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

Authors
Buch, Stephan; Schafmayer, Clemens; Völzke, Henry; Seeger, Marcus; Miquel, Juan F.; Sookoian, Silvia Cristina; Egberts, Jan H.; Arlt, Alexander; Pirola, Carlos Jose; Lerch, Markus M.; John, Ulrich; Franke, Andre; von Kampen, Oliver; Brosch, Mario; Nothnagel, Michael; Kratzer, Wolfgang; Boehm, Bernhard O.; Bröring, Dieter C.; Schreiber, Stefan; Krawczak, Michael; Hampe, Jochen
Publication Year
2010
Language
English
Format
article
Status
Published version
Description
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
Subject
Pigment gallstones
Cholelithiasis
Genetic variants
Genetic risk
Complex Disease
Gastroenterología y Hepatología
Medicina Clínica
CIENCIAS MÉDICAS Y DE LA SALUD
Access level
Restricted access
License
https://creativecommons.org/licenses/by-nc-nd/2.5/ar/
Repository
CONICET Digital (CONICET)
Institution
Consejo Nacional de Investigaciones Científicas y Técnicas
OAI Identifier
oai:ri.conicet.gov.ar:11336/15132