Complement factor 5 is a quantitative trait gene that modifies liver fibrogenesis in mice and humans.
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.
Hillebrandt
Sonja
S
Department of Medicine III, University Hospital Aachen, Aachen University, Aachen, Germany.
Wasmuth
Hermann E
HE
Weiskirchen
Ralf
R
Hellerbrand
Claus
C
Keppeler
Hildegard
H
Werth
Alexa
A
Schirin-Sokhan
Ramin
R
Wilkens
Gabriele
G
Geier
Andreas
A
Lorenzen
Johann
J
Köhl
Jörg
J
Gressner
Axel M
AM
Matern
Siegfried
S
Lammert
Frank
F
D000818:Animals; D002874:Chromosome Mapping; D003182:Complement C5 / Q000235:genetics* / Q000378:metabolism; D005838:Genotype; D006801:Humans; D008103:Liver Cirrhosis / Q000235:genetics*; D051379:Mice; D008815:Mice, Inbred Strains; D011110:Polymorphism, Genetic; D040641:Quantitative Trait Loci
D003182:Complement C5