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.

[1]  P. Bedossa,et al.  Natural history of liver fibrosis progression in patients with chronic hepatitis C , 1997, The Lancet.

[2]  A. Lentsch,et al.  Role of complement in in vitro and in vivo lung inflammatory reactions , 1998, Journal of leukocyte biology.

[3]  K. Schulz,et al.  Case-control studies: research in reverse , 2002, The Lancet.

[4]  Frank Buchholz,et al.  A new logic for DNA engineering using recombination in Escherichia coli , 1998, Nature Genetics.

[5]  D. Brenner,et al.  Erratum: Liver fibrosis (Journal of Clinical Investigation (2005) 115 (209-218) DOI:10.1172/JCI200524282) , 2005 .

[6]  Robert C. Elston,et al.  Testing for Hardy-Weinberg equilibrium in small samples , 1977 .

[7]  John D Lambris,et al.  Increased C5a receptor expression in sepsis. , 2002, The Journal of clinical investigation.

[8]  O. Smithies.  Many little things: one geneticist's view of complex diseases , 2005, Nature Reviews Genetics.

[9]  C. Haley,et al.  A simple regression method for mapping quantitative trait loci in line crosses using flanking markers , 1992, Heredity.

[10]  S. Friedman,et al.  Liver fibrosis -- from bench to bedside. , 2003, Journal of hepatology.

[11]  D. Vergani,et al.  Activation of the complement system in primary sclerosing cholangitis. , 1989, Gastroenterology.

[12]  Kenneth F. Manly,et al.  Overview of QTL mapping software and introduction to Map Manager QT , 1999, Mammalian Genome.

[13]  D. Fairlie,et al.  Development of C5a receptor antagonists. , 1999, IDrugs : the investigational drugs journal.

[14]  P. Sasieni.  From genotypes to genes: doubling the sample size. , 1997, Biometrics.

[15]  Paola Sebastiani,et al.  Minimal haplotype tagging , 2003, Proceedings of the National Academy of Sciences of the United States of America.

[16]  L. Cardon,et al.  The complex interplay among factors that influence allelic association , 2004, Nature Reviews Genetics.

[17]  William Valdar,et al.  Strategies for mapping and cloning quantitative trait genes in rodents , 2005, Nature Reviews Genetics.

[18]  J. Hoofnagle,et al.  Classification of chronic hepatitis: Diagnosis, grading and staging , 1994, Hepatology.

[19]  Serge Batalov,et al.  Use of a Dense Single Nucleotide Polymorphism Map for In Silico Mapping in the Mouse , 2004, PLoS biology.

[20]  J. Köhl,et al.  Anaphylatoxins and infectious and non-infectious inflammatory diseases. , 2001, Molecular immunology.

[21]  A. Gressner,et al.  Up‐regulated expression of the receptor for advanced glycation end products in cultured rat hepatic stellate cells during transdifferentiation to myofibroblasts , 2001, Hepatology.

[22]  N. Thèvenot,et al.  [Viral hepatitis C]. , 1991, Soins.

[23]  R. Ellison,et al.  Complement levels in patients with hepatic dysfunction , 1990, Digestive Diseases and Sciences.

[24]  T. Poynard,et al.  Biochemical markers of liver fibrosis in patients with hepatitis C virus infection: a prospective study , 2001, The Lancet.

[25]  John D Lambris,et al.  Protection of innate immunity by C5aR antagonist in septic mice , 2002, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[26]  H. Rosen,et al.  Development of C5a receptor antagonists. Differential loss of functional responses. , 1994, Journal of immunology.

[27]  Ron Korstanje,et al.  From QTL to gene: the harvest begins , 2002, Nature Genetics.

[28]  F. Lammert,et al.  CC chemokine receptor 5 Δ32 polymorphism in two independent cohorts of hepatitis C virus infected patients without hemophilia , 2003, Journal of Molecular Medicine.

[29]  T. Wynn.  Fibrotic disease and the TH1/TH2 paradigm , 2004, Nature Reviews Immunology.

[30]  A. Bosserhoff,et al.  Common heterozygous hemochromatosis gene mutations are risk factors for inflammation and fibrosis in chronic hepatitis C , 2004, Liver international : official journal of the International Association for the Study of the Liver.

[31]  M. Walport,et al.  Complement. Second of two parts. , 2001, The New England journal of medicine.

[32]  S. Sacks,et al.  Leaked protein and interstitial damage in the kidney: is complement the missing link? , 2002, Clinical and experimental immunology.

[33]  Peter Donnelly,et al.  A comparison of bayesian methods for haplotype reconstruction from population genotype data. , 2003, American journal of human genetics.

[34]  R. Doerge,et al.  Empirical threshold values for quantitative trait mapping. , 1994, Genetics.

[35]  R. Bataller,et al.  Amendment history : Corrigendum ( April 2005 ) Liver fibrosis Ramón Bataller , 2018 .

[36]  O. Götze,et al.  Expression and induction of anaphylatoxin C5a receptors in the rat liver. , 2003, Histology and histopathology.

[37]  R. Thrall,et al.  Inhibition of bleomycin-induced pulmonary fibrosis by cobra venom factor. , 1982, The American journal of pathology.

[38]  John D Lambris,et al.  A Novel Role of Complement: Mice Deficient in the Fifth Component of Complement (C5) Exhibit Impaired Liver Regeneration1 , 2001, The Journal of Immunology.

[39]  D. Craik,et al.  Low-molecular-weight peptidic and cyclic antagonists of the receptor for the complement factor C5a. , 1999, Journal of medicinal chemistry.

[40]  F. Lammert,et al.  From genotypes to haplotypes in hepatobiliary diseases: One plus one equals (sometimes) more than two , 2004, Hepatology.

[41]  S. Richards,et al.  Effect of eculizumab on hemolysis and transfusion requirements in patients with paroxysmal nocturnal hemoglobinuria. , 2004, The New England journal of medicine.

[42]  Gudmundur A. Thorisson,et al.  The International HapMap Project Web site. , 2005, Genome research.

[43]  F. Lammert,et al.  Genome-wide analysis of hepatic fibrosis in inbred mice identifies the susceptibility locus Hfib1 on chromosome 15. , 2002, Gastroenterology.

[44]  K. Whaley,et al.  Complement and Complement Deficiencies , 1997, Seminars in liver disease.

[45]  Robert W. Williams,et al.  The nature and identification of quantitative trait loci: a community's view , 2003, Nature Reviews Genetics.

[46]  D. Haviland,et al.  Deficiency of the murine fifth complement component (C5). A 2-base pair gene deletion in a 5'-exon. , 1990, The Journal of biological chemistry.

[47]  S. Friedman,et al.  Mechanisms of Disease: mechanisms of hepatic fibrosis and therapeutic implications , 2004, Nature Clinical Practice Gastroenterology &Hepatology.

[48]  Y. Belkaid,et al.  C5a negatively regulates toll-like receptor 4-induced immune responses. , 2005, Immunity.

[49]  D. Rockey,et al.  Strain-specific differences in mouse hepatic wound healing are mediated by divergent T helper cytokine responses. , 1997, Proceedings of the National Academy of Sciences of the United States of America.

[50]  John D Lambris,et al.  The Proinflammatory Mediators C3a and C5a Are Essential for Liver Regeneration , 2003, The Journal of experimental medicine.

[51]  J. Boyer,et al.  Primary Biliary Cirrhosis , 1984, Hepatology.

[52]  Charles E. Kahn,et al.  primary biliary cirrhosis , 1995 .