Cancers (Aug 2023)
Gallbladder Cancer Risk and Indigenous South American Mapuche Ancestry: Instrumental Variable Analysis Using Ancestry-Informative Markers
- Linda Zollner,
- Felix Boekstegers,
- Carol Barahona Ponce,
- Dominique Scherer,
- Katherine Marcelain,
- Valentina Gárate-Calderón,
- Melanie Waldenberger,
- Erik Morales,
- Armando Rojas,
- César Munoz,
- Javier Retamales,
- Gonzalo De Toro,
- Allan Vera Kortmann,
- Olga Barajas,
- María Teresa Rivera,
- Analía Cortés,
- Denisse Loader,
- Javiera Saavedra,
- Lorena Gutiérrez,
- Alejandro Ortega,
- Maria Enriqueta Bertrán,
- Leonardo Bartolotti,
- Fernando Gabler,
- Mónica Campos,
- Juan Alvarado,
- Fabricio Moisán,
- Loreto Spencer,
- Bruno Nervi,
- Daniel Carvajal,
- Héctor Losada,
- Mauricio Almau,
- Plinio Fernández,
- Jordi Olloquequi,
- Alice R. Carter,
- Juan Francisco Miquel Poblete,
- Bernabe Ignacio Bustos,
- Macarena Fuentes Guajardo,
- Rolando Gonzalez-Jose,
- Maria Cátira Bortolini,
- Victor Acuña-Alonzo,
- Carla Gallo,
- Andres Ruiz Linares,
- Francisco Rothhammer,
- Justo Lorenzo Bermejo
Affiliations
- Linda Zollner
- Statistical Genetics Research Group, Institute of Medical Biometry, Heidelberg University, 69120 Heidelberg, Germany
- Felix Boekstegers
- Statistical Genetics Research Group, Institute of Medical Biometry, Heidelberg University, 69120 Heidelberg, Germany
- Carol Barahona Ponce
- Statistical Genetics Research Group, Institute of Medical Biometry, Heidelberg University, 69120 Heidelberg, Germany
- Dominique Scherer
- Statistical Genetics Research Group, Institute of Medical Biometry, Heidelberg University, 69120 Heidelberg, Germany
- Katherine Marcelain
- Department of Basic and Clinical Oncology, Medical Faculty, University of Chile, Santiago 8380000, Chile
- Valentina Gárate-Calderón
- Statistical Genetics Research Group, Institute of Medical Biometry, Heidelberg University, 69120 Heidelberg, Germany
- Melanie Waldenberger
- Research Unit Molecular Epidemiology, Institute of Epidemiology, Helmholtz Zentrum München, German Research Center for Environmental Health, 85764 Neuherberg, Germany
- Erik Morales
- Hospital Regional de Talca, Talca 3460000, Chile
- Armando Rojas
- Facultad de Medicina, Universidad Católica del Maule, Talca 3460000, Chile
- César Munoz
- Hospital Regional de Talca, Talca 3460000, Chile
- Javier Retamales
- Instituto Nacional del Cáncer, Santiago 7500650, Chile
- Gonzalo De Toro
- Hospital de Puerto Montt, Puerto Montt 5480000, Chile
- Allan Vera Kortmann
- Hospital de Puerto Montt, Puerto Montt 5480000, Chile
- Olga Barajas
- Department of Basic and Clinical Oncology, Medical Faculty, University of Chile, Santiago 8380000, Chile
- María Teresa Rivera
- Hospital del Salvador, Santiago 7500922, Chile
- Analía Cortés
- Hospital del Salvador, Santiago 7500922, Chile
- Denisse Loader
- Hospital Padre Hurtado, Santiago 8880456, Chile
- Javiera Saavedra
- Hospital Padre Hurtado, Santiago 8880456, Chile
- Lorena Gutiérrez
- Hospital San Juan de Dios, Santiago 8320000, Chile
- Alejandro Ortega
- Hospital Regional, Arica 1000000, Chile
- Maria Enriqueta Bertrán
- Unidad Registro Hospitalario de Cáncer, Hospital Base de Valdivia, Valdivia 5090146, Chile
- Leonardo Bartolotti
- Hospital Base de Valdivia, Valdivia 5090000, Chile
- Fernando Gabler
- Hospital San Borja Arriarán, Santiago 8320000, Chile
- Mónica Campos
- Hospital San Borja Arriarán, Santiago 8320000, Chile
- Juan Alvarado
- Hospital Regional Guillermo Grant Benavente, Concepción 4070386, Chile
- Fabricio Moisán
- Hospital Regional Guillermo Grant Benavente, Concepción 4070386, Chile
- Loreto Spencer
- Hospital Regional Guillermo Grant Benavente, Concepción 4070386, Chile
- Bruno Nervi
- Departamento de Hematología y Oncología, Escuela de Medicina, Pontificia Universidad Católica de Chile, Santiago 8330077, Chile
- Daniel Carvajal
- Facultad de Medicina, Clínica Alemana Universidad del Desarrollo, Santiago 7650568, Chile
- Héctor Losada
- Departamento de Cirugía, Universidad de la Frontera, Temuco 4780000, Chile
- Mauricio Almau
- Hospital de Rancagua, Rancagua 2820000, Chile
- Plinio Fernández
- Hospital de Rancagua, Rancagua 2820000, Chile
- Jordi Olloquequi
- Department of Biochemistry and Physiology, Faculty of Pharmacy and Food Sciences, University of Barcelona, 08028 Barcelona, Spain
- Alice R. Carter
- MRC Integrative Epidemiology Unit, Population Health Sciences, Bristol Medical School, University of Bristol, Bristol BS8 1UD, UK
- Juan Francisco Miquel Poblete
- Departamento de Gastroenterología, Escuela de Medicina, Pontificia Universidad Católica de Chile, Santiago 8320000, Chile
- Bernabe Ignacio Bustos
- Ken and Ruth Davee Department of Neurology and Simpson Querrey Center for Neurogenetics, Northwestern University, Feinberg School of Medicine, Chicago, IL 60611, USA
- Macarena Fuentes Guajardo
- Departamento de Tecnología Médica, Facultad de Ciencias de la Salud, Tarapacá University, Arica 1000815, Chile
- Rolando Gonzalez-Jose
- Instituto Patagónico de Ciencias Sociales y Humanas, Centro Nacional Patagónico, CONICET, Puerto Madryn U9120ACD, Argentina
- Maria Cátira Bortolini
- Instituto de Biociências, Universidad Federal do Rio Grande do Sul, Puerto Alegre 15053, Brazil
- Victor Acuña-Alonzo
- National Institute of Anthropology and History, Mexico City 06600, Mexico
- Carla Gallo
- Laboratorios de Investigación y Desarrollo, Facultad de Ciencias y Filosofía, Universidad Peruana Cayetano Heredia, Lima 15102, Peru
- Andres Ruiz Linares
- Ministry of Education Key Laboratory of Contemporary Anthropology, Collaborative Innovation Center of Genetics and Development, School of Life Sciences and Human Phenome Institute, Fudan University, Shanghai 200434, China
- Francisco Rothhammer
- Instituto de Alta Investigación, Tarapacá University, Arica 1000000, Chile
- Justo Lorenzo Bermejo
- Statistical Genetics Research Group, Institute of Medical Biometry, Heidelberg University, 69120 Heidelberg, Germany
- DOI
- https://doi.org/10.3390/cancers15164033
- Journal volume & issue
-
Vol. 15,
no. 16
p. 4033
Abstract
A strong association between the proportion of indigenous South American Mapuche ancestry and the risk of gallbladder cancer (GBC) has been reported in observational studies. Chileans show the highest incidence of GBC worldwide, and the Mapuche are the largest indigenous people in Chile. We set out to assess the confounding-free effect of the individual proportion of Mapuche ancestry on GBC risk and to investigate the mediating effects of gallstone disease and body mass index (BMI) on this association. Genetic markers of Mapuche ancestry were selected based on the informativeness for assignment measure, and then used as instrumental variables in two-sample Mendelian randomization analyses and complementary sensitivity analyses. Results suggested a putatively causal effect of Mapuche ancestry on GBC risk (inverse variance-weighted (IVW) risk increase of 0.8% per 1% increase in Mapuche ancestry proportion, 95% CI 0.4% to 1.2%, p = 6.7 × 10−5) and also on gallstone disease (3.6% IVW risk increase, 95% CI 3.1% to 4.0%), pointing to a mediating effect of gallstones on the association between Mapuche ancestry and GBC. In contrast, the proportion of Mapuche ancestry showed a negative effect on BMI (IVW estimate −0.006 kg/m2, 95% CI −0.009 to −0.003). The results presented here may have significant implications for GBC prevention and are important for future admixture mapping studies. Given that the association between the individual proportion of Mapuche ancestry and GBC risk previously noted in observational studies appears to be free of confounding, primary and secondary prevention strategies that consider genetic ancestry could be particularly efficient.
Keywords
- gallbladder cancer
- gallstone disease
- genetic admixture
- indigenous South American Mapuche ancestry
- ancestry-informative markers
- causal inference