A genome-wide association scan identifies the hepatic cholesterol transporter ABCG8 as a susceptibility factor for human gallstone disease

• Published in: Nature genetics Vol. 39; no. 8; pp. 995 - 999
• Main Authors: Buch, Stephan, Schafmayer, Clemens, Völzke, Henry, Becker, Christian, Franke, Andre, von Eller-Eberstein, Huberta, Kluck, Christian, Bässmann, Ingelore, Brosch, Mario, Lammert, Frank, Miquel, Juan Francisco, Nervi, Flavio, Wittig, Michael, Rosskopf, Dieter, Timm, Birgit, Höll, Christine, Seeger, Marcus, ElSharawy, Abdou, Lu, Tim, Egberts, Jan, Fändrich, Fred, Fölsch, Ulrich R, Krawczak, Michael, Schreiber, Stefan, Nürnberg, Peter, Tepel, Jürgen, Hampe, Jochen
• Format: Journal Article
• Language: English
• Published: New York Nature Publishing Group US 01.08.2007; Nature Publishing Group
• Subjects: Adult; Aged; Agriculture; Animal Genetics and Genomics; ATP Binding Cassette Transporter, Sub-Family G, Member 8; ATP-Binding Cassette Transporters - genetics; ATP-Binding Cassette Transporters - metabolism; Biological and medical sciences; Biological transport; Biomedical and Life Sciences; Biomedicine; Cancer Research; Cholelithiasis - genetics; Cholelithiasis - metabolism; Cholesterol; Cholesterol - metabolism; Diagnosis; Fundamental and applied biological sciences. Psychology; Gallstones; Gastroenterology. Liver. Pancreas. Abdomen; Gene Function; Genetic aspects; Genetic Predisposition to Disease; Genetics of eukaryotes. Biological and molecular evolution; Genomics; Health problems; Human Genetics; Humans; letter; Liver; Liver. Biliary tract. Portal circulation. Exocrine pancreas; Medical sciences; Middle Aged; Other diseases. Semiology; Physiological aspects; Polymorphism, Single Nucleotide; Population genetics; Single nucleotide polymorphisms; Germany; Human; Digestive diseases; Lipids; Identification; Biliary tract disease; Genome; Cholelithiasis; Cholesterol
• ISSN: 1061-4036; 1546-1718
• DOI: 10.1038/ng2101

With an overall prevalence of 10–20%, gallstone disease (cholelithiasis) represents one of the most frequent and economically relevant health problems of industrialized countries 1 , 2 . 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 × 10 −9 ), which was subsequently attributed to coding variant rs11887534 (D19H). Additional replication was achieved in 728 German ( P = 2.8 × 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 × 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.