生物通报道：来自中山大学附属第三医院的高志良教授主要从事对病毒性肝炎、寄生虫病等传染病的诊断与治疗，去年其研究组在国际著名肝脏疾病杂志Hepatology上（最新影响因子11.665），发表了自体骨髓间充质干细胞（MSCs）移植治疗晚期肝病的新进展，今年又再次取得了外显子组学慢性乙肝研究的最新成果，相关成果公布在Hepatology上。

这项研究由中山大学附属第三医院感染科与中山医学院医学遗传学教研室合作完成，高志良教授和王一鸣教授为通讯作者，附属第三医院感染科彭亮副主任医师为第一作者之一，这项研究成果是目前国内外研究“慢性乙型肝炎”的遗传学机制的高层次论著。

全世界有3.5亿人慢性感染乙肝病毒，患上慢性乙肝（CHB），在我国感染人群约9300万，乙肝慢性引起急、慢性病毒性肝炎，与肝纤维化、肝癌的发生发展密切相关，严重威胁人类的健康。病毒感染人体后，病毒与宿主之间的相互作用决定感染的结局和疾病转归。然而，迄今为止，慢性乙肝的遗传背景与易感性关系还并不清楚。

从2008年至今的4年时间，这一研究组对3000余例乙肝患者及对照组人群进行“慢性乙肝”的遗传背景与易感性关系的研究，发现了数种可能与乙肝感染相关的基因。

这项研究将“外显子组学”的理念与方法引入慢性乙肝的研究领域，对“慢性乙肝”的易感性差异做出了人群遗传学背景上的初步分析，得到了初步结论，并为“乙肝病毒与肝脏细胞的结合、感染过程”、“乙肝发病机制”的研究开辟了新的道路。

去年高志良教授研究组在Hepatology上介绍了关于自体骨髓间充质干细胞（MSCs）移植治疗晚期肝病的研究进展，他们发现：相对于对照组而言，自体MSCs移植治疗乙肝肝衰竭疗效的显著改善最长可以达到术后第36周；且对于存在肝硬化的患者而言，能够相对降低发生肝脏肿瘤的危险及死亡率。

研究项目开展自2005年，研究人员经过系统的基础研究、并获得广东省卫生厅批准及医院伦理委员会审批通过后，就开始了“自体骨髓间充质干细胞移植治疗晚期肝病”治疗项目的研究，并获得了重要进展，研究组还进一步开展干细胞的基础机制研究与临床应用，希望能开辟肝病治疗的新途径。

（生物通：万纹）

原文摘要：

Rare inborn errors associated with chronic hepatitis B virus infection

Chronic hepatitis B (CHB) is a major global health issue. The role of rare genetic variants in CHB has not been elucidated. We aimed to identify rare allelic variants predisposing to CHB. We performed exome sequencing in 50 CHB patients who had no identifiable risk factors to CHB and 40 controls who were healthy and hepatitis B surface antibody positive, but had never received hepatitis B vaccination. We selected six rare variant alleles and followed up their association with disease status by Sanger sequencing in a case-control study comprising 1728 CHB patients and 1636 healthy controls. The latter had either not been immunized with hepatitis B vaccine or had uncertain vaccination status. Our results showed that transmembrane protein 2 p.Ser1254Asn, interferon alpha 2 p.Ala120Thr, its regulator NLR family member X1 p.Arg707Cys and complement component 2 p.Glu318Asp were associated with CHB, with P values of <1.0×10-7, 2.76×10-5, 5.08×10-5 , 2.78×10-4 and ORs of 2.45 , 4.08, 2.34 and 1.97 respectively. The combined P value was <2.0×10-16. As there has been no indication of immunological functions for the associated gene, transmembrane protein 2, we further studied its expression by immunohistochemistry, real time PCR and western blotting. Our results showed that it was strongly expressed by healthy hepatocytes, but its expression was reduced in liver tissues with CHB, hepatitis B viral (HBV) genome-containing HepG2.2.15 cells, as compared with healthy liver tissues and non-HBV genome-containing HepG2 cells (P= 0.022 and 0.0036 respectively).
Conclusion:
We have identified four missense mutations associated with CHB, our results providing evidence for rare inborn genetic defects that contribute to increased host susceptibility to CHB. (HEPATOLOGY 2012.)

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