Systems genetics of hepatocellular damage in vivo and in vitro: identification of a critical network on chromosome 11 in mouse.
Systems genetics of hepatocellular damage in vivo and in vitro: identification of a critical network on chromosome 11 in mouse.
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体内和体外肝细胞损伤的系统遗传学：小鼠 11 号染色体上关键网络的鉴定
DOI：
10.1152/physiolgenomics.00078.2013
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发表时间：
2013
影响因子：
4.6
通讯作者：
Lammert F
中科院分区：
文献类型：
--
作者：
Liebe R;Hall RA;Williams RW;Dooley S;Lammert F
数量性状基因座(QTL)定位是一种有效的方法，可以在不了解潜在遗传机制的情况下找到影响疾病风险和进展的修饰基因。这项研究的目的是确定导致慢性肝损伤后肝纤维化的个体差异的基因座。为此，我们利用转化生长因子-β攻击原代肝细胞48小时，对21个BXD重组近交系进行了定位研究，我们确定了11号染色体上一个6Mb的区间，它是转化生长因子-β引起肝细胞损伤的主要修饰者。相应的四氯化碳(CCl4ip，6wk)慢性肝毒性损伤后纤维化的体内遗传学分析突出了相同的基因座。BXD家系肝组织表达QTL(EQTL)分析发现，该区域存在6个与强顺式eQTL相关的多态，且与CCl4处理6wk和急性乙醇损伤后肝脏的基因表达密切相关。在这个区间内，我们将两个包含编码序列变体的基因列为可能调节肝纤维化严重程度的强有力的候选基因：1)细胞外蛋白酶抑制基因Expi(也称为Wdnm1或Wfdc18)和2)武藏RNA结合蛋白2(MSI2)。实验、遗传学和生物信息学方法的强大结合，以及体外和体内方法的结合，可以用来确定与肝毒性和纤维化相关的QTL、基因，甚至候选序列变异。
Quantitative trait locus (QTL) mapping is a powerful method to find modifier loci that influence disease risk and progression without prior knowledge of underlying genetic mechanisms. The aim of this study is to identify gene loci that contribute to individual differences in liver fibrosis following chronic liver damage. For this purpose, we carried out a mapping study across a panel of 21 BXD recombinant inbred strains using primary hepatocytes challenged with transforming growth factor (TGF)-β for 48 h. We identified a 6 Mb interval on chromosome 11 that is a major modifier of TGF-β-induced hepatocyte injury. Corresponding in vivo genetic analysis of fibrosis after chronic hepatotoxic injury by carbon tetrachloride (CCl4ip for 6 wk) highlighted the same locus. Expression QTL (eQTL) analysis in liver tissues in the BXD family identified six polymorphisms in this region that are associated with strong cis eQTLs and that correlate well with gene expression in liver after both 6 wk CCl4treatment and acute ethanol damage of the liver. Within this interval we rank two genes containing coding sequence variants as strong candidates that may modulate the severity of liver fibrosis:1) the extracellular proteinase inhibitor geneExpi(also known asWdnm1orWfdc18) and2) musashi RNA-binding protein 2 (Msi2). The powerful combination of experimental, genetics, and bioinformatics methods, as well as combined in vitro and in vivo approaches can be used to define QTLs, genes, and even candidate sequence variants linked to hepatotoxicity and fibrosis.
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酒精性肝病临床进展的当前实验观点。
DOI：
10.1111/j.1530-0277.2009.01015.x
发表时间：
2009-10
期刊：
Alcoholism, clinical and experimental research
影响因子：
--
作者：
Breitkopf K;Nagy LE;Beier JI;Mueller S;Weng H;Dooley S
通讯作者：
Dooley S
影响因子：
2.9
作者：
JAMALL, IS;FINELLI, VN;HEE, SSQ
通讯作者：
HEE, SSQ
影响因子：
11.2
作者：
T. Reichling;K. Goss;D. Carson;R. Holdcraft;Cathy Ley-Ebert;D. Witte;B. Aronow;J. Groden
通讯作者：
T. Reichling;K. Goss;D. Carson;R. Holdcraft;Cathy Ley-Ebert;D. Witte;B. Aronow;J. Groden
标记位点与影响数量性状的位点之间的联系
影响因子：
2.6
作者：
A. Robertson
通讯作者：
A. Robertson
影响因子：
3
作者：
Chesler, EJ;Wang, JT;Williams, RW
通讯作者：
Williams, RW