title: Association of FXR gene variants with cholelithiasis.
abstract: OBJECTIVE
  Impairment of bile acid homeostasis is the most important risk factor of gallstone disease. Thereby the bile acid sensor farnesoid X receptor (FXR) plays a pivotal role in hepatic and intestinal bile acid metabolism. In this explorative study, the FXR gene was investigated to identify gene variants, associated with gallstone formation in a Caucasian population.
  
  
  METHODS
  Sequencing of the FXR gene was conducted in a randomly selected cohort of gallstone carriers (n=30) and control subjects (n=16) from Stuttgart, Germany. Genomic DNA was obtained from blood leukocytes. Genotype frequencies were established in the total cohort (controls: n=133, gallstone carriers: n=74). For expression analysis, total RNA and protein were isolated from ileal biopsies.
  
  
  RESULTS
  The sequencing showed the sole appearance of 10 SNPs in gallstone carriers. Further genotype analysis revealed significant gender- and weight-dependent frequency differences of 3 SNPs between gallstone carriers and controls in males (rs35724: OR=4.73, P=0.022) and normal weight subjects (rs11110385: OR=3.67, P=0.027; rs11110386: OR=3.67, P=0.027) applying the 11+12<>22 allele model. Furthermore, rs11110385 carriers showed a significantly decreased FXR protein expression (11+12<>22: P=0.003). Significant mRNA expression differences between lean rs11110385 carriers and non-carriers were observed in FXR target genes (decrease: ILBP: P=0.042, OSTalpha: P=0.071, FGF19: P=0.011. Increase: LRH1: P=0.044).
  
  
  CONCLUSIONS
  Three FXR gene variants (rs35724, rs11110385, rs11110386) were identified as potential susceptibility factors for cholelithiasis in a German cohort in gender- and weight-dependent manners. Thereby the tag SNP rs11110385 seemed to influence the activation of the FXR gene.
authors.affiliation: Dr. Margarete Fischer-Bosch Institute for Clinical Pharmacology and University of Tuebingen, Stuttgart, Germany. Electronic address: S_HirobeJahn@uni-hohenheim.de.
authors.forename: Satoko
authors.initials: S
authors.lastname: Hirobe-Jahn
authors.affiliation: Dr. Margarete Fischer-Bosch Institute for Clinical Pharmacology and University of Tuebingen, Stuttgart, Germany. Electronic address: Simone.Harsch@ikp-stuttgart.de.
authors.forename: Simone
authors.initials: S
authors.lastname: Harsch
authors.affiliation: Dr. Margarete Fischer-Bosch Institute for Clinical Pharmacology and University of Tuebingen, Stuttgart, Germany. Electronic address: Olga.Renner@ikp-stuttgart.de.
authors.forename: Olga
authors.initials: O
authors.lastname: Renner
authors.affiliation: Dr. Margarete Fischer-Bosch Institute for Clinical Pharmacology and University of Tuebingen, Stuttgart, Germany. Electronic address: Dominique.Richter@ikp-stuttgart.de.
authors.forename: Dominique
authors.initials: D
authors.lastname: Richter
authors.affiliation: Department of Internal Medicine I, Robert Bosch Hospital, Stuttgart, Germany. Electronic address: Oliver.Mueller@rbk.de.
authors.forename: Oliver
authors.initials: O
authors.lastname: Müller
authors.affiliation: Department of Internal Medicine I, Robert Bosch Hospital, Stuttgart, Germany. Electronic address: Eduard.Stange@rbk.de.
authors.forename: Eduard F
authors.initials: EF
authors.lastname: Stange
mesh_terms: D005260:Female; D042882:Gallstones / Q000235:genetics*; D014644:Genetic Variation; D006801:Humans; D008297:Male; D020641:Polymorphism, Single Nucleotide; D018160:Receptors, Cytoplasmic and Nuclear / Q000235:genetics*; D000099150:Receptor, Farnesoid X-Activated
chemical_list: D018160:Receptors, Cytoplasmic and Nuclear; D000099150:Receptor, Farnesoid X-Activated