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Common variants in ABCG8 and TRAF3 genes confer risk for gallstone disease and gallbladder cancer in admixed Latinos with Mapuche Native American ancestry

Bernabé I. Bustos, Eduardo Pérez-Palma, Stephan Buch, Lorena Azócar, Eleodoro Riveras, Giorgia D. Ugarte, Mohammad Toliat, Peter Nürnberg, Wolfgang Lieb, Andre Franke, Sebastian Hinz, Greta Burmeister, Witigo von Shönfels, Clemens Schafmayer, Henry Völzke, Uwe Völker, Georg Homuth, Marcus M. Lerch, José Luis Santos, Klaus Puschel, Claudia Bambs, Rodrigo A. Gutiérrez, Jochen Hampe, Giancarlo V. De Ferrari, Juan Francisco Miquel
doi: https://doi.org/10.1101/265728
Bernabé I. Bustos
1Center for Biomedical Research, Faculty of Biological Sciences and Faculty of Medicine, Universidad Andres Bello, Santiago, Chile
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Eduardo Pérez-Palma
1Center for Biomedical Research, Faculty of Biological Sciences and Faculty of Medicine, Universidad Andres Bello, Santiago, Chile
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Stephan Buch
2Medical Department I, University Hospital Dresden, TU Dresden, Dresden, Germany
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Lorena Azócar
3Department of Gastroenterology, Faculty of Medicine, Pontificia Universidad Catolica de Chile, Santiago, Chile
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Eleodoro Riveras
3Department of Gastroenterology, Faculty of Medicine, Pontificia Universidad Catolica de Chile, Santiago, Chile
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Giorgia D. Ugarte
1Center for Biomedical Research, Faculty of Biological Sciences and Faculty of Medicine, Universidad Andres Bello, Santiago, Chile
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Mohammad Toliat
4Cologne Center for Genomics, University of Cologne, Cologne, Germany
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Peter Nürnberg
4Cologne Center for Genomics, University of Cologne, Cologne, Germany
5Center for Molecular Medicine Cologne (CMMC), University of Cologne, Cologne, Germany
6Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD), University of Cologne, Cologne, Germany
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Wolfgang Lieb
7Institute of Epidemiology and Biobank PopGen, Christian-Albrechts-University of Kiel, Kiel, Germany
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Andre Franke
8Institute of Clinical Molecular Biology, Christian-Albrechts-University of Kiel, Kiel, Germany
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Sebastian Hinz
9Department of Visceral and Thoracic Surgery, University Hospital Schleswig Holstein, Kiel, Germany
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Greta Burmeister
9Department of Visceral and Thoracic Surgery, University Hospital Schleswig Holstein, Kiel, Germany
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Witigo von Shönfels
9Department of Visceral and Thoracic Surgery, University Hospital Schleswig Holstein, Kiel, Germany
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Clemens Schafmayer
9Department of Visceral and Thoracic Surgery, University Hospital Schleswig Holstein, Kiel, Germany
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Henry Völzke
10Institute for Community Medicine, University Medicine Greifswald, Greifswald, Germany
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Uwe Völker
11Interfaculty Institute for Genetics and Functional Genomics, University Medicine Greifswald, Greifswald, Germany
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Georg Homuth
11Interfaculty Institute for Genetics and Functional Genomics, University Medicine Greifswald, Greifswald, Germany
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Marcus M. Lerch
11Interfaculty Institute for Genetics and Functional Genomics, University Medicine Greifswald, Greifswald, Germany
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José Luis Santos
12Department of Nutrition, Diabetes and Metabolism, School of Medicine, Pontificia Universidad Catolica de Chile, Santiago, Chile
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Klaus Puschel
13Department of Familiar Medicine, Faculty of Medicine, Pontificia Universidad Catolica de Chile, Santiago, Chile
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Claudia Bambs
14Department of Public Health, Faculty of Medicine, Pontificia Universidad Catolica de Chile, Santiago, Chile
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Rodrigo A. Gutiérrez
15Department of Molecular Genetics and Microbiology, Faculty of Biological Sciences, Pontificia Universidad Catolica de Chile, Santiago, Chile
16FONDAP Center for Genome Regulation (CGR), Santiago, Chile.
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Jochen Hampe
2Medical Department I, University Hospital Dresden, TU Dresden, Dresden, Germany
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Giancarlo V. De Ferrari
1Center for Biomedical Research, Faculty of Biological Sciences and Faculty of Medicine, Universidad Andres Bello, Santiago, Chile
16FONDAP Center for Genome Regulation (CGR), Santiago, Chile.
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Juan Francisco Miquel
3Department of Gastroenterology, Faculty of Medicine, Pontificia Universidad Catolica de Chile, Santiago, Chile
16FONDAP Center for Genome Regulation (CGR), Santiago, Chile.
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Abstract

Background Latin Americans and Chilean Amerindians have the highest prevalence of cholesterol gallstone disease (GSD) and gallbladder cancer (GBC) in the world. A handful of loci have been associated with GSD in populations of predominantly European ancestry, however they only explain a small portion of the population-attributable risk of the disease.

Methods We performed a genome-wide association study (GWAS) for GSD in 1,095 admixed Latinos with Mapuche Native American Ancestry, followed by a replication analysis of 10 candidate single nucleotide polymorphisms (SNPs) with suggestive genome-wide significance (P<1×10−5) in 1,643 individuals. Disease status was assessed by cholecystectomy or abdominal ultrasonography. Logistic regression analyses were adjusted for age, sex, BMI, Type 2 Diabetes and Amerindian ancestry. Associated variants were further examined in two large GSD European populations and in a Chilean gallbladder cancer (GBC) cohort. We determined the expression levels of a novel GSD-candidate gene in normal and GSD-tissue samples.

Results We consistently replicated the ABCG8 gene (rs11887534; P=3.24×10−8, OR=1.74) associated with GSD in admixed Latinos and identified a novel candidate signal within the TRAF3 gene on chromosome 14 (rs12882491; P=1.11×10−7, OR=1.40). ABCG8 and TRAF3 variants also conferred risk to GBC. Gene expression analyses indicated that TRAF3 levels were significantly decreased in the gallbladder (P=0.015) and the duodenal mucosa (P=0.001) of affected GSD individuals compared to healthy controls.

Conclusions We confirmed ABCG8 and identified TRAF3 both associated with GSD and GBC in admixed Latinos. Decreased TRAF3 expression levels could enhance gallbladder inflammation as is observed in GSD and GSD-associated GBC.

Copyright 
The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC-ND 4.0 International license.
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Posted February 20, 2018.
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Common variants in ABCG8 and TRAF3 genes confer risk for gallstone disease and gallbladder cancer in admixed Latinos with Mapuche Native American ancestry
Bernabé I. Bustos, Eduardo Pérez-Palma, Stephan Buch, Lorena Azócar, Eleodoro Riveras, Giorgia D. Ugarte, Mohammad Toliat, Peter Nürnberg, Wolfgang Lieb, Andre Franke, Sebastian Hinz, Greta Burmeister, Witigo von Shönfels, Clemens Schafmayer, Henry Völzke, Uwe Völker, Georg Homuth, Marcus M. Lerch, José Luis Santos, Klaus Puschel, Claudia Bambs, Rodrigo A. Gutiérrez, Jochen Hampe, Giancarlo V. De Ferrari, Juan Francisco Miquel
bioRxiv 265728; doi: https://doi.org/10.1101/265728
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Common variants in ABCG8 and TRAF3 genes confer risk for gallstone disease and gallbladder cancer in admixed Latinos with Mapuche Native American ancestry
Bernabé I. Bustos, Eduardo Pérez-Palma, Stephan Buch, Lorena Azócar, Eleodoro Riveras, Giorgia D. Ugarte, Mohammad Toliat, Peter Nürnberg, Wolfgang Lieb, Andre Franke, Sebastian Hinz, Greta Burmeister, Witigo von Shönfels, Clemens Schafmayer, Henry Völzke, Uwe Völker, Georg Homuth, Marcus M. Lerch, José Luis Santos, Klaus Puschel, Claudia Bambs, Rodrigo A. Gutiérrez, Jochen Hampe, Giancarlo V. De Ferrari, Juan Francisco Miquel
bioRxiv 265728; doi: https://doi.org/10.1101/265728

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