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PLoS One. 2014 Feb 28;9(2):e89279. doi: 10.1371/journal.pone.0089279. eCollection 2014.

Systems genetics of liver fibrosis: identification of fibrogenic and expression quantitative trait loci in the BXD murine reference population.

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Department of Medicine II, Saarland University Medical Center, Homburg, Germany.
Department of Medicine II, Saarland University Medical Center, Homburg, Germany ; Department of Medicine II, Section Molecular Hepatology, Medical Faculty Mannheim, Heidelberg University, Germany.
Department of Medicine III, Saarland University Medical Center, Homburg, Germany.
Department of Infection Genetics, Helmholtz Center for Infection Research, University of Veterinary Medicine Hannover and University of Tennessee Health Science Center, Braunschweig, Germany.
Department of Pathology, University Hospital Bonn, Bonn, Germany.
Department of Anatomy and Neurobiology, University of Tennessee, Memphis, Tennessee, United States of America.


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.

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