International Mammalian Genome Society

The 16th International Mouse Genome Conference (2002)


POSTER 9 - GENOME-WIDE ANALYSIS OF SUSCEPTIBILITY LOCI FOR HEPATIC FIBROSIS IN INBRED MOUSE STRAINS IDENTIFIES Hfib1 and Hfib2, FIBROGENIC LOCI ON CHROMOSOMES 2 AND 15

S Hillebrandt
Department of Medicine III, University Aachen

Lammert F
University Aachen

Background: Host genetic factors are likely to contribute to the variable course of hepatic fibrosis in response to chronic liver injury. Our aim was to identify unknown susceptibility loci for hepatic fibrosis in a cross between fibrosis-susceptible and resistant inbred mice. Methods: Seven inbred mouse strains were treated with CCl4 and hepatic fibrosis was phenotypically characterized by histology and hepatic hydroxyproline levels. Quantitative trait loci were identified in the intercross between susceptible BALB/cJ and resistant A/J mice by genome-wide scans and by in silico haplotype mapping with 109 SNPs covering the whole genome. Results: In this model, marked strain differences in fibrosis susceptibility exist, with BALB/c mice being most susceptible. QTL analysis identifies susceptibility loci on chromosomes 2 and 15 that significantly affect the stage of fibrosis and hydroxyproline levels. These loci are called Hfib1 and Hfib2, for hepatic fibrogenic genes 1 and 2. Hfib1 is defined by genetic markers D15Mit26 and D15Mit122 (LOD=4.2) and co-localizes with the gene for hyaluronan synthase (Has2). Hfib2 is defined by microsatellite markers D2Mit6 and D2Mit458 (LOD=4.5) and co-localizes with the Hc gene encoding complement factor 5 (C5), indicating a role of complement in modulating genetic susceptibility to hepatic fibrosis via Th cytokine subsets. Hfib1 and Hfib2 are confirmed by SNP haplotype mapping. Conclusions: This study provides evidence for the genetic control of hepatic fibrosis in mice and identifies individual QTLs. The knowledge on murine susceptibility genes for liver fibrosis could be useful for rapid identification of key molecular targets for antifibrotic drug design.


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