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Complement factor 5 is a quantitative trait gene that modifies liver fibrogenesis in mice and humans

Nature Genetics volume 37, pages 835–843 (2005)Cite this article

Abstract

Fibrogenesis or scarring of the liver is a common consequence of all chronic liver diseases. Here we refine a quantitative trait locus that confers susceptibility to hepatic fibrosis by in silico mapping and show, using congenic mice and transgenesis with recombined artificial chromosomes, that the gene Hc (encoding complement factor C5) underlies this locus. Small molecule inhibitors of the C5a receptor had antifibrotic effects in vivo, and common haplotype-tagging polymorphisms of the human gene C5 were associated with advanced fibrosis in chronic hepatitis C virus infection. Thus, the mouse quantitative trait gene led to the identification of an unknown gene underlying human susceptibility to liver fibrosis, supporting the idea that C5 has a causal role in fibrogenesis across species.

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Figure 1: Fine mapping of the fibrogenic QTL on chromosome 2 by in silico haplotype analysis using 143 SNPs with an average distance of 313 kb between microsatellite markers D2Mit6 (20.9 Mb) and D2Mit90 (65.6 Mb).
Figure 2: Phenotypic characterization of liver fibrosis in inbred mouse strains and Hc BAC-transgenic mice before and after treatment with CCl4 for 6 weeks.
Figure 3: Expression of C5R1 in rat HSCs.
Figure 4: Phenotypic characterization of CCl4-induced liver fibrosis in mice treated with C5a receptor antagonists (C5R1A).
Figure 5: Association of C5 haplotypes and genotypes with histological stages of liver fibrosis in 277 individuals with chronic HCV infection.

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Acknowledgements

We thank H. Matern, M.C. Carey, B. Paigen and T. Sauerbruch for discussions and comments. This study was supported by grants from Deutsche Forschungsgemeinschaft, the German Network of Excellence for Viral Hepatitis (Kompetenznetz Hepatitis), the Ministry of Science and Research of North-Rhine-Westphalia and Aachen University (cooperative project Identification of Molecular Markers and Gene Therapy for Fibrosis and Wound Healing). This study was presented in part at the Plenary Session of the Annual Meeting of the American Association for the Study of Liver Diseases, Boston, November 2002, and published in abstract form in Hepatology (36, 296A; 2002).

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Authors and Affiliations

  1. Department of Medicine III, University Hospital Aachen, Aachen University, Aachen, Germany

    Sonja Hillebrandt, Hermann E Wasmuth, Hildegard Keppeler, Alexa Werth, Ramin Schirin-Sokhan, Gabriele Wilkens, Andreas Geier, Siegfried Matern & Frank Lammert

  2. Department of Internal Medicine I, University Hospital Bonn, Bonner Forum Biomedizin, University of Bonn, Sigmund-Freud-Str. 25, Bonn, 53127, Germany

    Sonja Hillebrandt, Hildegard Keppeler & Frank Lammert

  3. Institute of Clinical Chemistry and Pathobiochemistry, University Hospital Aachen, Aachen University, Aachen, Germany

    Ralf Weiskirchen & Axel M Gressner

  4. Department of Medicine I, University Hospital Regensburg, University of Regensburg, Regensburg, Germany

    Claus Hellerbrand

  5. Institute of Pathology, University Hospital Aachen, Aachen University, Aachen, Germany

    Johann Lorenzen

  6. Division of Molecular Immunology, Department of Pediatrics, Cincinnati Children's Hospital Research Foundation, University of Cincinnati, Cincinnati, Ohio, USA

    Jörg Köhl

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  1. Sonja Hillebrandt
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Correspondence to Frank Lammert.

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Supplementary information

Supplementary Table 1

Association of human C5 haplotypes and htSNPs with serum C5 levels. (PDF 77 kb)

Supplementary Table 2

Primer and probe sequences for ET-recombination, sequencing and genotyping of Hc BAC-transgenic mice [FVB/NJ-Tg(Hc)]. (PDF 74 kb)

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Hillebrandt, S., Wasmuth, H., Weiskirchen, R. et al. Complement factor 5 is a quantitative trait gene that modifies liver fibrogenesis in mice and humans. Nat Genet 37, 835–843 (2005). https://doi.org/10.1038/ng1599

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