Z Gastroenterol 2009; 47 - P104
DOI: 10.1055/s-0029-1241355

Independent genetic associations of hepatic fibrosis and hepatocellular carcinoma in both murine reference and human populations

SN Weber 1, RA Hall 1, F Lammert 1, A Teufel 2
  • 1Universitätsklinikum des Saarlandes, Klinik für Innere Medizin II, Homburg, Germany
  • 2Johannes-Gutenberg Universität, 1. Medizinische Klinik und Poliklinik, Mainz, Germany

Aims: Beside environmental factors, hepatic fibrosis and progression to hepatocellular carcinoma (HCC) might be mediated by common risk genes.

Aim: The aim of our study was to assess potential genetic relationships between fibrosis and HCC in mice and humans.

Methods: Associations between human genes and liver fibrosis and HCC, respectively, were compiled in the LOGA (Library of Genetic Associations) database (http://www.medicalgenomics.org). For comparison, we analyzed genetic factors that predispose to fibrosis and HCC in a murine reference population. As reference population, we availed of phenotypic and genotypic data from recombinant inbred mouse strains (http://www.genenetworks.org). The strain set was generated by intercrossing C57BL/6 and DBA/2 mice and comprises up to 80 BXD lines. After 6 weeks of CCl4 treatment, hepatic collagen contents were determined and correlated to published BXD phenotypes (including tumor size of [DEN]-induced hepatocarcinogenesis and hepatic mRNA profiles at baseline) and genetic markers covering the whole genome. From human and murine data, intersections were generated and all involved pathways were analysed (KEGG).

Results: The LOGA database identified 253 genes that are associated with fibrosis and 593 genes with HCC, respectively. The intersection comprised 87 gene IDs, which equates to one third of fibrogenic genes and one seventh of HCC genes. In the murine reference population only 9 genes (Adam11, Asah3l, Atp5g1, Foxd3, Krt1-c29, Mirg, Mocs1, Olfr619, Sin3b) out of 20.842 basal hepatic transcripts show associations with both phenotypes. Interval mapping did not result in overlapping gene regions. Pathway analyses indicated the potential involvement of the PPAR signaling pathway only in both experimental fibrogenesis and carcinogenesis.

Conclusions: Applying in silico analyses of human and murine data sets, we could not detect a significant genetic association between hepatic fibrosis and HCC. The results indicate that both conditions are regulated through distinct gene sets.