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Barahona Ponce, C.* ; Scherer, D.* ; Brinster, R.* ; Boekstegers, F.* ; Marcelain, K.* ; Gárate, V.* ; Müller, B.* ; de Toro, G.* ; Retamales, J.* ; Barajas, O.* ; Ahumada, M.* ; Morales, E.* ; Rojas, A.* ; Sanhueza, V.* ; Loader, D.* ; Rivera, M.T.* ; Gutiérrez, L.* ; Bernal, G.* ; Ortega, A.* ; Montalvo, D.* ; Portiño, S.* ; Bertrán, M.E.* ; Gabler, F.* ; Spencer, L.* ; Olloquequi, J.* ; Fischer, C.* ; Jenab, M.* ; Aleksandrova, K.* ; Katzke, V.* ; Weiderpass, E.* ; Bonet, C.* ; Moradi, T.* ; Fischer, K.* ; Bossers, W.* ; Brenner, H.* ; Hveem, K.* ; Eklund, N.* ; Völker, U.* ; Waldenberger, M. ; Fuentes Guajardo, M. ; Gonzalez-Jose, R.* ; Bedoya, G.* ; Bortolini, M.C.* ; Canizales, S.* ; Gallo, C.* ; Ruiz Linares, A.* ; Rothhammer, F. ; Lorenzo Bermejo, J.*

Gallstones, body mass index, C-reactive protein and gallbladder cancer—Mendelian randomization analysis of chilean and European genotype data.

Hepatology 73, 1783-1796 (2021)
Free by publisher: Publ. Version/Full Text online available 02/2022 Open Access Green: Postprint online available 02/2022
BACKGROUND & 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 programmes as well as C-reactive protein (CRP) level as a marker of chronic inflammation. APPROACH & 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 programme 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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Publication type Article: Journal article
Document type Scientific Article
Keywords C-reactive Protein ; Gallbladder Cancer ; Gallstones ; Mendelian Randomization ; Native American Ancestry; Reproductive Factors; Genetic-variants; Risk-factors; Life-style; Disease; Association; Adiposity; Weight; Susceptibility; Inflammation
ISSN (print) / ISBN 0270-9139
e-ISSN 1527-3350
Journal Hepatology
Quellenangaben Volume: 73, Issue: 5, Pages: 1783-1796 Article Number: , Supplement: ,
Publisher Wiley
Publishing Place Hoboken, NJ
Reviewing status Peer reviewed
Grants Heidelberg University
Deutsche Forschungsgemeinschaft Universitaet Heidelberg - Programme Open Access Publishing
Bundesministerium für Bildung und Forschung
UK Biobank Resource
Biobanking and Biomolecular Research Infrastructure - Large Prospective Cohorts
H2020 European Research CouncilH2020 European Research Council