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Gallbladder Cancer Risk and Indigenous South American Mapuche Ancestry: Instrumental Variable Analysis Using Ancestry-Informative Markers

2023; Multidisciplinary Digital Publishing Institute; Volume: 15; Issue: 16 Linguagem: Inglês

10.3390/cancers15164033

2072-6694

Linda Zollner, Felix Boekstegers, Carol Barahona Ponce, Dominique Scherer, Katherine Marcelain, Valentina Gárate‐Calderón, Mélanie 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 Beltr n Ortega, Maria Enriqueta Bertrán, Leonardo Bartolotti, Fernando Gabler, Mónica Campos, Juan Alvarado, Fabricio Moisán, M. Loreto Spencer, Bruno Nervi, Daniel Carvajal, H. Losada Morales, Mauricio Almau, Plinio Fernández, Jordi Olloquequi, Alice R Carter, Juan Francisco Miquel, Bernabé I. Bustos, Macarena Fuentes‐Guajardo, Rolando González‐José, María Cátira Bortolini, Víctor Acuña-Alonzo, Carla Gallo, Andrés Ruiz‐Linares, Francisco Rothhammer, Justo Lorenzo Bermejo,

Colorectal Cancer Screening and Detection

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.