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 | |
| 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).
