从测序到肝病治疗 Nature及其子刊获得新进展

　　

生物通报道：基因组测序技术的发展促进了个性化医疗的发展，近期来自英国的两个研究小组，一个从全基因组相关性研究中，找到了与肝功能有关的基因，一个通过改变肝病患者基因，修正了该突变基因，在肝脏遗传疾病个性化治疗道路上迈进了一大步。这两项研究成果无疑是基础医学到临床转化医学的新范例。

来自英国帝国理工学院的研究人员比对了6万多人的基因组，从中找到了42个与肝功能有关的区域，其中32个区域是首次发现。除此之外，研究人员在这些区域还找了69个与肝功能有关的基因。

研究人员发现这些基因中部分基因与机体其它功能有关，比如炎症与免疫，以及葡萄糖和其它糖类物质的代谢。

这项迄今为止最大规模的肝功能研究成果将有助于更加深入地理解肝脏功能异常的机制，也将从根本上有助于研发肝病新治疗方法。

同时来自英国剑桥大学，Sanger研究院的研究人员则完成了一个肝病患者干细胞中基因变异的首次精确修正，这项研究不仅可以帮助科学家们深入了解该变异基因，而且这一新系统也许在未来能用于个性化医疗。

这一突变基因就是α1-抗胰蛋白酶变异基因，α1-抗胰蛋白酶是在肝脏内非常活跃的一个基因，负责制造一种能抵抗过多炎症的蛋白。如果α1-抗胰蛋白酶发生变异，会让人罹患肝硬化和肺气肿，这是肝脏和肺最常见的遗传紊乱。

在这篇文章中，研究人员分别采用了iPS技术，和直接提取干细胞技术进行修正实验——之前他们曾成功的获得来源于皮肤细胞的iPS细胞，并分化成肝细胞。这项研究则首先利用转座子修订了突变基因，然后让iPS细胞分化成肝细胞，结果获得了正确序列的α1-抗胰蛋白酶基因。这一成果已经在小鼠实验，和人类病患实验中得到证实。

这些从基础医学到临床转化医学的系列成果，不仅对于本系统疾病的治疗具有重要意义，而且对转化医学的发展也具有了积极意义。

（生物通：万纹）

原文摘要：

Targeted gene correction of α1-antitrypsin deficiency in induced pluripotent stem cells

Human induced pluripotent stem cells (iPSCs) represent a unique opportunity for regenerative medicine because they offer the prospect of generating unlimited quantities of cells for autologous transplantation, with potential application in treatments for a broad range of disorders. However, the use of human iPSCs in the context of genetically inherited human disease will require the correction of disease-causing mutations in a manner that is fully compatible with clinical applications. The methods currently available, such as homologous recombination, lack the necessary efficiency and also leave residual sequences in the targeted genome. Therefore, the development of new approaches to edit the mammalian genome is a prerequisite to delivering the clinical promise of human iPSCs. Here we show that a combination of zinc finger nucleases (ZFNs)7 and piggyBac technology in human iPSCs can achieve biallelic correction of a point mutation (Glu342Lys) in the α1-antitrypsin (A1AT, also known as SERPINA1) gene that is responsible for α1-antitrypsin deficiency. Genetic correction of human iPSCs restored the structure and function of A1AT in subsequently derived liver cells in vitro and in vivo. This approach is significantly more efficient than any other gene-targeting technology that is currently available and crucially prevents contamination of the host genome with residual non-human sequences. Our results provide the first proof of principle, to our knowledge, for the potential of combining human iPSCs with genetic correction to generate clinically relevant cells for autologous cell-based therapies.

Genome-wide association study identifies loci influencing concentrations of liver enzymes in plasma

Concentrations of liver enzymes in plasma are widely used as indicators of liver disease. We carried out a genome-wide association study in 61,089 individuals, identifying 42 loci associated with concentrations of liver enzymes in plasma, of which 32 are new associations (P = 10 8 to P = 10 190). We used functional genomic approaches including metabonomic profiling and gene expression analyses to identify probable candidate genes at these regions. We identified 69 candidate genes, including genes involved in biliary transport (ATP8B1 and ABCB11), glucose, carbohydrate and lipid metabolism (FADS1, FADS2, GCKR, JMJD1C, HNF1A, MLXIPL, PNPLA3, PPP1R3B, SLC2A2 and TRIB1), glycoprotein biosynthesis and cell surface glycobiology (ABO, ASGR1, FUT2, GPLD1 and ST3GAL4), inflammation and immunity (CD276, CDH6, GCKR, HNF1A, HPR, ITGA1, RORA and STAT4) and glutathione metabolism (GSTT1, GSTT2 and GGT), as well as several genes of uncertain or unknown function (including ABHD12, EFHD1, EFNA1, EPHA2, MICAL3 and ZNF827). Our results provide new insight into genetic mechanisms and pathways influencing markers of liver function.