Multiple quantitative trait loci modeling (MQM) of hepatic fibrosis in a murine intercross

Most common diseases are attributed to multiple genetic variants. The feasibility of identifying inherited risk factors is often restricted to the identification of alleles with high or intermediate effect sizes. In our previous studies we identified single susceptibility loci associated with hepatic fibrosis (Hfib1-Hfib4). New advances in analysis tools allow us to model loci interactions for liver fibrosis. Overall we analysed 322 progeny from an F2 intercross of the fibrosis-susceptible inbred mouse strain BALB/cJ and the resistant strain FVB/NJ. The mice were challenged with carbon tetrachloride (CCl4) for six weeks to induce liver fibrosis. We quantified fibrosis progression by determining histological fibrosis stages and hepatic collagen (hydroxproline) contents. Phenotypic data were correlated to genome-wide markers to identify quantitative trait loci (QTL). Thirteen susceptibility loci were localized by single and composite interval mapping, and were included in the subsequent multiple QTL model (MQM) testing. Models provided evidence for susceptibility loci with strongest association to hydroxyproline (chromosomes 1, 2, 8 and 13) or fibrosis stages (chromosomes 1, 2, 12 and 14). These loci contain the fibrosis modifier genes Hc, Fasl, and Foxa2. The MQM were displayed as a fibrosis network. Interestingly, we identified only one overlapping hepatic fibrosis locus on chromosome 1 for both phenotypes. Including MQM to association studies adds valuable information on gene-gene interactions and may eventually be accomplished in human cohorts. This study presents an initial step towards a refined understanding of profibrogenic gene networks.

Corresponding author: Hall, Rabea A.

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