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Letter

Nature Genetics 39, 995–999 (1 August 2007) | doi:10.1038/ng2101

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

Stephan Buch , Clemens Schafmayer , Henry V|[ouml]|lzke , Christian Becker , Andre Franke , Huberta von Eller-Eberstein , Christian Kluck , Ingelore B|[auml]|ssmann , Mario Brosch , Frank Lammert , Juan Francisco Miquel , Flavio Nervi , Michael Wittig , Dieter Rosskopf , Birgit Timm , Christine H|[ouml]|ll , Marcus Seeger , Abdou ElSharawy , Tim Lu , Jan Egberts , Fred F|[auml]|ndrich , Ulrich R F|[ouml]|lsch , Michael Krawczak , Stefan Schreiber , Peter N|[uuml]|rnberg , J|[uuml]|rgen Tepel & Jochen Hampe

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 PCCA = 4.1 |[times]| 10|[minus]|9), which was subsequently attributed to coding variant rs11887534 (D19H). Additional replication was achieved in 728 German (P = 2.8 |[times]| 10|[minus]|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 |[times]| 10|[minus]|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.