Genetic and functional identification of the likely causative variant for cholesterol gallstone disease at the ABCG5/8 lithogenic locus


BACKGROUND & AIMS: The sterolin locus (ABCG5/ABCG8) has been solidly shown to confer susceptibility for cholesterol gallstone disease in humans. Both the responsible variant and the molecular mechanism causing an increased incidence of gallstones in these patients have as yet not been identified. METHODS: Genetic mapping utilized patient samples from Germany (2808 cases, 2089 controls), Chile (680 cases, 442 controls), Denmark (366 cases, 766 controls), India (247 cases, 224 controls) and China (280 cases, 244 controls). Analysis of allelic imbalance in cDNA samples from human liver (N=22) was performed using pyrosequencing. Transiently transfected HEK293 cells were used for [3H]-cholesterol export assays, analysis of protein expression and localisation of allelic constructs. RESULTS: Through fine mapping in German and Chilean samples, a ∼250kB disease-associated interval could be defined for this locus. Lack of allelic imbalance or allelic splicing of the ABCG5 and ABCG8 transcripts in human liver limited the search to coding SNPs. Subsequent mutation detection and genotyping yielded two disease-associated variants ABCG5-R50C (p=4.94×10(-9) ) and ABCG8-D19H (p=1.74×10(-10) ) in high pair-wise LD (r(2) =0.95). [3H]-cholesterol export assays of allelic constructs harbouring these genetic candidate variants demonstrated increased transport activity (3.2-fold, p=0.003) only for the ABCG8-19H variant, which was also superior in nested logistic regression models in German (p=0.018), Chilean (p=0.030) and Chinese (p=0.040) patient samples. CONCLUSION: This variant thus provides a molecular basis for biliary cholesterol hypersecretion as the mechanism for cholesterol gallstone formation thereby drawing a link between "post-genomic" and "pre-genomic" pathophysiological knowledge about this common complex disorder. (HEPATOLOGY 2012.).


Projects: G: Clinical translation

Hepatology 57(6): 2407-17
18th Aug 2012

Oliver von Kampen, Stephan Buch, Michael Nothnagel, Lorena Azocar, Hector Molina, Mario Brosch, Wiebke Erhart, Witigo von Schönfels, Jan Egberts, Marcus Seeger, Alexander Arlt, Tobias Balschun, Andre Franke, Markus M Lerch, Julia Mayerle, Wolfgang Kratzer, Bernhard O Boehm, Klaus Huse, Bodo Schniewind, Katharina Tiemann, Zhao-Yyan Jiang, Tian-Quan Han, Balraj Mittal, Anshika Srivastava, Mogens Fenger, Torben Jørgensen, Ramin Schirin-Sokhan, Anke Tönjes, Henning Wittenburg, Michael Stumvoll, Holger Kalthoff, Frank Lammert, Jürgen Tepel, Klaus Puschel, Thomas Becker, Stefan Schreiber, Matthias Platzer, Henry Völzke, Michael Krawczak, Juan Francisco Miquel, Clemens Schafmayer, Jochen Hampe

help Authors

[Oliver Von Kampen] [Mario Brosch] [Witigo Von Schönfels] [Clemens Schafmayer] [Jochen Hampe]

help Attributions


help Scales

Views: 2939
  • Created: 4th Oct 2012 at 19:37
  • Last updated: 24th Oct 2013 at 16:16

Related items


Log in / Register

Need an account?
Sign up

Forgotten password?

Front Page

Virtual Liver Network


Related Projects and friends

Imprint Taverna workflow workbench myExperiment JWS Online ISATAB myGrid Sabio-RK BioPortal Semantic SBML

Powered by:


Silk icons 1.3
Crystal Clear icons