Gallstones, Body Mass Index, C-Reactive Protein, and Gallbladder Cancer: Mendelian Randomization Analysis of Chilean and European Genotype Data.
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Barahona Ponce Carol, Scherer Dominique, Brinster Regina, Boekstegers Felix, Marcelain Katherine, Gárate-Calderón Valentina, Müller Bettina, de Toro Gonzalo, Retamales Javier, Barajas Olga, Ahumada Monica, Morales Erik, Rojas Armando, Sanhueza Verónica, Loader Denisse, Rivera María Teresa, Gutiérrez Lorena, Bernal Giuliano, Ortega Alejandro, Montalvo Domingo, Portiño Sergio, Bertrán Maria Enriqueta, Gabler Fernando, Spencer Loreto, Olloquequi Jordi, Fischer Christine, Jenab Mazda, Aleksandrova Krasimira, Katzke Verena, Weiderpass Elisabete, Bonet Catalina, Moradi Tahereh, Fischer Krista, Bossers Willem, Brenner Hermann, Hveem Kristian, Eklund Niina, Völker Uwe, Waldenberger Melanie, Fuentes Guajardo Macarena, Gonzalez-Jose Rolando, Bedoya Gabriel, Bortolini Maria C, Canizales-Quinteros Samuel, Gallo Carla, Ruiz-Linares Andres, Rothhammer Francisco, Lorenzo Bermejo Justo
Аннотация
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.