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128. Kongress der Deutschen Gesellschaft für Chirurgie

Deutsche Gesellschaft für Chirurgie

03.05. - 06.05.2011, München

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Loci from a genome-wide analysis of bilirubin levels are associated with gallstone risk and composition

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  • Clemens Schafmayer - Universitätsklinikum Schleswig-Holstein, Campus Kiel, Klinik für Allgemeine Chirurgie und Thoraxchirurgie, Kiel
  • Stephan Buch - Universitätsklinikum Schleswig-Holstein, Campus Kiel, Klinik für Innere Medizin I, Kiel
  • Henry Völzke - Universitätsklinikum Schleswig-Holstein, Campus Kiel, Klinik für Innere Medizin I, Kiel
  • Marcus Seeger - Universitätsklinikum Schleswig-Holstein, Campus Kiel, Klinik für Innere Medizin I, Kiel
  • Witigo von Schönfels - Universitätsklinikum Schleswig-Holstein, Campus Kiel, Klinik für Allgemeine Chirurgie und Thoraxchirurgie, Kiel
  • Juan Francisco Miquel - Pontificia Universidad Catolica, Departamento de Gastroenterologia, Santiago de Chile
  • Silvia Sookoian - Universidad de Buenos Aires, Institutos de Investigaciones Médicas, Buenos Aires
  • Jan Egberts - Universitätsklinikum Schleswig-Holstein, Campus Kiel, Klinik für Allgemeine Chirurgie und Thoraxchirurgie, Kiel
  • Alexander Arlt - Universitätsklinikum Schleswig-Holstein, Campus Kiel, Klinik für Innere Medizin I, Kiel
  • Carlos Pirola - Universidad de Buenos Aires, Institutos de Investigaciones Médicas, Buenos Aires
  • Markus Lerch - Universitätsklinikum Greifswald, Klinik für Innere Medizin, Greifswald
  • Ulrich John - Universitätsklinikum Greifswald, Institut für Epidemiologie, Greifswald
  • Andre Franke - Universitätsklinikum Schleswig-Holstein, Campus Kiel, Klinik für Innere Medizin I, Kiel
  • Oliver von Kampen - Universitätsklinikum Schleswig-Holstein, Campus Kiel, Klinik für Innere Medizin I, Kiel
  • Mario Brosch - Universitätsklinikum Schleswig-Holstein, Campus Kiel, Klinik für Innere Medizin I, Kiel
  • Michael Nothnagel - Universitätsklinikum Schleswig-Holstein, Campus Kiel, Institut für medizinische Informatik und Statistik, Kiel
  • Wolfgang Kratzer - Universitätsklinikum Ulm, Klinik für Innere Medizin, Ulm
  • Bernhard Boehm - Universitätsklinikum Ulm, Klinik für Innere Medizin, Ulm
  • Dieter C. Bröring - Universitätsklinikum Schleswig-Holstein, Campus Kiel, Klinik für Allgemeine Chirurgie und Thoraxchirurgie, Kiel
  • Stephan Schreiber - Universitätsklinikum Schleswig-Holstein, Campus Kiel, Klinik für Innere Medizin I, Kiel
  • Michael Krawczak - Universitätsklinikum Schleswig-Holstein, Campus Kiel, Institut für medizinische Informatik und Statistik, Kiel
  • Jochen Hampe - Universitätsklinikum Schleswig-Holstein, Campus Kiel, Klinik für Innere Medizin I, Kiel

Deutsche Gesellschaft für Chirurgie. 128. Kongress der Deutschen Gesellschaft für Chirurgie. München, 03.-06.05.2011. Düsseldorf: German Medical Science GMS Publishing House; 2011. Doc11dgch815

doi: 10.3205/11dgch815, urn:nbn:de:0183-11dgch8153

Published: May 20, 2011

© 2011 Schafmayer et al.
This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by-nc-nd/3.0/deed.en). You are free: to Share – to copy, distribute and transmit the work, provided the original author and source are credited.

Outline

Text

Introduction: Genome-wide association studies have mapped loci that are associated with serum levels of bilirubin. Bilirubin is a major component of gallstones, so we investigated whether these variants predict gallstone bilirubin content and overall risk for gallstones.

Materials and methods: Loci that were identified in a meta-analysis to meet a genome-wide significance level of P<1.0×10-7 (UGT1A1, SLCO1B1, LST-3TM12, SLCO1A2) were analyzed in 1018 individuals with known gallstone composition. Gallstone risk was analyzed in 2606 German individuals that received operations for gallstone disease and 1121 controls and replicated in 210 cases and 496 controls from South America.

Results: Using the presence of bilirubin as a phenotype, variants rs6742078 (UGT1A1, P=0.003), rs4149056 (SLCO1B1, P=0.003), and rs4149000 (SLCO1A2, P=0.015) were associated with gallstone composition. In regression analyses, only UGT1A1 and SLCO1B1 were independently retained in the model (r2rs4149056_rs4149000=0.66). UGT1A1 (rs6742078, P=0.018) was associated with overall gallstone risk. In a sex-stratified, post-hoc analysis, only male carriers of rs6742078 had an increased risk for gallstone disease (P=2.1×10-7; ORrecessive=2.34; Pwomen=0.47). The sex-specific association of rs6742078 was confirmed in samples from South America (Pmen=0.046; ORrec=2.19, Pwomen=0.96).

Conclusion: The UGT1A1 Gilbert syndrome variant rs6742078 is associated with gallstone disease in men; further studies are required into the sex-specific physiology of bilirubin and bile acid metabolism. Most gallstones associated with UGT1A1 variants are cholesterol gallstones, indicating the role of pigment particles in the pathogenesis of gallstone disease – possibly as nucleation factors. Variants of ABCG8 and UGT1A1 are the 2 major risk factors for overall gallstone disease – they contribute a population attributable fraction of 21.2% among men.