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

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-Yan 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

doi:10.1002/hep.26009

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

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 TiemannZhao-Yan 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

Institut for Folkesundhedsvidenskab

51 Citationer (Scopus)

Abstract

The sterolin locus (ABCG5/ABCG8) confers 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. Genetic mapping utilized patient samples from Germany (2,808 cases, 2,089 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 complementary DNA (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 localization of allelic constructs. Through fine mapping in German and Chilean samples, an ∼250 kB 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 single nucleotide polymorphisms. 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 pairwise linkage disequilibrium (r² = 0.95). [³H]-cholesterol export assays of allelic constructs harboring 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 "postgenomic" and "pregenomic" pathophysiological knowledge about this common complex disorder.

Originalsprog	Engelsk
Tidsskrift	Hepatology
Vol/bind	57
Udgave nummer	6
Sider (fra-til)	2407–2417
ISSN	0270-9139
DOI	https://doi.org/10.1002/hep.26009
Status	Udgivet - jun. 2013

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von Kampen, O., Buch, S., Nothnagel, M., Azocar, L., Molina, H., Brosch, M., Erhart, W., von Schönfels, W., Egberts, J., Seeger, M., Arlt, A., Balschun, T., Franke, A., Lerch, M. M., Mayerle, J., Kratzer, W., Boehm, B. O., Huse, K., Schniewind, B., ... Hampe, J. (2013). Genetic and functional identification of the likely causative variant for cholesterol gallstone disease at the ABCG5/8 lithogenic locus. Hepatology, 57(6), 2407–2417. https://doi.org/10.1002/hep.26009

von Kampen, O, Buch, S, Nothnagel, M, Azocar, L, Molina, H, Brosch, M, Erhart, W, von Schönfels, W, Egberts, J, Seeger, M, Arlt, A, Balschun, T, Franke, A, Lerch, MM, Mayerle, J, Kratzer, W, Boehm, BO, Huse, K, Schniewind, B, Tiemann, K, Jiang, Z-Y, Han, T-Q, Mittal, B, Srivastava, A, Fenger, M, Jørgensen, T, Schirin-Sokhan, R, Tönjes, A, Wittenburg, H, Stumvoll, M, Kalthoff, H, Lammert, F, Tepel, J, Puschel, K, Becker, T, Schreiber, S, Platzer, M, Völzke, H, Krawczak, M, Miquel, JF, Schafmayer, C & Hampe, J 2013, 'Genetic and functional identification of the likely causative variant for cholesterol gallstone disease at the ABCG5/8 lithogenic locus', Hepatology, bind 57, nr. 6, s. 2407–2417. https://doi.org/10.1002/hep.26009

@article{93554f16d8e44f7a9afbde9f7d96c0b2,

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

abstract = "The sterolin locus (ABCG5/ABCG8) confers 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. Genetic mapping utilized patient samples from Germany (2,808 cases, 2,089 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 complementary DNA (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 localization of allelic constructs. Through fine mapping in German and Chilean samples, an ∼250 kB 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 single nucleotide polymorphisms. 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 pairwise linkage disequilibrium (r2 = 0.95). [3H]-cholesterol export assays of allelic constructs harboring 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 {"}postgenomic{"} and {"}pregenomic{"} pathophysiological knowledge about this common complex disorder.",

author = "{von Kampen}, Oliver and Stephan Buch and Michael Nothnagel and Lorena Azocar and Hector Molina and Mario Brosch and Wiebke Erhart and {von Sch{\"o}nfels}, Witigo and Jan Egberts and Marcus Seeger and Alexander Arlt and Tobias Balschun and Andre Franke and Lerch, {Markus M} and Julia Mayerle and Wolfgang Kratzer and Boehm, {Bernhard O} and Klaus Huse and Bodo Schniewind and Katharina Tiemann and Zhao-Yan Jiang and Tian-Quan Han and Balraj Mittal and Anshika Srivastava and Mogens Fenger and Torben J{\o}rgensen and Ramin Schirin-Sokhan and Anke T{\"o}njes and Henning Wittenburg and Michael Stumvoll and Holger Kalthoff and Frank Lammert and J{\"u}rgen Tepel and Klaus Puschel and Thomas Becker and Stefan Schreiber and Matthias Platzer and Henry V{\"o}lzke and Michael Krawczak and Miquel, {Juan Francisco} and Clemens Schafmayer and Jochen Hampe",

note = "Copyright {\textcopyright} 2012 American Association for the Study of Liver Diseases.",

year = "2013",

month = jun,

doi = "10.1002/hep.26009",

language = "English",

volume = "57",

pages = "2407–2417",

journal = "Hepatology",

issn = "0270-9139",

publisher = "JohnWiley & Sons, Inc.",

number = "6",

}

TY - JOUR

T1 - Genetic and functional identification of the likely causative variant for cholesterol gallstone disease at the ABCG5/8 lithogenic locus

AU - von Kampen, Oliver

AU - Buch, Stephan

AU - Nothnagel, Michael

AU - Azocar, Lorena

AU - Molina, Hector

AU - Brosch, Mario

AU - Erhart, Wiebke

AU - von Schönfels, Witigo

AU - Egberts, Jan

AU - Seeger, Marcus

AU - Arlt, Alexander

AU - Balschun, Tobias

AU - Franke, Andre

AU - Lerch, Markus M

AU - Mayerle, Julia

AU - Kratzer, Wolfgang

AU - Boehm, Bernhard O

AU - Huse, Klaus

AU - Schniewind, Bodo

AU - Tiemann, Katharina

AU - Jiang, Zhao-Yan

AU - Han, Tian-Quan

AU - Mittal, Balraj

AU - Srivastava, Anshika

AU - Fenger, Mogens

AU - Jørgensen, Torben

AU - Schirin-Sokhan, Ramin

AU - Tönjes, Anke

AU - Wittenburg, Henning

AU - Stumvoll, Michael

AU - Kalthoff, Holger

AU - Lammert, Frank

AU - Tepel, Jürgen

AU - Puschel, Klaus

AU - Becker, Thomas

AU - Schreiber, Stefan

AU - Platzer, Matthias

AU - Völzke, Henry

AU - Krawczak, Michael

AU - Miquel, Juan Francisco

AU - Schafmayer, Clemens

AU - Hampe, Jochen

PY - 2013/6

Y1 - 2013/6

N2 - The sterolin locus (ABCG5/ABCG8) confers 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. Genetic mapping utilized patient samples from Germany (2,808 cases, 2,089 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 complementary DNA (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 localization of allelic constructs. Through fine mapping in German and Chilean samples, an ∼250 kB 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 single nucleotide polymorphisms. 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 pairwise linkage disequilibrium (r2 = 0.95). [3H]-cholesterol export assays of allelic constructs harboring 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 "postgenomic" and "pregenomic" pathophysiological knowledge about this common complex disorder.

AB - The sterolin locus (ABCG5/ABCG8) confers 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. Genetic mapping utilized patient samples from Germany (2,808 cases, 2,089 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 complementary DNA (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 localization of allelic constructs. Through fine mapping in German and Chilean samples, an ∼250 kB 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 single nucleotide polymorphisms. 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 pairwise linkage disequilibrium (r2 = 0.95). [3H]-cholesterol export assays of allelic constructs harboring 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 "postgenomic" and "pregenomic" pathophysiological knowledge about this common complex disorder.

U2 - 10.1002/hep.26009

DO - 10.1002/hep.26009

M3 - Journal article

C2 - 22898925

SN - 0270-9139

VL - 57

SP - 2407

EP - 2417

JO - Hepatology

JF - Hepatology

IS - 6

ER -

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

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