Publication Details

FXR and ABCG5/ABCG8 as determinants of cholesterol gallstone formation from quantitative trait locus mapping in mice.

Authors:Wittenburg H, Lyons MA, Li R, Churchill GA, Carey MC, Paigen B
Title:FXR and ABCG5/ABCG8 as determinants of cholesterol gallstone formation from quantitative trait locus mapping in mice.
Journal:Gastroenterology Sep 2003 , Vol 125 , pp. 868-81
Abstract: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.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.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.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.   PUBMED: 12949731
Ontological Annotations:
  • D040641: Quantitative Trait Loci (Publication, NCBO Annotator)
  • D001646: Bile (Publication, NCBO Annotator)
  • D002875: Chromosomes (Publication, NCBO Annotator)
  • D051379: Mice (Publication, NCBO Annotator)
  • D002627: Chemistry, Physical (Publication, NCBO Annotator)
  • D002769: Cholelithiasis (Publication, NCBO Annotator)
  • D002886: Chromosomes, Human, Pair 17 (Publication, NCBO Annotator)
  • GO:0005694: chromosome (Publication, NCBO Annotator)
  • D012313: RNA (Publication, NCBO Annotator)
  • D042882: Gallstones (Publication, NCBO Annotator)
  • D002879: Chromosomes, Human, Pair 10 (Publication, NCBO Annotator)
  • D002894: Chromosomes, Human, Pair 4 (Publication, NCBO Annotator)
  • D008815: Mice, Inbred Strains (Publication, NCBO Annotator)
  • GO:0009058: biosynthetic process (Publication, NCBO Annotator)
  • MA:0002513: bile (Publication, NCBO Annotator)
  • GO:0009405: pathogenesis (Publication, NCBO Annotator)
  • D012380: Role (Publication, NCBO Annotator)
  • D000483: Alleles (Publication, NCBO Annotator)
  • D016133: Polymerase Chain Reaction (Publication, NCBO Annotator)
  • MP:0002830: gallstones (Publication, NCBO Annotator)
  • D002621: Chemistry (Publication, NCBO Annotator)
  • D020022: Genetic Predisposition to Disease (Publication, NCBO Annotator)
  • D002784: Cholesterol (Publication, NCBO Annotator)
  • D004032: Diet (Publication, NCBO Annotator)
  • D012333: RNA, Messenger (Publication, NCBO Annotator)

1 GeneSets from this Publication:

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Expand Tier II Mouse 758 Genes GS136148: lithogenic gene 8 (Lith8, Published QTL Chr 4)