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.
Department of Medicine III, University Hospital Aachen, Aachen University, Aachen, Germany.
Sonja
S
Hillebrandt
Hermann E
HE
Wasmuth
Ralf
R
Weiskirchen
Claus
C
Hellerbrand
Hildegard
H
Keppeler
Alexa
A
Werth
Ramin
R
Schirin-Sokhan
Gabriele
G
Wilkens
Andreas
A
Geier
Johann
J
Lorenzen
Jörg
J
Köhl
Axel M
AM
Gressner
Siegfried
S
Matern
Frank
F
Lammert
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