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

      Nature genetics

      Chromosome Mapping, Quantitative Trait Loci, Polymorphism, Genetic, Mice, Inbred Strains, Mice, genetics, Liver Cirrhosis, Humans, Genotype, metabolism, Complement C5, Animals

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          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 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.

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          Most cited references 43

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          A comparison of bayesian methods for haplotype reconstruction from population genotype data.

          In this report, we compare and contrast three previously published Bayesian methods for inferring haplotypes from genotype data in a population sample. We review the methods, emphasizing the differences between them in terms of both the models ("priors") they use and the computational strategies they employ. We introduce a new algorithm that combines the modeling strategy of one method with the computational strategies of another. In comparisons using real and simulated data, this new algorithm outperforms all three existing methods. The new algorithm is included in the software package PHASE, version 2.0, available online (http://www.stat.washington.edu/stephens/software.html).
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            Liver fibrosis.

            Liver fibrosis is the excessive accumulation of extracellular matrix proteins including collagen that occurs in most types of chronic liver diseases. Advanced liver fibrosis results in cirrhosis, liver failure, and portal hypertension and often requires liver transplantation. Our knowledge of the cellular and molecular mechanisms of liver fibrosis has greatly advanced. Activated hepatic stellate cells, portal fibroblasts, and myofibroblasts of bone marrow origin have been identified as major collagen-producing cells in the injured liver. These cells are activated by fibrogenic cytokines such as TGF-beta1, angiotensin II, and leptin. Reversibility of advanced liver fibrosis in patients has been recently documented, which has stimulated researchers to develop antifibrotic drugs. Emerging antifibrotic therapies are aimed at inhibiting the accumulation of fibrogenic cells and/or preventing the deposition of extracellular matrix proteins. Although many therapeutic interventions are effective in experimental models of liver fibrosis, their efficacy and safety in humans is unknown. This review summarizes recent progress in the study of the pathogenesis and diagnosis of liver fibrosis and discusses current antifibrotic strategies.
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              A simple regression method for mapping quantitative trait loci in line crosses using flanking markers.

              The use of flanking marker methods has proved to be a powerful tool for the mapping of quantitative trait loci (QTL) in the segregating generations derived from crosses between inbred lines. Methods to analyse these data, based on maximum-likelihood, have been developed and provide good estimates of QTL effects in some situations. Maximum-likelihood methods are, however, relatively complex and can be computationally slow. In this paper we develop methods for mapping QTL based on multiple regression which can be applied using any general statistical package. We use the example of mapping in an F(2) population and show that these regression methods produce very similar results to those obtained using maximum likelihood. The relative simplicity of the regression methods means that models with more than a single QTL can be explored and we give examples of two lined loci and of two interacting loci. Other models, for example with more than two QTL, with environmental fixed effects, with between family variance or for threshold traits, could be fitted in a similar way. The ease, speed of application and generality of regression methods for flanking marker analysis, and the good estimates they obtain, suggest that they should provide the method of choice for the analysis of QTL mapping data from inbred line crosses.
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                Author and article information

                Journal
                15995705
                10.1038/ng1599

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