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Gallstones, Body Mass Index, C‐Reactive Protein, and Gallbladder Cancer: Mendelian Randomization Analysis of Chilean and European Genotype Data
Author(s) -
Barahona Ponce Carol,
Scherer Dominique,
Brinster Regina,
Boekstegers Felix,
Marcelain Katherine,
GárateCalderón Valentina,
Müller Bettina,
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,
GonzalezJose Rolando,
Bedoya Gabriel,
Bortolini Maria C.,
CanizalesQuinteros Samuel,
Gallo Carla,
RuizLinares Andres,
Rothhammer Francisco,
Lorenzo Bermejo Justo
Publication year - 2021
Publication title -
hepatology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 5.488
H-Index - 361
eISSN - 1527-3350
pISSN - 0270-9139
DOI - 10.1002/hep.31537
Subject(s) - mendelian randomization , gallbladder cancer , body mass index , medicine , gallstones , mediation , oncology , gallbladder disease , cancer , gallbladder , genotype , genetics , biology , genetic variants , gene , political science , law
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.