The genetics of complex cholestatic disorders.
The genetics of complex cholestatic disorders.
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DOI：
10.1053/j.gastro.2013.03.053
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发表时间：
2013-06
期刊：
影响因子：
29.4
通讯作者：
Mason AL
中科院分区：
文献类型：
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作者：
Hirschfield GM;Chapman RW;Karlsen TH;Lammert F;Lazaridis KN;Mason AL
胆汁淤积性肝病是由一系列肝胆损伤引起的，涉及环境和遗传因素之间复杂的相互作用。关于特定胆汁淤积性疾病的致病机制知之甚少，这限制了我们管理这些疾病患者的能力。然而，最近的全基因组研究提供了深入了解胆结石，原发性胆汁性肝硬化，原发性硬化性胆管炎的发病机制。编码肝胆转运蛋白ABCG 8的基因中的致石性变体已被鉴定为胆石病的危险因素;该变体与胆固醇排泄和代谢的改变相关。编码影响胆汁组成的转运蛋白的基因的其他变体与胆汁淤积相关，即编码胆盐输出泵的ABCB 11和编码肝管磷脂酰胆碱翻转酶的ABCB 4。许多与胆结石相关的基因也与胆管消失综合征和其他胆汁淤积性疾病有关。相比之下，研究已经将原发性胆汁性肝硬化和原发性硬化性胆管炎与编码主要组织相容性复合体蛋白的基因相关联，并鉴定了与该区域外的微生物传感和免疫调节途径相关的基因座，例如编码IL 12、STAT 4、IRF 5、IL 2及其受体（IL 2 R）、CD 28和CD 80的基因。这些发现引起了人们对开发靶向这些基因产物的试剂的兴趣。我们回顾了胆汁淤积性肝病患者遗传研究的最新发现。未来在动物模型中对遗传变异的表征、根据临床病程对风险等位基因的分层以及相互作用的环境因素的鉴定将增加我们对这些复杂的胆汁淤积性疾病的理解。
Cholestatic liver diseases are caused by a range of hepatobiliary insults and involve complex interactions among environmental and genetic factors. Little is known about the pathogenic mechanisms of specific cholestatic diseases, which has limited our ability to manage patients with these disorders. However, recent genome-wide studies have provided insight into the pathogenesis of gallstones, primary biliary cirrhosis, and primary sclerosing cholangitis. A lithogenic variant in the gene that encodes the hepatobiliary transporter ABCG8 has been identified as a risk factor for gallstone disease; this variant has been associated with altered cholesterol excretion and metabolism. Other variants of genes encoding transporters that affect the composition of bile have been associated with cholestasis, namely ABCB11, which encodes the bile salt export pump, and ABCB4, which encodes hepatocanalicular phosphatidylcholine floppase. Many genes associated with gallstones have also been linked with vanishing bile duct syndromes and other cholestatic disorders. In contrast, studies have associated primary biliary cirrhosis and primary sclerosing cholangitis with genes encoding major histocompatibility complex proteins and identified loci associated with microbial sensing and immune regulatory pathways outside this region, such as genes encoding IL12, STAT4, IRF5, IL2 and its receptor (IL2R), CD28, and CD80. These discoveries have raised interest in the development of reagents that target these gene products. We review recent findings from genetic studies of patients with cholestatic liver disease. Future characterization of genetic variants in animal models, stratification of risk alleles by clinical course, and identification of interacting environmental factors will increase our understanding of these complex cholestatic diseases.
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影响因子：
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作者：
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通讯作者：
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Virgin HW
影响因子：
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作者：
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