Cellular and Molecular Gastroenterology and Hepatology ( IF 7.1 ) Pub Date : 2020-08-28 , DOI: 10.1016/j.jcmgh.2020.08.010 Iina Tuominen 1 , Brie K Fuqua 2 , Calvin Pan 2 , Nicole Renaud 3 , Kevin Wroblewski 1 , Mete Civelek 2 , Kara Clerkin 1 , Ashot Asaryan 1 , Sara G Haroutunian 1 , Joseph Loureiro 3 , Jason Borawski 3 , Guglielmo Roma 4 , Judith Knehr 4 , Walter Carbone 4 , Samuel French 5 , Brian W Parks 2 , Simon T Hui 2 , Margarete Mehrabian 2 , Clara Magyar 5 , Rita M Cantor 6 , Chinweike Ukomadu 3 , Aldons J Lusis 2 , Simon W Beaven 1
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Background & Aims
Liver fibrosis is a multifactorial trait that develops in response to chronic liver injury. Our aim was to characterize the genetic architecture of carbon tetrachloride (CCl4)-induced liver fibrosis using the Hybrid Mouse Diversity Panel, a panel of more than 100 genetically distinct mouse strains optimized for genome-wide association studies and systems genetics.
Methods
Chronic liver injury was induced by CCl4 injections twice weekly for 6 weeks. Four hundred thirty-seven mice received CCl4 and 256 received vehicle, after which animals were euthanized for liver histology and gene expression. Using automated digital image analysis, we quantified fibrosis as the collagen proportionate area of the whole section, excluding normal collagen.
Results
We discovered broad variation in fibrosis among the Hybrid Mouse Diversity Panel strains, demonstrating a significant genetic influence. Genome-wide association analyses revealed significant and suggestive loci underlying susceptibility to fibrosis, some of which overlapped with loci identified in mouse crosses and human population studies. Liver global gene expression was assessed by RNA sequencing across the strains, and candidate genes were identified using differential expression and expression quantitative trait locus analyses. Gene set enrichment analyses identified the underlying pathways, of which stellate cell involvement was prominent, and coexpression network modeling identified modules associated with fibrosis.
Conclusions
Our results provide a rich resource for the design of experiments to understand mechanisms underlying fibrosis and for rational strain selection when testing antifibrotic drugs.
中文翻译：
四氯化碳诱导的小鼠肝纤维化的遗传结构。
背景与目标
肝纤维化是响应于慢性肝损伤而发展的多因素特征。我们的目标是使用 Hybrid Mouse Diversity Panel 来表征四氯化碳 (CCl 4 ) 诱导的肝纤维化的遗传结构，该面板由 100 多种基因不同的小鼠品系组成，针对全基因组关联研究和系统遗传学进行了优化。
方法
通过每周两次注射CCl 4诱导慢性肝损伤，持续6周。437 只小鼠接受了 CCl 4和 256 只接受了载体，之后对动物实施安乐死以进行肝脏组织学和基因表达。使用自动数字图像分析，我们将纤维化量化为整个切片的胶原比例区域，不包括正常胶原。
结果
我们发现 Hybrid Mouse Diversity Panel 菌株之间的纤维化存在广泛差异，表明存在显着的遗传影响。全基因组关联分析揭示了对纤维化易感性的重要和提示基因座，其中一些与小鼠杂交和人群研究中确定的基因座重叠。通过跨菌株的 RNA 测序评估肝脏全局基因表达，并使用差异表达和表达数量性状基因座分析鉴定候选基因。基因集富集分析确定了潜在的途径，其中星状细胞参与是突出的，共表达网络建模确定了与纤维化相关的模块。
结论
我们的结果为设计实验提供了丰富的资源，以了解纤维化的潜在机制以及在测试抗纤维化药物时进行合理的菌株选择。
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