International Mammalian Genome Society

17th International Mouse Genome Conference

9-12 November 2003, Braunschweig, Germany


POSTER 95 - COMPLEMENT FACTOR 5 IS A GENETIC DETERMINANT OF LIVER FIBROGENESIS IN MICE AND HUMANS

Hillebrandt S
Department of Medicine III, University Hospital Aachen, Aachen University (RWTH)

Co-Authors: Matern S, Lammert F
Institutions: Department of Medicine III, University Hospital Aachen, Aachen University (RWTH)

Previously we employed QTL mapping to identify murine gene loci (Hifb loci) that confer susceptibility to hepatic fibrosis. Our aims now were (i) to assess whether the gene encoding complement factor 5 (C5) underlies the murine QTL on chromosome 2, and (ii) to confirm the association between C5 and liver fibrosis in humans. Genetic mapping demonstrates that the Hfib2 locus co-localizes with the gene encoding C5 on mouse chromosome 2. The maximum LOD scores for the stage of hepatic fibrosis (2.3) and hepatic collagen concentrations (3.4) are localized close to the C5 gene. C5 (-/-) mice display significantly (P < 0.05) lower stages of fibrosis (1.8 ± 0.2 vs. 2.4 ± 0.2) and collagen levels (399 ± 36 vs. 598 ± 69 µg hydroxyproline/g liver) after CCl4 challenge compared to C5 (+/+) mice, indicating that C5 deficiency is protective against liver fibrosis. The hypothesis that C5 modulates liver fibrogenesis is supported by the fact that fibrogenic hepatic stellate cells continue to express the C5 receptor after activation and transformation into myofibroblasts in culture. In humans, a single-nucleotide polymorphism of the C5 gene is independently associated with the stage of liver fibrosis in chronic hepatitis C. This study provides several lines of evidence supporting the identity of C5 and the fibrogenic susceptibility gene on mouse chromosome 2. Our findings establish C5 as potential modifier of liver fibrogenesis in both mice and humans, thus providing a molecular target for antifibrotic drug design in chronic liver diseases.


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