Z Gastroenterol 2010; 48 - P399
DOI: 10.1055/s-0030-1263839

Systems genetics of liver fibrogenesis in a murine reference population: Association mapping and pair scans in BXD recombinant inbred lines

R Hall 1, R Muellenbach 1, K Hochrath 1, S Weber 1, K Schughart 2, F Lammert 1
  • 1Department of Medicine II, Saarland University Hospital, Homburg, Germany
  • 2Dept. of Experimental Mouse Genetics/The Helmholtz Centre for Infection Research, Braunschweig, Germany

Aims: Complex phenotypes are not only due to single locus variation, but are influenced by environmental covariates as well as epistatic interactions. Association mapping is based on phenotypic variations between inbred strains to identify genetic determinants of complex traits. Within the framework of the German Network of Systems Genetics (GeNeSys), we are investigating the BXD panel of recombinant inbred lines, which were generated by intercrossing C57BL/6J and DBA/2J mice, in a systems genetics approach to identify genetic loci and loci interactions that confer susceptibility to liver fibrosis.

Methods: In total, 30 genetically distinct BXD lines (n=392) were analysed after fibrosis induction by intraperitoneal CCl4 injections (12 injections, 0.7mg/kg). We determined histological fibrosis stages and hepatic collagen contents. Furthermore we assessed gender-specific differences in fibrosis progression. Association mapping was performed with genome-wide scans and pair-scans using the WebQTL platform of GeNeSys (http://genesys.helmholtz-hzi.de).

Results: The BXD lines display line- and gender-specific differences in susceptibility to CCl4-induced fibrosis. Histological fibrosis stages vary from F0 to F3. Mean collagen contents range from 181 to 702mg/g liver across the BXD lines. Collagen concentrations are normally distributed among all mice, consistent with polygenic inheritance of liver fibrosis. We identified fibrosis susceptibility loci on chromosomes (chr) 12 (pnom=0.002) and chr16 (pnom=0.0001, pgw<0.05), both contributed by the parental C57BL/6J alleles. Additionally, composite mapping with background markers identified a suggestive peak on chr 7, whereas pair-scans identified suggestive additive effects between loci on chr 16 and loci on chromosomes 7 and 17.

Conclusions: Our findings demonstrate that BXD recombinant inbred lines represent a genetic reference population for the analysis of profibrogenic susceptibility genes. The panel of BXD lines provides an experimental framework for modelling the gene networks that regulate liver fibrogenesis.