Identification of eQTLs for hepatic Xbp1s and Socs3 gene expression in mice fed a high-fat, high-caloric diet.
Bottom Line: We identified two overlapping loci for Xbp1s and Socs3 on Chr 1 (164.0-185.4 Mb and 174.4-190.5 Mb, respectively) and Chr 11 (41.1-73.1 Mb and 44.0-68.6 Mb, respectively), and an additional locus for Socs3 on Chr 12 (109.9-117.4 Mb).In addition, we replicated the eQTLs on Chr 1 and Chr 12 (LOD scores ≥3.5) using mice from the BXD murine reference panel challenged with CCl4 to induce chronic liver injury and fibrosis.Identification of the genes for these eQTLs will lead to a better understanding of the genetic factors responsible for NAFLD and potentially other hepatic diseases.
Affiliation: Department of Internal Medicine, Northwestern University, Chicago, Illinois Department of Internal Medicine, University of North Carolina, Chapel Hill, North Carolina.Show MeSH
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Mentions: To further confirm that the regulation of hepatic Xbp1s and Socs3 expression is altered in a second animal model of liver injury, we used the carbon tetrachloride (CCl4) model of chronic liver injury and fibrogenesis. Wild-type mice fed chow without CCl4 do not develop spontaneous hepatic fibrosis. For this analysis, we searched for coinciding regulatory loci within the Socs3 and Xbp1 eQTLs on mouse chromosome 1 (164.4–190.5 Mb), chromosome 11 (41.1–73.1 Mb), and chromosome 12 (109.9–117.4 Mb) in the BXD reference population to allow systematic mapping and integration of multiple complex traits (Andreux et al. 2012). We initially mapped hepatic expression values of Socs3 and Xbp1s using our microarray-based expression dataset. Figure 5 shows the interval mapping/regression analysis for the phenotype of hepatic Socs3 expression. The most significant loci were identified on chromosome 1 at 185.2–186.6 Mb for Xbp1 (LOD 3.5; PG = 0.08) and 193.3–197.1 Mb for Socs3 (LOD 4.4, PG = 0.01), chromosome 4 at 62.4–68.9 Mb for Xbp1 (LOD 3.1, PG= 0.02), and chromosome 12 at 83.9–89.9 Mb for Socs3 (LOD 5.6; PG = 0.002). Of note, the eQTLs for Socs3 and Xbp1 on chromosomes 1 that determine hepatic expression levels after CCl4 challenge coincide with loci that determine gene expression on the HFHC diet as well as eQTLs in control BXD. These findings suggest that baseline expression differences due to genetic variation confer susceptibility to liver injury. Furthermore, the expression differences are inversely correlated with Sirius red-stained collagen areas in livers from CCl4-treated animals (P < 0.001) (Hall et al. 2014). We also identified several genes potentially regulated from within the Socs3 and Xbp1 eQTLs. Table 3 summarizes these cis-regulated differentially expressed genes identified using the BXD lines that co-localize with the eQTLs identified in the HFHC model. Among the regulated genes, only Darc and Zfp39 inherit nsSNPs in coding regions differentiating between C57BL/6J and A/J or DBA/2J mice, respectively.
Affiliation: Department of Internal Medicine, Northwestern University, Chicago, Illinois Department of Internal Medicine, University of North Carolina, Chapel Hill, North Carolina.