主基因與EV71 感受性的關係, 及與臨床嚴重度。 EV71 has caused large epidemics with lots of fatal cases and cases with sequelae. However, the clinical syndromes and severity of the same EV71 strain are very diverse, ranging from asymptomatic (71%) to fatal (0.05%) diseases. To date, no clear viral virulence factor has been found and there is no association between EV71 genotypes and clinical outcomes. Therefore, host factors may be important to the clinical outcomes of EV71 infections. By investigating host genetic background, we may find some genetic variants that influence susceptibility and disease severity to EV71 infection. A total of 150 EV71 cases were collected and about 100 control cases had been collected. The clinical diagnosis and outcome of the 150 EV71 cases are as the following: 38% (57/150) of the cases were uncomplicated, 44% (66/150) of our EV71 cases had central nervous system involvement, such as meningitis, myoclonic jerk, encephalitis, polio-like syndrome, etc and 18% (27/150) developed cardiopulmonary failure soon after CNS involvement. After intensive resuscitation and medical care, eleven (7%) children died and 36 (24%) children had sequelae of dysphagia, central hypoventilation, cranial nerve palsy and limb weakness/atrophy. With PCR, SNP detection with appropriate restriction enzyme and automatic gene sequencing, polymorphisms of immune-related genes are being studied and correlated with susceptibility and clinical outcomes of EV71 infection. In allelic association study for the candidate genes with case-control study, EV71 cases had higher percentage of type II TNF-a promoter polymorphism in comparison with normal control children (26% vs. 14%, p=0.045). However, there was no significant difference of IL6 promoter polymorphism between EV71 cases and normal control children. TNF-a promoter polymorphism did not correlate with clinical severity and clinical outcome. IL6 promoter polymorphism did not correlate with clinical severity and clinical outcome, either. From our preliminary results, TNF-a promoter polymorphism seem related to susceptibility of EV71 infection and whether the TNF-a promoter regulates or enhances the susceptibility of EV71 needs further investigation. Further case collection, and sequencing of other immune-related genes and the second group of candidate genes such as EV71 receptor and their regulatory genes will be done in the future. Thereafter, we will compare genetic variants among EV71 cases with different severity and normal children to find susceptible or resistant genes and genetic polymorphism related to clinical outcomes, to find the strength of disease associations with different combinations of polymorphism. |
URI: | http://ntur.lib.ntu.edu.tw//handle/246246/22889 | 其他識別: | 913112B002029 | Rights: | 國立臺灣大學醫學院小兒科 |
顯示於: | 醫學系 |
檔案 | 描述 | 大小 | 格式 | |
---|---|---|---|---|
913112B002029.pdf | 460.34 kB | Adobe PDF | 檢視/開啟 |
在 IR 系統中的文件,除了特別指名其著作權條款之外,均受到著作權保護,並且保留所有的權利。