{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,10]],"date-time":"2026-10-10T16:06:31Z","timestamp":1791648391670,"version":"4.3.4"},"reference-count":57,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"5","license":[{"start":{"date-parts":[[2021,4,29]],"date-time":"2021-04-29T00:00:00Z","timestamp":1619654400000},"content-version":"unspecified","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"}],"content-domain":{"domain":["lww.com","ovid.com"],"crossmark-restriction":true},"short-container-title":["Hepatology"],"published-print":{"date-parts":[[2021,5]]},"abstract":"<jats:sec>\n            <jats:title>Background and Aims<\/jats:title>\n            <jats:p>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\u2010reactive protein (CRP) level as a marker of chronic inflammation.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Approach and Results<\/jats:title>\n            <jats:p>We applied two\u2010sample 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\u2010Egger regression, and weighted median estimates complemented with sensitivity analyses on potential heterogeneity and pleiotropy, two\u2010step MR, and mediation analysis. We found evidence for a causal effect of gallstone disease on GBC risk in Chileans (<jats:italic toggle=\"yes\">P<\/jats:italic>\u00a0=\u00a09\u00a0\u00d7\u00a010<jats:sup>\u22125<\/jats:sup>) and Europeans (<jats:italic toggle=\"yes\">P<\/jats:italic>\u00a0=\u00a09\u00a0\u00d7\u00a010<jats:sup>\u22125<\/jats:sup>). A genetically elevated body mass index (BMI) increased GBC risk in Chileans (<jats:italic toggle=\"yes\">P<\/jats:italic>\u00a0=\u00a00.03), while higher CRP concentrations increased GBC risk in Europeans (<jats:italic toggle=\"yes\">P<\/jats:italic>\u00a0=\u00a04.1\u00a0\u00d7\u00a010<jats:sup>\u22126<\/jats:sup>). European results suggest causal effects of BMI on gallstone disease (<jats:italic toggle=\"yes\">P<\/jats:italic>\u00a0=\u00a00.008); public Chilean data were not, however, available to enable assessment of the mediation effects among causal GBC risk factors.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Conclusions<\/jats:title>\n            <jats:p>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.<\/jats:p>\n          <\/jats:sec>","DOI":"10.1002\/hep.31537","type":"journal-article","created":{"date-parts":[[2020,9,24]],"date-time":"2020-09-24T12:26:59Z","timestamp":1600950419000},"page":"1783-1796","update-policy":"https:\/\/doi.org\/10.1097\/lww.0000000000001000","source":"Crossref","is-referenced-by-count":71,"title":["Gallstones, Body Mass Index, C\u2010Reactive Protein, and Gallbladder Cancer: Mendelian Randomization Analysis of Chilean and European Genotype Data"],"prefix":"10.1097","volume":"73","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-9505-4965","authenticated-orcid":false,"given":"Carol","family":"Barahona Ponce","sequence":"first","affiliation":[{"name":"Statistical Genetics Group,Institute of Medical Biometry and Informatics,University of Heidelberg,Heidelberg,Germany"},{"name":"Department of Basic and Clinical Oncology,Medical Faculty,University of Chile,Santiago de Chile,Chile"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4430-296X","authenticated-orcid":false,"given":"Dominique","family":"Scherer","sequence":"additional","affiliation":[{"name":"Statistical Genetics Group,Institute of Medical Biometry and Informatics,University of Heidelberg,Heidelberg,Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Regina","family":"Brinster","sequence":"additional","affiliation":[{"name":"Statistical Genetics Group,Institute of Medical Biometry and Informatics,University of Heidelberg,Heidelberg,Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0587-7624","authenticated-orcid":false,"given":"Felix","family":"Boekstegers","sequence":"additional","affiliation":[{"name":"Statistical Genetics Group,Institute of Medical Biometry and Informatics,University of Heidelberg,Heidelberg,Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Katherine","family":"Marcelain","sequence":"additional","affiliation":[{"name":"Department of Basic and Clinical Oncology,Medical Faculty,University of Chile,Santiago de Chile,Chile"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Valentina","family":"G\u00e1rate\u2010Calder\u00f3n","sequence":"additional","affiliation":[{"name":"Statistical Genetics Group,Institute of Medical Biometry and Informatics,University of Heidelberg,Heidelberg,Germany"},{"name":"Department of Basic and Clinical Oncology,Medical Faculty,University of Chile,Santiago de Chile,Chile"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bettina","family":"M\u00fcller","sequence":"additional","affiliation":[{"name":"Servicio de Oncolog\u00eda M\u00e9dica,Instituto Nacional del C\u00e1ncer,Santiago,Chile"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gonzalo","family":"de Toro","sequence":"additional","affiliation":[{"name":"Escuela de Tecnologia Medica,Universidad Austral de Chile sede Puerto Montt,Puerto Montt,Chile"},{"name":"Servicio de Anatom\u00eda Patol\u00f3gica,Hospital de Puerto Montt,Puerto Montt,Chile"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Javier","family":"Retamales","sequence":"additional","affiliation":[{"name":"Servicio de Oncolog\u00eda M\u00e9dica,Instituto Nacional del C\u00e1ncer,Santiago,Chile"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Olga","family":"Barajas","sequence":"additional","affiliation":[{"name":"Department of Basic and Clinical Oncology,Medical Faculty,University of Chile,Santiago de Chile,Chile"},{"name":"Department of Basic and Clinical Oncology, Medical Faculty,University of Chile,Santiago,Chile"},{"name":"Oncology Department,Hospital Cl\u00ednico Universidad de 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