Loci from a genome-wide analysis of bilirubin levels are associated with gallstone risk and composition

BACKGROUND & AIMS: Genome-wide association studies have mapped loci that are associated with serum levels of bilirubin. Bilirubin is a major component of gallstones so we investigated whether these variants predict gallstone bilirubin content and overall risk for gallstones. METHODS: Loci that were identified in a meta-analysis to attain a genome-wide significance level of a P value less than 1.0 107 (UGT1A1, SLCO1B1, LST-3TM12, SLCO1A2) were analyzed in 1018 individuals with known gallstone composition. Gallstone risk was analyzed in 2606 German choleystecomized individuals and 1121 controls and was replicated in 210 cases and 496 controls from South America. RESULTS: By using the presence of bilirubin as a phenotype, variants rs6742078 (UGT1A1; P .003), rs4149056 (SLCO1B1; P .003), and rs4149000 (SLCO1A2; P .015) were associated with gallstone composition. In regression analyses, only UGT1A1 and SLCO1B1 were independently retained in the model. UGT1A1 (rs6742078; P .018) was associated with overall gallstone risk. In a sex-stratified analysis, only male carriers of rs6742078 had an increased risk for gallstone disease (P 2.1 107; odds ratiorecessive, 2.34; Pwomen .47). The sex-specific association of rs6742078 was confirmed in samples from South America (Pmen .046; odds ratiorecessive, 2.19; Pwomen .96). CONCLUSIONS: The UGT1A1 Gilbert syndrome variant rs6742078 is associated with gallstone disease in men; further studies are required regarding the sex-specific physiology of bilirubin and bile acid metabolism. Variants of ABCG8 and UGT1A1 are the 2 major risk factors for overall gallstone disease, they contribute a population attributable risk of 21.2% among men. Fil: Buch, Stephan. University Hospital Schleswig-Holstein; Alemania Fil: Schafmayer, Clemens. University Hospital Schleswig-Holstein; Alemania Fil: Völzke, Henry. University of Greifswald; Alemania Fil: Seeger, Marcus. University Hospital Schleswig-Holstein; Alemania Fil: Miquel, Juan F.. Pontificia Universidad Católica de Chile; Chile Fil: Sookoian, Silvia Cristina. Consejo Nacional de Investigaciones Cientificas y Tecnicas. Oficina de Coordinacion Administrativa Houssay. Instituto de Investigaciones Medicas; Argentina. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Investigaciones Médicas; Argentina Fil: Egberts, Jan H.. University Hospital Schleswig-Holstein; Alemania Fil: Arlt, Alexander. University Hospital Schleswig-Holstein; Alemania Fil: Pirola, Carlos Jose. University Hospital Schleswig-Holstein; Alemania. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina Fil: Lerch, Markus M.. University of Greifswald; Alemania Fil: John, Ulrich. University of Greifswald; Alemania Fil: Franke, Andre. University Hospital Schleswig-Holstein; Alemania Fil: von Kampen, Oliver. University Hospital Schleswig-Holstein; Alemania Fil: Brosch, Mario. University Hospital Schleswig-Holstein; Alemania Fil: Nothnagel, Michael. University Hospital Schleswig-Holstein; Alemania Fil: Kratzer, Wolfgang. Universitat Ulm; Alemania Fil: Boehm, Bernhard O.. Universitat Ulm; Alemania Fil: Bröring, Dieter C.. University Hospital Schleswig-Holstein; Alemania Fil: Schreiber, Stefan. University Hospital Schleswig-Holstein; Alemania Fil: Krawczak, Michael. University Hospital Schleswig-Holstein; Alemania Fil: Hampe, Jochen. University Hospital Schleswig-Holstein; Alemania