artículo
Gallbladder Cancer Risk and Indigenous South American Mapuche Ancestry: Instrumental Variable Analysis Using Ancestry-Informative Markers
Fecha
2023Registro en:
10.3390/cancers15164033
Autor
Zollner, Linda
Boekstegers, Felix
Barahona Ponce, Carol
Scherer, Dominique
Marcelain, Katherine
Gárate-Calderón, Valentina
Waldenberger, Melanie
Morales Mejías, Erik
Rojas, Armando
Muñoz, César
Retamales, Javier
Toro, Gonzalo De
Vera Kortmann, Allan
Barajas, Olga
Rivera, María Teresa
Cortés, Analía
Loader, Denisse
Saavedra, Javiera
Gutiérrez, Lorena
Ortega, Alejandro
Bertrán, María Enriqueta
Bartolotti, Leonardo
Gabler, Fernando
Campos, Mónica
Alvarado, Juan
Moisán, Fabricio
Spencer, María Loreto
Nervi Nattero, Bruno
Carvajal-Hausdorf, Daniel
Losada, Héctor
Almau, Mauricio
Fernández, Plinio
Olloquequi, Jordi
Carter, Alice R.
Miquel P., Juan Francisco
Bustos, Bernabé I.
Fuentes Guajardo, Macarena
Gonzalez-Jose, Rolando
Bortolini, Maria Cátira
Acuña-Alonzo, Victor
Gallo, Carla
Ruiz Linares, Andrés
Rothhammer, Francisco
Bermejo, Justo Lorenzo
Institución
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.