title: Investigation of the Lith1 candidate genes ABCB11 and LXRA in human gallstone disease.
abstract: Genetic susceptibility in the causation of gallbladder diseases was recognized as early as 1937. A major gallstone susceptibility locus (Lith1) was identified in 1995 by quantitative trait locus mapping in mice. Two attractive positional and functional candidate genes in LXRA and ABCB11 are located in this interval. ABCB11 is associated with progressive familial cholestasis. This study was undertaken to investigate LXRA and ABCB11 as candidate genes for gallstone disease in humans. Eight hundred and ten patients who underwent cholecystectomy for symptomatic gallstone disease (median age of onset, 50 years) were compared with 718 sex-matched control individuals. Control individuals were sonographically free of gallstones. Haplotype tagging and all known coding single nucleotide polymorphisms (SNPs) were genotyped for ABCB11 (n=29) and LXRA (n=10). The investigated high-risk patient sample provides a power of greater than 80% for the detection of odds ratios down to 1.55. No evidence of association of the two genes in the single point tagging markers, coding variants or in the sliding window haplotype analysis was detected (all nominal single-point P values>or=.08). In conclusion, in the investigated German sample, no evidence of association of ABCB11 and LXRA to gallstone susceptibility was detected. The gallstone trait is not allelic to progressive familial cholestasis at the ABCB11 locus. Systematic fine mapping of the Lith1 region is required to identify the causative genetic variants for gallstone in mice and humans.
authors.affiliation: Department of General and Thoracic Surgery, Christian-Albrechts-University, Kiel, and Department of Internal Medicine I, University Hospital Bonn, Germany.
authors.forename: Clemens
authors.initials: C
authors.lastname: Schafmayer
authors.forename: Jürgen
authors.initials: J
authors.lastname: Tepel
authors.forename: Andre
authors.initials: A
authors.lastname: Franke
authors.forename: Stephan
authors.initials: S
authors.lastname: Buch
authors.forename: Sören
authors.initials: S
authors.lastname: Lieb
authors.forename: Marcus
authors.initials: M
authors.lastname: Seeger
authors.forename: Frank
authors.initials: F
authors.lastname: Lammert
authors.forename: Bernd
authors.initials: B
authors.lastname: Kremer
authors.forename: Ulrich R
authors.initials: UR
authors.lastname: Fölsch
authors.forename: Fred
authors.initials: F
authors.lastname: Fändrich
authors.forename: Stefan
authors.initials: S
authors.lastname: Schreiber
authors.forename: Jochen
authors.initials: J
authors.lastname: Hampe
mesh_terms: D000074020:ATP Binding Cassette Transporter, Subfamily B, Member 11; D018528:ATP-Binding Cassette Transporters / Q000235:genetics*; D004247:DNA / Q000235:genetics*; D004268:DNA-Binding Proteins / Q000235:genetics*; D005260:Female; D005500:Follow-Up Studies; D042882:Gallstones / Q000235:genetics* / Q000378:metabolism; D005787:Gene Frequency; D020022:Genetic Predisposition to Disease; D005838:Genotype; D006801:Humans; D000071518:Liver X Receptors; D008297:Male; D008875:Middle Aged; D016017:Odds Ratio; D057093:Orphan Nuclear Receptors; D020641:Polymorphism, Single Nucleotide; D011379:Prognosis; D018160:Receptors, Cytoplasmic and Nuclear / Q000235:genetics*; D012189:Retrospective Studies
chemical_list: C093491:ABCB11 protein, human; D000074020:ATP Binding Cassette Transporter, Subfamily B, Member 11; D018528:ATP-Binding Cassette Transporters; D004268:DNA-Binding Proteins; D000071518:Liver X Receptors; C000605213:NR1H3 protein, human; C000605214:Nr1h3 protein, mouse; D057093:Orphan Nuclear Receptors; D018160:Receptors, Cytoplasmic and Nuclear; D004247:DNA