title: Association of cholecystokinin A receptor gene polymorphism with cholelithiasis and the molecular mechanisms of this polymorphism.
abstract: BACKGROUND
  The etiology of gallstone formation is multifactorial, and genetic factors are involved. The genetic variations of cholecystokinin A receptor (CCK-AR) in patients having gallstones and the molecular mechanisms of this polymorhpism were examined. The involvement of CCK-AR in gallstone formation was confirmed using CCK-AR gene knockout mice.
  
  
  METHODS
  CCK-AR gene expression was determined by Northern transfer analysis in gallbladders with or without gallstones. Genetic variations were determined by Southern blot and by direct sequencing. Molecular mechanisms in terms of the transcriptional activity and methylation status were examined. Finally, we investigated whether gallstone formation was enhanced in CCK-AR gene knockout mice.
  
  
  RESULTS
  The gene expression of CCK-AR was significantly decreased in gallbladders with gallstones compared to those without gallstones. No genetic variations were detected in the coding region, but two sequence variations were detected in the promoter region in gallstone patients. However, no significant differences were found for the promoter activities of polymorphic promoter constructs. In contrast, less methylation in the promoter region was related to substantial expression of the CCK-AR gene. Gallstone formation was enhanced in CCK-AR gene knockout mice. The homozygote (GG/TT) polymorphism of the CCK-AR gene showed a significantly higher percentage of body fat.
  
  
  CONCLUSIONS
  Deteriorating gallbladder contractions, possibly induced by alterations in the CCK-AR gene, as well as CCK-AR gene polymorphism, promoted gallstone formation.
authors.affiliation: Department of Clinical Physiology, Tokyo Metropolitan Institute of Gerontology, 35-2 Sakaecho, Itabashiku, Tokyo 173-0015, Japan.
authors.forename: Kyoko
authors.initials: K
authors.lastname: Miyasaka
authors.forename: Yutaka
authors.initials: Y
authors.lastname: Takata
authors.forename: Akihiro
authors.initials: A
authors.lastname: Funakoshi
mesh_terms: D000230:Adenocarcinoma / Q000235:genetics / Q000601:surgery; D000368:Aged; D000818:Animals; D016022:Case-Control Studies; D002769:Cholelithiasis / Q000235:genetics* / Q000601:surgery; D046508:Culture Techniques; D005260:Female; D005706:Gallbladder Neoplasms / Q000235:genetics / Q000601:surgery; D005786:Gene Expression Regulation; D020022:Genetic Predisposition to Disease; D014644:Genetic Variation; D006801:Humans; D010535:Laparoscopy; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D008875:Middle Aged; D011110:Polymorphism, Genetic; D011401:Promoter Regions, Genetic; D043886:Receptor, Cholecystokinin A; D011949:Receptors, Cholecystokinin / Q000235:genetics*; D012016:Reference Values; D012680:Sensitivity and Specificity; D013045:Species Specificity
chemical_list: D043886:Receptor, Cholecystokinin A; D011949:Receptors, Cholecystokinin