Loci from a genome-wide analysis of bilirubin levels are associated with gallstone risk and composition.
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.
Buch
Stephan
S
Department of Internal Medicine I, University Hospital Schleswig-Holstein, Kiel, Germany.
Schafmayer
Clemens
C
Völzke
Henry
H
Seeger
Marcus
M
Miquel
Juan F
JF
Sookoian
Silvia C
SC
Egberts
Jan H
JH
Arlt
Alexander
A
Pirola
Carlos J
CJ
Lerch
Markus M
MM
John
Ulrich
U
Franke
Andre
A
von Kampen
Oliver
O
Brosch
Mario
M
Nothnagel
Michael
M
Kratzer
Wolfgang
W
Boehm
Bernhard O
BO
Bröring
Dieter C
DC
Schreiber
Stefan
S
Krawczak
Michael
M
Hampe
Jochen
J
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
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