Abstract
The progression of liver fibrosis in response to chronic injury varies considerably among individual patients. The underlying genetics is highly complex due to large numbers of potential genes, environmental factors and cell types involved. Here, we provide the first toxicogenomic analysis of liver fibrosis induced by carbon tetrachloride in the murine ‘genetic reference panel’ of recombinant inbred BXD lines. Our aim was to define the core of risk genes and gene interaction networks that control fibrosis progression. Liver fibrosis phenotypes and gene expression profiles were determined in 35 BXD lines. Quantitative trait locus (QTL) analysis identified seven genomic loci influencing fibrosis phenotypes (pQTLs) with genome-wide significance on chromosomes 4, 5, 7, 12, and 17. Stepwise refinement was based on expression QTL mapping with stringent selection criteria, reducing the number of 1,351 candidate genes located in the pQTLs to a final list of 11 cis-regulated genes. Our findings demonstrate that the BXD reference population represents a powerful experimental resource for shortlisting the genes within a regulatory network that determine the liver's vulnerability to chronic injury.
Highlights
Liver fibrosis is a common consequence of chronic injury
Liver fibrosis in parental strains A significant (p,0.0001) accumulation of collagen was observed in all livers after six weeks of CCl4 challenge in comparison to untreated mice
The parental inbred strain DBA/2J is more susceptible to liver fibrosis than the C57BL/6J strain, indicated by significantly (p,0.05) increased collagen areas and higher hepatic collagen (Hyp) contents; this is paralleled by liver injury as assessed by serum as clinical-chemical parameters (ALT) activities (Figure 1)
Summary
Liver fibrosis is a common consequence of chronic injury. Inducing agents vary from hepatotoxins, metabolic disorders and autoimmune reactions to viral infections. In patients with an exposure to similar environmental risk factors, the progression of liver fibrosis varies markedly. Based on the rate of fibrosis progression, patients may be classified as ‘slow’ or ‘rapid fibrosers’ [3]. These interindividual differences have been attributed to environmental, and to genetic (and epigenetic) factors [1,4,5]. Two recent genome-wide association studies [11,12] identified a set of novel potential susceptibility genes for liver fibrosis, including PNPLA3, but no specific networks underlying fibrogenesis were reported. Due to the large number of factors involved, the systematic identification of genetic determinants and networks affecting hepatic fibrosis remains a major challenge
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