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研究生:林聖凱
研究生(外文):Sheng-kai Lin
論文名稱:Anti-HBs陰性之高中生IGF2、IGFBP3及SRD5A2基因多形性與追加B型肝炎疫苗反應性之相關研究
論文名稱(外文):An association study on the genetic polymorphisms in IGF2, IGFBP3 and SRD5A2 and responsiveness to booster hepatitis B vaccination in residual anti-HBs-seronegative senior high school students
指導教授:王豊裕
指導教授(外文):Li-yu Wang
學位類別:碩士
校院名稱:慈濟大學
系所名稱:原住民健康研究所
學門:醫藥衛生學門
學類:公共衛生學類
論文種類:學術論文
論文出版年:2006
畢業學年度:94
語文別:中文
論文頁數:83
中文關鍵詞:IGF2IGFBP3B型肝炎疫苗種族性荷爾蒙基因多形性SRD5A2
外文關鍵詞:polymorphismSRD5A2IGFBP3IGF2hepatitis B vaccineethnicsex hormone
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全國性的B型肝炎注射疫苗計畫在台灣實施之後,有效地降低學童的帶原率及肝癌發生率,但約有5-10 %的孩童對B型肝炎疫苗為不反應性或低反應性。一些研究顯示,B型肝炎疫苗的效果有性別與種族的變異性:男性為不反應性的比率高於女性;B型肝炎疫苗對原住民族群的保護效力低於一般族群。因此本研究以92-94學年度,就讀於花蓮縣內高中職學校、出生於實施全國性B型肝炎疫苗注射計畫之後、入學健康檢查HBsAg 及anti-HBs皆為陰性、且有補接種一劑B型肝炎疫苗的男性新生為研究對象。依其對補接種B型肝炎疫苗的反應性區分為不反應性組與慢反應性組,分別從原住民族群與漢人族群,依不反應性組與慢反應性組比為1:2,隨機選取196人為研究樣本。本研究並以PCR-RFLP (polymerase chain reaction - restriction fragment length polymorphism)法,進行IGF2 G820A、IGFBP3 A-202C及SRD5A2 V89L之基因定性,且檢測研究對象補接種B型肝炎疫苗前之血漿睪固酮(testosterone)、性荷爾蒙結合球蛋白(SHBG)與膽固醇(cholesterol)濃度。本研究結果顯示在帶有低5a-還原酶活性的SRD5A2 L對偶基因的受試對象中,高睪固酮濃度及高TC比值(睪固酮/膽固醇)者,皆有顯著較高的疫苗不反應性風險;且不論在不同種族或基因分層下,較高的SHBG/睪固酮比值,均有較低的疫苗不反應性風險。
本研究結果顯示,性荷爾蒙會影響個體對於補接種B型肝炎疫苗之反應性。尤其是帶有低5a-還原酶活性的SRD5A2 L對偶基因者,會因體內有較高濃度的睪固酮,而有較高的疫苗不反應性風險。此外,本研究的結果也顯示,ST比值可作為預測B型肝炎疫苗不反應性的指標。
In Taiwan, the implement of universal hepatitis B (HB) vaccination program (UHBVP) had successfully reduced the rates of HBsAg-seropositivity and hepatocellular carcinoma incidence in children. However, approximately 5-10% of vaccinated-children were low- or non-response to hepatitis B vaccine. Several researches had shown that there were gender and ethnic variations in the response to hepatitis B vaccine. The non-response rate was higher in male children than in female children and the efficacy of HB vaccination was lower in indigenous children than in Hans children. Accordingly, the specific aim of the present study was to investigate the effects of sex hormones and genetic polymorphisms of several important genes that are involved in development and metabolism of sex hormone in male indigenous and Hans adolescents. The inclusion criteria included male students who entered senior high schools during Sep 2003 to Sep 2005, born after the start of HBUVP, had both HBsAg and anti-HBs seronegativities, and received a booster dose of 20 ug of HB vaccine. Based on their responses and ethnicity, eligible subjects were divided into four groups, which were low-response indigenes, non-response indigenes, low-response Hans, and non-response Hans. There were 32 non-response indigenes and 32 non-response Hans. Two folds of the number of non-responders were randomly selected from low-response indigenes and Hans separately. We used polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) to determine the IGF2 G820A, IGFBP3 A-202C and SRD5A2 V89L genetic polymorphisms. Concentrations of testosterone, sex hormone-binding globulin (SHBG) and cholesterol in plasma were also detected for each subject. We found that in those subjects carrying SRD5A2 L allele, higher testosterone concentration and higher testosterone-to-cholesterol (TC) ratio were both significantly associated with higher risk of non-response to HB vaccine. Higher SHBG-to-testosterone (ST) ratio was consistently associated with lower risk of non-response to HB vaccine in different ethnic and genetic strata.
In conclusion, our results indicate that sex hormones maybe influence the immune response to booster HB vaccination, especially in subjects who carry the SRD5A2 L allele. Our results also suggest that the ST ratio is a good predictor of the responsiveness to HB vaccine.
致謝------------------------------------------------------- I
中文摘要--------------------------------------------------- II
英文摘要--------------------------------------------------- III
目錄------------------------------------------------------- IV
圖目錄----------------------------------------------------- VI
表目錄----------------------------------------------------- VII
第一章 前言------------------------------------------------ 1
第二章 文獻探討-------------------------------------------- 2
第一節 B型肝炎病毒----------------------------------------- 2
2.1.1 B型肝炎病毒的發現---------------------------------- 2
2.1.2 B型肝炎病毒的結構---------------------------------- 2
2.1.3 B型肝炎病毒基因------------------------------------ 2
2.1.4 B型肝炎病毒進入人體與複製-------------------------- 3
2.1.5 B型肝炎病毒的傳染途徑------------------------------ 4
2.1.6 B型肝炎病毒引發的免疫反應-------------------------- 4
第二節 B型肝炎與肝細胞癌的流行病學研究--------------------- 6
2.2.1 B型肝炎表面抗原陽性率肝癌的流行病學---------------- 6
2.2.2 感染B型肝炎病毒、肝細胞癌發生率與死亡率的性別差異-- 6
2.2.3 感染B型肝炎病毒的種族差異-------------------------- 7
第三節 B型肝炎疫苗----------------------------------------- 7
第四節 全國性B型肝炎疫苗注射計畫--------------------------- 8
第五節 台灣B型肝炎疫苗的防治成效與性別差異----------------- 10
第六節 對全國性B型肝炎疫苗注射計畫的挑戰與種族差異--------- 12
第七節 荷爾蒙---------------------------------------------- 12
第八節 雄性荷爾蒙的作用與SRD5A2基因------------------------ 14
2.8.1 睪固酮與DHT的作用機制------------------------------ 14
2.8.2 SRD5A2基因多形性----------------------------------- 15
第九節 類胰島素生長因子與類胰島素結合蛋白------------------ 16
第十節 IGF2及IGFBP3基因多形性------------------------------ 16
第三章 材料與方法------------------------------------------ 19
第一節 研究對象與疫苗反應性分組---------------------------- 19
第二節 實驗室分析------------------------------------------ 20
3.2.1 血液的處理與檢驗項目------------------------------- 20
3.2.2 分析基因多形性------------------------------------- 22
第三節 統計分析-------------------------------------------- 25
第四章 結果------------------------------------------------ 26
第一節 不同族群之基本資料---------------------------------- 26
第二節 不同疫苗反應性之基本資料與迴歸分析------------------ 27
第三節 不同族群之迴歸分析---------------------------------- 28
第四節 分層分析-依不同基因型者之迴歸分析------------------- 30
4.4.1 帶有IGF2 AA或AG基因型者---------------------------- 30
4.4.2 帶有IGF2 GG基因型者-------------------------------- 30
4.4.3 帶有IGFBP3 AC或CC基因型者-------------------------- 30
4.4.4 帶有IGFBP3 AA基因型者------------------------------ 31
4.4.5 帶有SRD5A2 VL或LL基因型者-------------------------- 31
4.4.6 帶有SRD5A2 VV基因型者------------------------------ 32
第五節 統整迴歸分析結果與多因子對數迴歸分析---------------- 33
第六節 不同基因多形性之荷爾蒙濃度-------------------------- 33
第七節 荷爾蒙變項之淨相關---------------------------------- 34
第五章 討論------------------------------------------------ 35
參考文獻--------------------------------------------------- 39
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