Systems genetics of hepatocellular damage in vivo and in vitro: Identification of a critical network on chromosome 11 in mouse

Roman Liebe, Rabea A. Hall, Robert Williams, Steven Dooley, Frank Lammert

Research output: Contribution to journalArticle

3 Citations (Scopus)

Abstract

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 (CCl4 ip 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 CCl4 treatment 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 gene Expi (also known as Wdnm1 or Wfdc18) and 2) 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.

Original languageEnglish (US)
Pages (from-to)931-939
Number of pages9
JournalPhysiological Genomics
Volume45
Issue number20
DOIs
StatePublished - Oct 15 2013

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Chromosomes, Human, Pair 11
Quantitative Trait Loci
Liver
Transforming Growth Factors
Liver Cirrhosis
Genes
Hepatocytes
Fibrosis
RNA-Binding Proteins
Carbon Tetrachloride
Wounds and Injuries
Computational Biology
Individuality
Disease Progression
Peptide Hydrolases
Ethanol
Gene Expression
In Vitro Techniques

All Science Journal Classification (ASJC) codes

  • Physiology
  • Genetics

Cite this

Systems genetics of hepatocellular damage in vivo and in vitro : Identification of a critical network on chromosome 11 in mouse. / Liebe, Roman; Hall, Rabea A.; Williams, Robert; Dooley, Steven; Lammert, Frank.

In: Physiological Genomics, Vol. 45, No. 20, 15.10.2013, p. 931-939.

Research output: Contribution to journalArticle

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