Gallbladder Cancer Risk and Indigenous South American Mapuche Ancestry: Instrumental Variable Analysis Using Ancestry-Informative Markers
Autor
Zollner, Linda
Boekstegers, Felix
Barahona Ponce, Carol
Scherer, Dominique
Marcelain, Katherine
Gárate-Calderón, Valentina
Waldenberger, Melanie
Morales, Erik
Rojas, Armando
Munoz, César
Retamales, Javier
De Toro, Gonzalo
Kortmann, Allan Vera
Barajas, Olga
Rivera, María Teresa
Cortés, Analía
Loader, Denisse
Saavedra, Javiera
Gutiérrez, Lorena
Ortega, Alejandro
Bertrán, Maria Enriqueta
Bartolotti, Leonardo
Gabler, Fernando
Campos, Mónica
Alvarado, Juan
Moisán, Fabricio
Spencer, Loreto
Nervi, Bruno
Carvajal, Daniel
Losada, Héctor
Almau, Mauricio
Fernández, Plinio
Olloquequi, Jordi
Carter, Alice R.
Miquel Poblete, Juan Francisco
Bustos, Bernabe Ignacio
Fuentes Guajardo, Macarena
Gonzalez-Jose, Rolando
Bortolini, Maria Cátira
Acuña-Alonzo, Victor
Gallo, Carla
Ruiz Linares, Andres
Rothhammer, Francisco
Lorenzo Bermejo, Justo
Resumen
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. © 2023 by the authors.
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