| First Author | Wittenburg H | Year | 2003 |
| Journal | Gastroenterology | Volume | 125 |
| Issue | 3 | Pages | 868-81 |
| PubMed ID | 12949731 | Mgi Jnum | J:84582 |
| Mgi Id | MGI:2668309 | Doi | 10.1016/s0016-5085(03)01053-9 |
| Citation | Wittenburg H, et al. (2003) FXR and ABCG5/ABCG8 as determinants of cholesterol gallstone formation from quantitative trait locus mapping in mice. Gastroenterology 125(3):868-81 |
| abstractText | Background & Aims: Cholesterol gallstone formation is a complex genetic trait. To identify additional cholesterol gallstone susceptibility loci, we performed a quantitative trait locus analysis using an intercross of PERA/Ei and I/LnJ inbred strains of mice. Methods: Mice of both sexes were examined for gallstone weight and evaluated according to a scoring system for the physical chemistry of cholelithiasis during feeding of a lithogenic diet. Intercross offspring were genotyped, and linkage analysis was performed by interval mapping. Differences in messenger RNA expression of positional candidate genes were determined using reverse-transcription and real-time polymerase chain reaction. Results: We identified significant loci associated with gallstone weight on chromosomes 10 and 4, named Lith7 and Lith8, respectively (both susceptibility alleles conferred by strain I/LnJ). Positional candidate genes with higher expression in I/LnJ mice are Fxr (official symbol, Nr1h4), encoding the nuclear bile salt receptor, on chromosome 10 and Shp1 (official symbol, Nr0b2), encoding the small heterodimer partner 1, on chromosome 4. A significant locus associated with gallstone score on chromosome 17, named Lith9 (susceptibility allele conferred by strain PERA/Ei), colocalizes with the genes Abcg5 and Abcg8 that encode the canalicular cholesterol transporter. Higher hepatic messenger RNA expression of Abcg5 and Abcg8 in strain PERA/Ei correlates positively with higher biliary cholesterol levels. Conclusions: Our findings suggest a primary role of the nuclear bile salt receptor FXR and the canalicular cholesterol transporter ABCG5/ABCG8 in the genetic susceptibility and pathogenesis of cholesterol cholelithiasis in these strains of inbred mice. |
