Ⅰ型干扰素受体启动子多态性与慢性乙型肝炎易感性的相关性研究  

Genetic variations of type Ⅰ interferon receptor 1 promoter and their association with chronic hepatitis B virus infection

作　　者：周婕[1] 吕力为[2] 张斌[3] 王松[3] 陈煜[4] 潘国文[1] 姜世勃 郑伯建[1] 

机构地区：[1]香港大学微生物系 [2]香港大学病理系 [3]深圳市东湖医院 [4]北京市佑安医院 [5]美国纽约血液中心Lindsley F.Kimball研究所

出　　处：《微生物与感染》2007年第1期19-25,共7页Journal of Microbes and Infections

摘　　要：目的研究Ⅰ型干扰素受体启动子(IFNAR1)的基因多态性在不同个体间的差异,以及它们与慢性乙型肝炎病毒(HBV)感染之间的相关性。方法对320例慢性乙型肝炎患者、148例自发康复者、148例健康对照和114例正常高加索人的IFNAR1进行基因分型,分析基因的多态性与慢性HBV感染的易感性之间的相关性;构建IFNAR1启动子-荧光素酶报告基因载体,比较不同IFNAR1启动子变异体的转录活性。结果在-568,-408,-77和-3位点发现基因多态性,其中-568和-77位点,以及-408和-3位点之间存在等位基因连锁。相关性分析结果表明,-568G、-408C和单体型-568G/-408C/-3C/-77(M)与病毒清除有关,-568C、-408T和单体型-568C/-408T/-3T/-77(L)与HBV感染的慢性化有关。启动子-荧光素酶报告基因载体的检测显示,-408和(或)-3位点的多态性可影响调节IFNAR1启动子的转录水平,而-568位点的多态性总体上对转录活性无明显的影响。-77(9)在高加索人中明显多见,携带这一基因型启动子的转录活性明显高于其他基因型启动子的转录活性。结论IFNAR1的基因多态性与慢性HBV感染的易感性有相关性。Objective Exposure to the hepatitis B virus （HBV） follows a distinct clinical course that is related to host genetic variability. The antiviral effect of type Ⅰ interferons on HBV, which is elicited by binding of these cytokines to their receptor, has been demonstrated both in vitro and in animal modds. In the current study, we aimed to determine a relationship between type Ⅰ interferon receptor Ⅰ promoter polymorphisms and individual differences in susceptibility to chronic HBV infection. Methods We examined type Ⅰ interferon receptor Ⅰ promoter polymorphisnrs in four groups of participants：320 chronic hepatitis B patients, 148 spontaneously recovered individuals, 148 healthy, Chinese donors and 114 healthy, Caucasiml donors. Results Four polymorphic sites were identified at loci - 568, - 408, - 77 and - 3. Polymorphisms at - 568 and - 77, as well as - 408 and - 3 were in complete linkage. Association analysis revealed that alleles - 568G, - 408C and haplotype - 568G/- 408C/- 3C/- 77 contained more GT repeats and were resistant to chronic HBV infection, whereas alleles - 568C, - 408T and heplotype - 568C/- 408T/- 3T/- 77 contained fewer GT repeats and were associated with chronic hepatitis B infection. We then constructed a promoter reporter gene system and performed a lucifemse assay to validate these genetic associations. It was indicated that a single - 408 and/or - 3 nucleotide polymorphism did, in fact, confer altered transcriptional activity, where as a - 568G/C polymorphism did not significantly modulate transcriptional levels. Interestingly, we observed that an allele with 9 GT repeats, which is much more prevalent in Caucasians than Chinese, appeared to exhibit a higher transcriptional level than all other promoter variants. Conclusion It is suggested that type Ⅰ interferon receptor Ⅰ promoter polymorphisms contribute to variable outcomes of HBV infection.

关 键 词：单核苷酸多态性 病毒清除 慢性乙型肝炎病毒感染 转录活性 

分 类 号：R512.62[医药卫生—内科学]