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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Recently CC chemokine receptor 5 (CCR5) related immune mechanisms and a functional mutation of the CCR5 gene have been implicated in hepatitis C virus (HCV) infection in a cohort of predominantly hemophiliac patients. The present study investigated the frequency and clinical consequences of the CCR5 Delta32 mutation in two genetically homogeneous populations of HCV infected patients with a different risk profile for infection. Genomic DNA samples from 333 German patients with chronic HCV infection were screened by PCR for the presence of the CCR5 Delta32 polymorphism. In-hospital patients admitted for other diseases than viral hepatitis but with a comparable risk for HCV exposure were used as control population ( n=125). Allele frequencies of CCR5 Delta32 polymorphism did not differ significantly between the two groups (7.6% and 9.5%, respectively) and control subjects (10.4%), and did not deviate from Hardy-Weinberg equilibrium in any group. Furthermore, there were no major differences between patients with respect to HCV genotypes, viral loads, liver enzymes, or fibrosis scores in relation to the presence or absence of the heterozygous CCR5 Delta32 mutation. Differences in inflammatory scores in liver biopsy samples and response to antiviral therapy in CCR5 Delta32 heterozygotes in one cohort could neither be reproduced in the other group of patients nor when both cohorts were pooled. These results argue against a strong effect of the CCR5 Delta32 deletion regarding these phenotypes. In conclusion, we found no increased frequency of the CCR5 Delta32 polymorphism in two independent cohorts of patients with HCV infection but without hemophilia as the main risk factor for infection. As the major difference to investigations demonstrating an association between CCR5 Delta32 and HCV infection is the selection of cases and controls, our study emphasizes the importance of epidemiological criteria for association studies of HCV infection.

The response to antiviral therapy for chronic hepatitis C virus (HCV) is complex and is determined by both environmental and genetic factors. Recently, interacting gene polymorphisms of the chemokine RANTES have been shown to affect HIV disease progression. Our aim was to assess if these RANTES variants are associated with response to anti-HCV therapy. Three linked RANTES single nucleotide polymorphisms (403 G/A, Int1.1 T/C, and 3 222 T/C) were determined in 297 Caucasian patients who were treated for chronic HCV infection and 152 control subjects. Characteristic nucleotide combinations on single chromosomes (haplotypes) were reconstructed and tested for disease association. Four common RANTES haplotypes (prevalence 73%) were identified in patients and controls. There was a strong association of RANTES haplotype distribution with outcome of antiviral combination therapy (P ‫؍‬ .007). Specifically, RANTES haplotypes carrying Int1.1 C and 3 222 C alleles were more frequent in nonresponders than in patients with a sustained response to antiviral therapy (odds ratio 1.9, P ‫؍‬ .01). The influence of these RANTES haplotypes on the outcome of therapy was more pronounced in patients infected with HCV genotypes 1 and 4 (odds ratio 2.3, P ‫؍‬ .02). Because RANTES haplotypes carrying Int1.1 C are known to down-regulate RANTES transcriptional activity in vitro, the haplotype analysis fits the hypothesis of a diminished T helper 1 lymphocyte response in patients with a negative response to antiviral therapy. In conclusion, RANTES haplotypes might contribute to the polygenic interaction between HCV and the host immune system and could help to risk stratify patients prior to antiviral therapy. ( T he CC chemokine RANTES (regulated on activation normally T cell expressed and secreted; systematic name CCL5) attracts T lymphocytes to inflamed tissues and is produced by T lymphocytes, monocytes, fibroblasts, and endothelial cells. 1,2 In hepatitis C virus (HCV)-infected liver RANTES messenger RNA has been shown to be up-regulated, and its intrahepatic expression levels correlate with serum alanine aminotransferase activities. 3,4 Furthermore, expression of full-length HCV complementary DNA induces the expression of RANTES in hepatocyte cell lines, 5 possibly mediated through activation of nuclear factor B. 6 Interestingly, a 32-base pair deletion in the gene of the CC chemokine receptor 5 (CCR5 ⌬32), which results in decreased receptor expression, 7 has recently been linked to a negative response to interferon monotherapy in hepatitis C. 8 Because the CCR5 ligand RANTES preferentially attracts T helper 1 lymphocytes, 9 RANTES might also be associated with treatment response to antiviral therapy, which is thought to depend on a sufficient proinflammatory cytokine response. 10,11 The human RANTES gene spans 8.5 kb on chromosome 17q11-q12 and has the characteristic three exons/ two introns organization of the CC chemokine family. 12 Upon sequencing of the entire RANTES gene, seven single nucleotide polymorphisms (SNPs) were identifi...