Genome-wide analysis of hepatic fibrosis in inbred mice identifies the susceptibility locus Hfib1 on chromosome 15
Genome-wide analysis of hepatic fibrosis in inbred mice identifies the susceptibility locus Hfib1 on chromosome 15
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DOI：
10.1053/gast.2002.37069
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发表时间：
2002-12-01
期刊：
影响因子：
29.4
通讯作者：
Lammert, F
中科院分区：
文献类型：
--
作者：
Hillebrandt, S;Goos, C;Lammert, F
背景与目的：宿主遗传因素可能导致慢性肝损伤后肝纤维化的变化过程。同样，在CCI4攻击后，不同近交系小鼠的纤维化反应也不同。我们的目的是在纤维化易感和耐药的近交系小鼠杂交中确定未知的肝纤维化易感位点。方法：用CCI4处理7株近交系小鼠，通过组织学、肝脏羟脯氨酸水平和血清替代标志物观察肝纤维化的表型特征。将敏感的BALE/cJ与抗性的A/J杂种F-1进行杂交，得到358个F-2后代。通过全基因组区间作图和单倍型分析确定了决定肝纤维化的数量性状位点（QTL）。结果：在该模型中，纤维化易感性存在明显的品系差异，以BALB/c近交系小鼠最为易感。F-1小鼠的羟脯氨酸水平与抗性亲本菌株相似，表明纤维化易感性是一种隐性性状。QTL分析确定了15号染色体上一个显著影响纤维化分期和羟脯氨酸水平的易感位点。根据标准命名法，这个位点被称为Hfib1（肝纤维化基因1）。Hfib(1)由遗传标记D15Mit26和D15Mit122定义：2号染色体上的一个暗暗性QTL与补体因子5基因共定位，已知在抗性菌株A中发生突变。结论：这组近交系为系统分析纤维化基因提供了框架。QTL定位有助于确定肝纤维化的遗传易感性位点，可能为抗纤维化药物设计提供新的分子靶点。
Background & Aims: Host genetic factors are likely to contribute to the variable course of hepatic fibrosis in response to chronic liver injury. Similarly, the fibrotic response differs among inbred mouse strains after challenge with CCI4. Our aim was to identify unknown susceptibility loci for hepatic fibrosis in a cross between fibrosis-susceptible and -resistant inbred mice. Methods: Seven inbred mouse strains were treated with CCI4, and hepatic fibrosis was phenotypically characterized by histology, hepatic hydroxyproline levels, and serum surrogate markers. F-1 hybrids of susceptible BALE/cJ and resistant A/J inbred strains were intercrossed to obtain 358 F-2 progeny. Quantitative trait loci (QTL) that determine hepatic fibrosis were identified by genome-wide interval mapping and haplotype analysis. Results: In this model, marked strain differences in fibrosis susceptibility exist, with BALB/c inbred mice being most susceptible. The hydroxyproline levels of F-1 mice resemble the resistant parental strains, indicating that fibrosis susceptibility is a recessive trait. QTL analysis identifies a susceptibility locus on chromosome 15 that significantly affects the stage of fibrosis and hydroxyproline levels. According to standard nomenclature, this locus is called Hfib1 (hepatic fibrogenic gene 1). Hfib(1) is defined by genetic markers D15Mit26 and D15Mit122: A suggestive QTL on chromosome 2 colocalizes with the complement factor 5 gene, known to be mutated in the resistant strain A. Conclusions: The set of inbred strains provides a framework for systematic analysis of fibrogenic genes. QTL mapping is useful to identify genetic susceptibility loci for hepatic fibrosis that might harbor new molecular targets for antifibrotic drug design.