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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 inLXRAandABCB11are located in this interval.ABCB11is associated with progressive familial cholestasis. This study was undertaken to investigateLXRAandABCB11as 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 forABCB11(n = 29) andLXRA(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-pointPvalues ≥ .08).In conclusion, in the investigated German sample, no evidence of association ofABCB11andLXRAto gallstone susceptibility was detected. The gallstone trait is not allelic to progressive familial cholestasis at theABCB11locus. Systematic fine mapping of theLith1region is required to identify the causative genetic variants for gallstone in mice and humans.