Loci From a Genome-Wide Analysis of Bilirubin Levels Are Associated With Gallstone Risk and Composition

STEPHAN BUCH; CLEMENS SCHAFMAYER; HENRY VÖLZKE; MARCUS SEEGER; JUAN F. MIQUEL,; SILVIA C. SOOKOIAN; JAN H. EGBERTS; ALEXANDER ARLT; CARLOS J. PIROLA; MARKUS M. LERCH; ULRICH JOHN; ANDRE FRANKE; OLIVER VON KAMPEN,*; MARIO BROSCH; MICHAEL NOTHNAGEL; WOLFGANG KRATZER; BERNHARD O. BOEHM; DIETER C. BRÖRING; STEFAN SCHREIBER; MICHAEL KRAWCZAK; JOCHEN HAMPE

GASTROENTEROLOGY

W B SAUNDERS CO-ELSEVIER INC

Año: 2010 vol. 139 p. 1942 - 1951

0016-5085

BACKGROUND & AIMS: Genome-wide association studieshave mapped loci that are associated with serum levelsof bilirubin. Bilirubin is a major component of gallstonesso we investigated whether these variants predict gallstonebilirubin content and overall risk for gallstones.METHODS: Loci that were identified in a meta-analysisto attain a genome-wide significance level of a P value lessthan 1.0
107 (UGT1A1, SLCO1B1, LST-3TM12,SLCO1A2) were analyzed in 1018 individuals with knowngallstone composition. Gallstone risk was analyzed in2606 German choleystecomized individuals and 1121controls and was replicated in 210 cases and 496 controlsfrom South America. RESULTS: By using the presenceof bilirubin as a phenotype, variants rs6742078 (UGT1A1;P  .003), rs4149056 (SLCO1B1; P  .003), andrs4149000 (SLCO1A2; P  .015) were associated withgallstone composition. In regression analyses, onlyUGT1A1 and SLCO1B1 were independently retained inthe model. UGT1A1 (rs6742078; P  .018) was associatedwith overall gallstone risk. In a sex-stratified analysis,only male carriers of rs6742078 had an increased risk forgallstone disease (P  2.1
107; odds ratiorecessive, 2.34;Pwomen  .47). The sex-specific association of rs6742078was confirmed in samples from South America (Pmen .046; odds ratiorecessive, 2.19; Pwomen  .96). CONCLUSIONS:The UGT1A1 Gilbert syndrome variantrs6742078 is associated with gallstone disease in men;further studies are required regarding the sex-specificphysiology of bilirubin and bile acid metabolism.Variants of ABCG8 and UGT1A1 are the 2 major riskfactors for overall gallstone disease, they contribute apopulation attributable risk of 21.2% among men.