Z Gastroenterol 2006; 44 - V31
DOI: 10.1055/s-2006-950757

Identification of the chemokine CXCL9 (MIG) as a genetic modifier of liver fibrosis in patients with hepatitis C

HE Wasmuth 1, T Wiederholt 2, E Dahl 3, C Hellerbrand 4, J Halangk 5, T Berg 5, S Hillebrandt 6, D Scholten 1, R Weiskirchen 7, C Trautwein 1, F Lammert 6
  • 1Universitätsklinikum Aachen, Medizinische Klinik III, Aachen, Germany
  • 2Universitätsklinikum Aachen, Klinik für Dermatologie, Aachen, Germany
  • 3Universitätsklinikum Aachen, Institut für Pathologie, Aachen, Germany
  • 4Universität Regensburg, Medizinische Klinik I und Poliklinik, Regensburg, Germany
  • 5Charité, Abteilung für Gastroenterologie und Hepatologie, Berlin, Germany
  • 6Universitätsklinikum Bonn, Medizinische Klinik I, Bonn, Germany
  • 7Universitätsklinikum Aachen, Institut für Klinische Chemie und Pathobiochemie, Aachen, Germany

Aims: Liver fibrosis in chronic hepatitis C (HCV) infection is influenced by multiple genetic and exogenous factors. Employing quantitative trait locus (QTL) analysis, we have recently identified the distal haplotype of mouse chromosome 5 as a genetic modifier of liver fibrosis. The present study was designed to validate this genetic association in patients with HCV infection and to investigate the expression of CXCL9 at different stages of fibrosis and in isolated human myofibroblasts of different donors.

Methods: A human haplotype study was performed with 8 validated SNPs (HapMap) that cover the distal CXC chemokine cluster on human chromosome 4 in two independent cohorts of patients with HCV infection (224 and 216 patients, respectively). Additionally, all four exons of CXCL9 were directly sequenced by the dye-terminator method in 20 patients. Serum concentrations of CXCL9 were measured in 77 healthy individuals by ELISA and CXCL9 expression was determined in total liver and isolated human myofibroblasts by quantitative (Taqman) RT-PCR.

Results: In the first cohort of HCV patients, a CXC haplotype which is tagged by a regulatory SNP in the 3'-untranslated region of the chemokine CXCL9 was significantly associated with severity of liver fibrosis (OR 2.1, P=0.03). This finding was replicated in the second independent cohort of patients (P=0.02). Of note, CXCL9 serum concentrations in healthy individuals were significantly associated with the presence of the associated CXC haplotype (P<0.001). Direct sequencing of CXCL9 revealed no genetic variation in the exons in strong linkage disequilibrium with the fibrosis associated functional SNP. CXCL9 expression in HCV infected liver was linearly related to the stage of fibrosis (n=54, Desmet-Scheuer Score; P<0.05 by ANOVA). Activated human myofibroblasts showed a basal expression of CXCL9, which increased 4-fold after stimulation of the cells (P=0.02).

Conclusions: The haplotype analyses and the expression studies identify the CXC chemokine CXCL9 as a potential genetic modifier of liver fibrogenesis. The link between CXCL9 and liver fibrosis under different experimental settings and the functional data support the pathophysiological relevance of our findings.