A genome-wide association scan identifies the hepatic cholesterol transporter ABCG8 as a susceptibility factor for human gallstone disease.
With an overall prevalence of 10-20%, gallstone disease (cholelithiasis) represents one of the most frequent and economically relevant health problems of industrialized countries. We performed an association scan of >500,000 SNPs in 280 individuals with gallstones and 360 controls. A follow-up study of the 235 most significant SNPs in 1,105 affected individuals and 873 controls replicated the disease association of SNP A-1791411 in ABCG8 (allelic P value P(CCA) = 4.1 x 10(-9)), which was subsequently attributed to coding variant rs11887534 (D19H). Additional replication was achieved in 728 German (P = 2.8 x 10(-7)) and 167 Chilean subjects (P = 0.02). The overall odds ratio for D19H carriership was 2.2 (95% confidence interval: 1.8-2.6, P = 1.4 x 10(-14)) in the full German sample. Association was stronger in subjects with cholesterol gallstones (odds ratio = 3.3), suggesting that His19 might be associated with a more efficient transport of cholesterol into the bile.
Buch
Stephan
S
First Department of Medicine, University Hospital Schleswig-Holstein, 24105 Kiel, Germany.
Schafmayer
Clemens
C
Völzke
Henry
H
Becker
Christian
C
Franke
Andre
A
von Eller-Eberstein
Huberta
H
Kluck
Christian
C
Bässmann
Ingelore
I
Brosch
Mario
M
Lammert
Frank
F
Miquel
Juan Francisco
JF
Nervi
Flavio
F
Wittig
Michael
M
Rosskopf
Dieter
D
Timm
Birgit
B
Höll
Christine
C
Seeger
Marcus
M
ElSharawy
Abdou
A
Lu
Tim
T
Egberts
Jan
J
Fändrich
Fred
F
Fölsch
Ulrich R
UR
Krawczak
Michael
M
Schreiber
Stefan
S
Nürnberg
Peter
P
Tepel
Jürgen
J
Hampe
Jochen
J
D000071019:ATP Binding Cassette Transporter, Subfamily G, Member 8; D018528:ATP-Binding Cassette Transporters / Q000235:genetics* / Q000378:metabolism; D000328:Adult; D000368:Aged; D002769:Cholelithiasis / Q000235:genetics* / Q000378:metabolism; D002784:Cholesterol / Q000378:metabolism; D020022:Genetic Predisposition to Disease; D006801:Humans; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide
C416946:ABCG8 protein, human; D000071019:ATP Binding Cassette Transporter, Subfamily G, Member 8; D018528:ATP-Binding Cassette Transporters; D002784:Cholesterol