期刊
CELLULAR AND MOLECULAR GASTROENTEROLOGY AND HEPATOLOGY
卷 11, 期 1, 页码 199-220出版社
ELSEVIER INC
DOI: 10.1016/j.jcmgh.2020.08.010
关键词
CCl4; Systems Genetics; Liver Toxicity and Injury; Genome-Wide Association Study
资金
- Sigrid Juselius Foundation
- Orion-Farmos Research Foundation [K99 HL121172, HL28481, HL144651, DK117850, K08DK088998]
- Ruth L. Kirschstein National Research Service Award [T32HL069766]
The study characterized the genetic architecture of CCl4-induced liver fibrosis using the Hybrid Mouse Diversity Panel, identifying significant genetic variation among mouse strains. Genome-wide association analyses revealed loci underlying susceptibility to fibrosis, with gene expression and enrichment analyses providing insights into the pathways and modules associated with fibrosis. These results offer valuable resources for designing experiments to understand fibrosis mechanisms and selecting appropriate strains for testing antifibrotic drugs.
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.
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