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

Sonja Hillebrandt; Hermann E. Wasmuth; Ralf Weiskirchen; Claus Hellerbrand; Hildegard Keppeler; Alexa Werth; Ramin Schirin-Sokhan; Gabriele Wilkens; Andreas Geier; Johann Lorenzen; Jörg Köhl; Axel M. Gressner; Siegfried Matern; Frank Lammert

doi:10.1038/ng1599

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

Sonja Hillebrandt, Hermann E. Wasmuth, Ralf Weiskirchen, Claus Hellerbrand, Hildegard Keppeler, Alexa Werth, Ramin Schirin-Sokhan, Gabriele Wilkens, Andreas Geier, Johann Lorenzen, Jörg Köhl, Axel M. Gressner, Siegfried Matern, Frank Lammert^*

^*Corresponding author for this work

Institute of Systemic Inflammation Research

236 Citations (Scopus)

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 117 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 CS 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.

Original language	English
Journal	Nature Genetics
Volume	37
Issue number	8
Pages (from-to)	835-843
Number of pages	9
ISSN	1061-4036
DOIs	https://doi.org/10.1038/ng1599
Publication status	Published - 01.08.2005

Funding

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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Hillebrandt, S., Wasmuth, H. E., Weiskirchen, R., Hellerbrand, C., Keppeler, H., Werth, A., Schirin-Sokhan, R., Wilkens, G., Geier, A., Lorenzen, J., Köhl, J., Gressner, A. M., Matern, S., & Lammert, F. (2005). Complement factor 5 is a quantitative trait gene that modifies liver fibrogenesis in mice and humans. Nature Genetics, 37(8), 835-843. https://doi.org/10.1038/ng1599

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

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 117 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 CS 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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Hillebrandt, S, Wasmuth, HE, Weiskirchen, R, Hellerbrand, C, Keppeler, H, Werth, A, Schirin-Sokhan, R, Wilkens, G, Geier, A, Lorenzen, J, Köhl, J, Gressner, AM, Matern, S & Lammert, F 2005, 'Complement factor 5 is a quantitative trait gene that modifies liver fibrogenesis in mice and humans', Nature Genetics, vol. 37, no. 8, pp. 835-843. https://doi.org/10.1038/ng1599

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AU - Hillebrandt, Sonja

AU - Wasmuth, Hermann E.

AU - Weiskirchen, Ralf

AU - Hellerbrand, Claus

AU - Keppeler, Hildegard

AU - Werth, Alexa

AU - Schirin-Sokhan, Ramin

AU - Wilkens, Gabriele

AU - Geier, Andreas

AU - Lorenzen, Johann

AU - Köhl, Jörg

AU - Gressner, Axel M.

AU - Matern, Siegfried

AU - Lammert, Frank

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N2 - 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 117 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 CS 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.

AB - 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 117 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 CS 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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Complement factor 5 is a quantitative trait gene that modifies liver fibrogenesis in mice and humans

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