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

Nature Genetics volume 39, pages 995–999 (2007)Cite this article

Abstract

With an overall prevalence of 10–20%, gallstone disease (cholelithiasis) represents one of the most frequent and economically relevant health problems of industrialized countries1,2. 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 PCCA = 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.

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Figure 1: Overview of the physical and genetic structure of the ABCG5/ABCG8 region.

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Acknowledgements

The cooperation of all patients, their families and physicians is gratefully acknowledged. The authors gratefully acknowledge the support by the following heads of surgical departments: I. Vogel (Städtisches Krankenhaus Kiel), H. Dittrich (Rendsburg), J. Belz (Husum), R. Quäschling (Eckernförde), H. Shekarriz (Schleswig), V. Mendel (Flensburg), W. Neugebauer (Flensburg), F. Kallinowski (Heide), J. Klima (Niebüll), M. Sailer (Hamburg) and A. Schafmayer (Lüneburg). Special thanks are given to C. Fürstenau, T. Wesse, B. Petersen, L. Bossen, T. Henke, S. Ehlers, A. Dietsch and V. Pucken for technical assistance. This study was supported by the German Ministry of Education and Research through the POPGEN biobank project (01GS0426, 01GR0468), the MediGrid project and the National Genotyping Platforms in Kiel and Cologne and by the German Research Council (Ha 3091/2-1, 4-1, La 997/3-1), Applied Biosystems, Mucosaimmunologie gGmbH and the Medical Faculty Kiel. The SHIP recruitment project is funded by the Federal Ministry of Education and Research (ZZ9603), the Ministry of Cultural Affairs and the Social Ministry of the Federal State of Mecklenburg-West Pomerania. The Chilean study was supported by grants from FONDECYT (Fondo Nacional de Desarrollo Científico y Tecnologógico) (numbers 1040820 (to J.F.M.) and 1030744 (to F.N.)).

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Author notes

  1. Stephan Buch and Clemens Schafmayer: These authors contributed equally to this work.

Authors and Affiliations

  1. First Department of Medicine, University Hospital Schleswig-Holstein, Kiel, 24105, Germany

    Stephan Buch, Mario Brosch, Marcus Seeger, Ulrich R Fölsch & Jochen Hampe

  2. Institute for Clinical Molecular Biology, University Hospital Schleswig-Holstein, Kiel, 24105, Germany

    Stephan Buch, Andre Franke, Michael Wittig, Abdou ElSharawy & Stefan Schreiber

  3. POPGEN Biobank, University Hospital Schleswig-Holstein, Kiel, 24105, Germany

    Stephan Buch, Clemens Schafmayer, Huberta von Eller-Eberstein, Birgit Timm, Christine Höll, Michael Krawczak & Stefan Schreiber

  4. Department of General and Thoracic Surgery, University Hospital Schleswig-Holstein, Kiel, 24105, Germany

    Clemens Schafmayer, Jan Egberts, Fred Fändrich & Jürgen Tepel

  5. Institute for Community Medicine, University Hospital Greifswald, Walther Rathenau Str. 48, Greifswald, 17487, Germany

    Henry Völzke

  6. Cologne Center for Genomics, University of Cologne, Zülpicher Strasse 47, Cologne, 50674, Germany

    Christian Becker, Christian Kluck, Ingelore Bässmann & Peter Nürnberg

  7. RZPD German Resource Center for Genome Research, Heubnerweg 6, Berlin, 14059, Germany

    Christian Becker, Christian Kluck & Ingelore Bässmann

  8. Department of Internal Medicine I, University Hospital Bonn, Sigmund Freud-Strasse 25, Bonn, 53105, Germany

    Frank Lammert

  9. Departamento de Gastroenterologia, Facultad de Medicina, Pontificia Universidad Católica de Chile, Santiago, Chile

    Juan Francisco Miquel & Flavio Nervi

  10. Institute of Pharmacology, Ernst-Moritz-Arndt University Greifswald, Friedrich Loeffler Str. 23d, Greifswald, 17487, Germany

    Dieter Rosskopf

  11. Institute of Medical Statistics and Informatics, University Hospital Schleswig-Holstein, Kiel, 24105, Germany

    Tim Lu & Michael Krawczak

  12. Center for Molecular Medicine Cologne (CMMC), University of Cologne, Joseph-Stelzmann-Strasse 52, Köln, 50931, Germany

    Peter Nürnberg

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  1. Stephan Buch
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Contributions

S.B. performed the SNP selection, genotyping and data analysis and prepared the figures and tables; C.S. coordinated the Kiel recruitment, phenotyped patients and helped write the paper; J.E., H.v.E., C.H., B.T. and M.S. recruited patients and helped write the paper. C.B., I.B., C.K. and P.N. performed the chip genotyping and chip data analysis; H.V. and D.R. coordinated the SHIP recruitment and participated in experimental design; J.F.M., F.N. coordinated the recruitment in Chile and participated in experimental design; A.F., M.B., A.E., T.L. and M.W. helped with data analysis and genotyping and F.L., F.F., U.R.F., S.S., P.N. and J.T. helped design the experiment, supported recruitment and helped write the paper. M.K. supervised and performed the statistical analysis and edited the paper. J.H. designed and supervised the experiment, performed data analysis and wrote the manuscript. All authors have revised the manuscript for intellectual content.

Corresponding author

Correspondence to Jochen Hampe.

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The authors declare no competing financial interests.

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Supplementary Figures 1–2, Supplementary Tables 1–2, Supplementary Methods, Supplementary Note (PDF 205 kb)

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Buch, S., Schafmayer, C., Völzke, H. et al. A genome-wide association scan identifies the hepatic cholesterol transporter ABCG8 as a susceptibility factor for human gallstone disease. Nat Genet 39, 995–999 (2007). https://doi.org/10.1038/ng2101

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