中國人慢性C型肝炎病人其人類白血球組織抗原-DQA1, -DQB1 等位基因多型性分析之相關性研究

Study of the polymorphism of human leukocyte antigen –DQA1, –DQB1 alleles in Chinese patients with chronic hepatitis C

馮貞芬(Chen-Fen Feng)

指導教授 ： 陳百薰

高雄醫學大學/醫學院/醫學研究所/碩士(2006年)

https://doi.org/10.6832/KMU.2006.00002

摘要

背景與目的：
C型肝炎病毒(Hepatitis C virus)感染是造成非A非B型肝炎之主因。感染急性C型肝炎病人大部分會演變成慢性C型肝炎，其中部分在感染20-30年後會演變成肝硬化，甚至肝細胞癌。在台灣南部地區存在有數個C型肝炎高盛行區，未來的數年內，C型肝炎在南台灣的肝臟疾病中，將會佔極重要的角色。近年來有許多研究C型肝炎病毒之感染自然病程與宿主免疫功能之關係。容易罹患此疾病之個體，在人類第六對染色體之主要組織相容性複合體(major histocompatibility complex, MHC)上有特異性的基因型存在。其中又以HLA第二級分子，DP、DQ及DR特別重要。本研究之目的是希望對高雄醫學大學附設中和紀念醫院經診斷為慢性C型肝炎患者進行HLA-DQAl及DQBl之基因型分析，及探討此症與性別、甲型干擾素治療是否有特殊HLA-DQ分佈情況，以期能得到是否有專屬於台灣地區慢性C型肝炎患者之感受性基因及保護性基因。

材料與方法：本研究共收集90位被診斷為慢性C型肝炎感染患者(男性患者為41位，女性患者為49位；平均年齡為52.4±13.2歲，年齡範圍從24~80歲)及157位健康個體，分別作為本實驗之研究組及對照組，且研究之對象均為居住在南台灣的中國人。我們應用 Olerup等提出與過去此症相關研究不少採用之聚合酶連鎖合成反應合併序列特異性引子(PCR-SSP)分析的方法，對所收集的檢體進行HLA-DQAl及HLA-DQBl基因型分類。

結果：感受性對偶基因DQAl*0101在研究組中的比率比對照組高(pc<0.001)。保護性對偶基因分別為DQAl*0103及DQBl*0303 (pc<0.001，pc<0.001)。我們亦發現在性別上，DQAl及DQBl之頻率在男性及女性患者間並無有意義之差異。而針對在甲型干擾素治療上，有效及失敗之慢性C型肝炎患者其DQAl及DQBl之頻率並無有意義之差異。

結論：針對國人慢性C型肝炎感染患者的研究結果中，顯示此疾病的感受性及保護性和特定的對偶基因具有關聯性。在本研究中性別在HLA-DQ和慢性C型肝炎感染之間無關聯性。另DQAl及DQBl等位基因多形性分析也和甲型干擾素治療療效無關聯。

關鍵字

C型肝炎 ； 感受性基因 ； 保護性基因 ； 人類白血球抗原 ； 基因多型性 ； 甲型干擾素 ； 聚合酶連鎖合成反應合併序列特異性引子 ； 連鎖不平衡反應

並列摘要

Background and Aim : The main cause of non-A non-B hepatitis is hepatitis C virus （HCV）infection. Most acute hepatitis C infection will lead to chroni several studies of hepatitis C with natural history and the relation of host immunity. HCV is associated with particular HLA types, suggesting a role for HLA genes in disease susceptibility. Of the three classes of HLA genes that affect immune function in this complex, the class II DP, DQ and DR seem to be especially important. The purpose of our study is to investigate HLA-DQA1 and HLA-DQB1 genotypes frequency among chronic HCV patients in Taiwan and also investigate the influence of gender, the response to IFN-α therapy on the association of HLA-DQ an c hepatitis C status. Cirrhosis, even hepatocellular carcinoma, will develop 20-30 years after chronic hepatitis C infection. There are several hyperendemic areas in southern Taiwan. Hepatitis C infection will become the major causes of chronic liver disease in the nearly future. Recently there are d HCV susceptibility.

Materials and Methods: We investigated 90 patients with chronic HCV infection (male：female= 41：49, mean age= 52.4 ± 13.2 years, age from 24 to 80 years) and 157 healthy control subjects among Chinese living in southern Taiwan using PCR amplification with sequence-specific primers (PCR-SSP) methods. This method is an accurate and rapid technique for detecting genetic variability with a high degree of resolution.

Result: Our study revealed that the frequencies of DQAl*0101 alleles were significantly increased in HCV group than that in the controls (pc<0.001). The protective alleles were DQA1*0103 and DQB1*0303 (pc<0.001, pc<0.001, respectively). There was no significant difference of DQA1, DQB1 frequencies between male and female patients. HLA-DQA1 and DQB1 polymorphism were not related to chronic hepatitis C infection with the response to IFN-α therapy.

Conclusion: our result indicated that genetic susceptibility and resistance to chronic HCV were associated with particular HLA-DQ alleles in Taiwan Chinese. Additionally, gender could not influence the association of HLA-DQ with chronic HCV. Besides, HLA-DQA1 and DQB1 polymorphism was not be related to chronic hepatitis C infection with the response to IFN-α therapy.

並列關鍵字

Hepatitis C ； genetic susceptibility ； protective alleles ； human leukocyte antigen ； IFN-α ； PCR-SSP ； linkage disequilibrium

參考文獻

1. Choo QL, Kuo G, Weiner AJ, Overby LR and et al. Isolation of a cDNA clone derived from a blood borne non-A, non-B viral hepatitis genome. Science 1989; 244: 359-362.

2. Kuo G, Choo QL, Alter HJ, Gitnick GL and et al. An assay for circulating antibodies to a major etiologic virus of human non-A, non-B hepatitis. Science 1989; 244: 362-364.

3. Bradley DW, McCaustland KA, Cook EH, Schable CA and et al. Posttransfusion non-A, non-B hepatisis in chimpanzees. Physicochemical evidence that the tubule-forming agent is a small, enveloped virus. Gastroenterology 1985; 88: 773-779.

4. Kaito M, Watanabe S, Tsukiyama-Kohara K, Yamaguchi K and et al. Hepatitis C virus particle detected by immunoelectron microscopic study. J Gen Virol. 1994;75:1755-1760.

5. Reed KE, Rice CM. Overview of hepatitis C virus genome structure, polyprotein processing, and protein properties. Curr Top Microbiol Immunol. 2000;242:55-84.