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Gallstones, body mass index, C-reactive protein, and Gallbladder cancer: mendelian randomization analysis of Chilean and European genotype data

Background and Aims Gallbladder cancer (GBC) is a neglected disease with substantial geographical variability: Chile shows the highest incidence worldwide, while GBC is relatively rare in Europe. Here, we investigate the causal effects of risk factors considered in current GBC prevention programs as...

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Main Authors: Barahona Ponce, Carol (Author) , Scherer, Dominique (Author) , Krisam, Regina (Author) , Boekstegers, Felix (Author) , Marcelain, Katherine (Author) , Gárate-Calderón, Valentina (Author) , Müller, Bettina (Author) , Toro, Gonzalo de (Author) , Retamales, Javier (Author) , Barajas, Olga (Author) , Ahumada, Monica (Author) , Morales, Erik (Author) , Rojas, Armando (Author) , Sanhueza, Verónica (Author) , Loader, Denisse (Author) , Rivera, María Teresa (Author) , Gutiérrez, Lorena (Author) , Bernal, Giuliano (Author) , Ortega, Alejandro (Author) , Montalvo, Domingo (Author) , Portiño, Sergio (Author) , Bertrán, Maria Enriqueta (Author) , Gabler, Fernando (Author) , Spencer, Loreto (Author) , Olloquequi, Jordi (Author) , Fischer, Christine (Author) , Jenab, Mazda (Author) , Aleksandrova, Krasimira (Author) , Katzke, Verena (Author) , Weiderpass, Elisabete (Author) , Bonet, Catalina (Author) , Moradi, Tahereh (Author) , Fischer, Krista (Author) , Bossers, Willem (Author) , Brenner, Hermann (Author) , Rothhammer Engel, Francisco (Author) , Lorenzo Bermejo, Justo (Author)
Format: Article (Journal)
Language:English
Published: 2021
In: Hepatology
Year: 2021, Volume: 73, Issue: 5, Pages: 1783-1796
ISSN:1527-3350
DOI:10.1002/hep.31537
Online Access:Verlag, kostenfrei, Volltext: https://doi.org/10.1002/hep.31537
Verlag, kostenfrei, Volltext: https://aasldpubs.onlinelibrary.wiley.com/doi/abs/10.1002/hep.31537
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Author Notes:Carol Barahona Ponce, Dominique Scherer, Regina Brinster, Felix Boekstegers, Katherine Marcelain, Valentina Gárate-Calderón, Bettina Müller, Gonzalo de Toro, Javier Retamales, Olga Barajas, Monica Ahumada, Erik Morales, Armando Rojas, Verónica Sanhueza, Denisse Loader, María Teresa Rivera, Lorena Gutiérrez, Giuliano Bernal, Alejandro Ortega, Domingo Montalvo, Sergio Portiño, Maria Enriqueta Bertrán, Fernando Gabler, Loreto Spencer, Jordi Olloquequi, Christine Fischer, Mazda Jenab, Krasimira Aleksandrova, Verena Katzke, Elisabete Weiderpass, Catalina Bonet, Tahereh Moradi, Krista Fischer, Willem Bossers, Hermann Brenner, Kristian Hveem, Niina Eklund, Uwe Völker, Melanie Waldenberger, Macarena Fuentes Guajardo, Rolando Gonzalez-Jose, Gabriel Bedoya, Maria C. Bortolini, Samuel Canizales-Quinteros, Carla Gallo, Andres Ruiz-Linares, Francisco Rothhammer, and Justo Lorenzo Bermejo

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520 |a Background and Aims Gallbladder cancer (GBC) is a neglected disease with substantial geographical variability: Chile shows the highest incidence worldwide, while GBC is relatively rare in Europe. Here, we investigate the causal effects of risk factors considered in current GBC prevention programs as well as C-reactive protein (CRP) level as a marker of chronic inflammation. Approach and Results We applied two-sample Mendelian randomization (MR) using publicly available data and our own data from a retrospective Chilean and a prospective European study. Causality was assessed by inverse variance weighted (IVW), MR-Egger regression, and weighted median estimates complemented with sensitivity analyses on potential heterogeneity and pleiotropy, two-step MR, and mediation analysis. We found evidence for a causal effect of gallstone disease on GBC risk in Chileans (P = 9 × 10−5) and Europeans (P = 9 × 10−5). A genetically elevated body mass index (BMI) increased GBC risk in Chileans (P = 0.03), while higher CRP concentrations increased GBC risk in Europeans (P = 4.1 × 10−6). European results suggest causal effects of BMI on gallstone disease (P = 0.008); public Chilean data were not, however, available to enable assessment of the mediation effects among causal GBC risk factors. Conclusions Two risk factors considered in the current Chilean program for GBC prevention are causally linked to GBC risk: gallstones and BMI. For Europeans, BMI showed a causal effect on gallstone risk, which was itself causally linked to GBC risk. 
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