title: Loci from a genome-wide analysis of bilirubin levels are associated with gallstone risk and composition.
abstract: OBJECTIVE
  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 1.0×10(-7) (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 = 2.1×10(-7); odds ratio(recessive), 2.34; P(women) = .47). The sex-specific association of rs6742078 was confirmed in samples from South America (P(men) = .046; odds ratio(recessive), 2.19; P(women) = .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.
authors.affiliation: Department of Internal Medicine I, University Hospital Schleswig-Holstein, Kiel, Germany.
authors.forename: Stephan
authors.initials: S
authors.lastname: Buch
authors.forename: Clemens
authors.initials: C
authors.lastname: Schafmayer
authors.forename: Henry
authors.initials: H
authors.lastname: Völzke
authors.forename: Marcus
authors.initials: M
authors.lastname: Seeger
authors.forename: Juan F
authors.initials: JF
authors.lastname: Miquel
authors.forename: Silvia C
authors.initials: SC
authors.lastname: Sookoian
authors.forename: Jan H
authors.initials: JH
authors.lastname: Egberts
authors.forename: Alexander
authors.initials: A
authors.lastname: Arlt
authors.forename: Carlos J
authors.initials: CJ
authors.lastname: Pirola
authors.forename: Markus M
authors.initials: MM
authors.lastname: Lerch
authors.forename: Ulrich
authors.initials: U
authors.lastname: John
authors.forename: Andre
authors.initials: A
authors.lastname: Franke
authors.forename: Oliver
authors.initials: O
authors.lastname: von Kampen
authors.forename: Mario
authors.initials: M
authors.lastname: Brosch
authors.forename: Michael
authors.initials: M
authors.lastname: Nothnagel
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Kratzer
authors.forename: Bernhard O
authors.initials: BO
authors.lastname: Boehm
authors.forename: Dieter C
authors.initials: DC
authors.lastname: Bröring
authors.forename: Stefan
authors.initials: S
authors.lastname: Schreiber
authors.forename: Michael
authors.initials: M
authors.lastname: Krawczak
authors.forename: Jochen
authors.initials: J
authors.lastname: Hampe
mesh_terms: D000071019:ATP Binding Cassette Transporter, Subfamily G, Member 8; D018528:ATP-Binding Cassette Transporters / Q000235:genetics*; D000328:Adult; D001663:Bilirubin / Q000097:blood*; D005260:Female; D042882:Gallstones / Q000453:epidemiology / Q000235:genetics / Q000378:metabolism; D020022:Genetic Predisposition to Disease / Q000453:epidemiology; D055106:Genome-Wide Association Study; D005838:Genotype; D005858:Germany / Q000453:epidemiology; D005878:Gilbert Disease / Q000453:epidemiology / Q000235:genetics / Q000378:metabolism; D014453:Glucuronosyltransferase / Q000235:genetics*; D006801:Humans; D008297:Male; D008875:Middle Aged; D008957:Models, Genetic; D027361:Organic Anion Transporters / Q000235:genetics*; D010641:Phenotype; D011237:Predictive Value of Tests; D012307:Risk Factors; D013020:South America / Q000453:epidemiology; D000099148:UGT1A1 Enzyme
chemical_list: D000071019:ATP Binding Cassette Transporter, Subfamily G, Member 8; D018528:ATP-Binding Cassette Transporters; D001663:Bilirubin; D014453:Glucuronosyltransferase; D027361:Organic Anion Transporters; D000099148:UGT1A1 Enzyme; C416946:ABCG8 protein, human; C512988:SLCO1A2 protein, human