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

doi:10.3390/cancers15164033

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

School of Science and Engineering

Heidelberg University
German Cancer Research Center
Universidad de Chile
German Research Center for Environmental Health
Unidad de Anatomía Patológica del Hospital Regional de Talca
Catholic University of the Maule
Instituto Nacional del Cáncer, Chile
Hospital de Puerto Montt
Universidad Austral de Chile
Hospital Clínico Universidad De Chile
Hospital del Salvador
Hospital Padre Hurtado
Hospital San Juan de Dios, Santiago de Chile
Hospital Regional
Hospital Base Valdivia
Hospital Clínico “San Borja Arriarán”
Hospital Regional Guillermo Grant Benavente
Escuela de Medicina
Faculty of Medicine Clinica Alemana Universidad del Desarrollo
Universidad de la Frontera
Hospital de Rancagua
Universitat de Barcelona
Universidad Autónoma de Chile
Bristol Medical School
Northwestern University Feinberg School of Medicine
Instituto de Alta Investigación Universidad de Tarapacá
CENPAT-CONICET
Universidade Federal do Rio Grande do Sul
National Institute of Anthropology and History
Fudan University
ADES
University College London
Institut de Cancérologie Strasbourg Europe

Research output: Contribution to journal › Article › peer-review

23 Scopus citations

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.

Original language	English
Article number	4033
Journal	Cancers
Volume	15
Issue number	16
DOIs	https://doi.org/10.3390/cancers15164033
State	Published - Aug 2023

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

SDG 3 Good Health and Well-being

Keywords

Mendelian randomization
ancestry-informative markers
causal inference
gallbladder cancer
gallstone disease
genetic admixture
indigenous South American Mapuche ancestry
instrumental variables

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10.3390/cancers15164033

Cite this

Zollner, L., Boekstegers, F., Barahona Ponce, C., Scherer, D., Marcelain, K., Gárate-Calderón, V., Waldenberger, M., Morales, E., Rojas, A., Munoz, C., Retamales, J., De Toro, G., Kortmann, A. V., Barajas, O., Rivera, M. T., Cortés, A., Loader, D., Saavedra, J., Gutiérrez, L., ... Lorenzo Bermejo, J. (2023). Gallbladder Cancer Risk and Indigenous South American Mapuche Ancestry: Instrumental Variable Analysis Using Ancestry-Informative Markers. Cancers, 15(16), Article 4033. https://doi.org/10.3390/cancers15164033

@article{27b6e3e3545047b0bae98404bcee2ea5,

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

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 = "Mendelian randomization, ancestry-informative markers, causal inference, gallbladder cancer, gallstone disease, genetic admixture, indigenous South American Mapuche ancestry, instrumental variables",

author = "Linda Zollner and Felix Boekstegers and \{Barahona Ponce\}, Carol and Dominique Scherer and Katherine Marcelain and Valentina G{\'a}rate-Calder{\'o}n and Melanie Waldenberger and Erik Morales and Armando Rojas and C{\'e}sar Munoz and Javier Retamales and \{De Toro\}, Gonzalo and Kortmann, \{Allan Vera\} and Olga Barajas and Rivera, \{Mar{\'i}a Teresa\} and Anal{\'i}a Cort{\'e}s and Denisse Loader and Javiera Saavedra and Lorena Guti{\'e}rrez and Alejandro Ortega and Bertr{\'a}n, \{Maria Enriqueta\} and Leonardo Bartolotti and Fernando Gabler and M{\'o}nica Campos and Juan Alvarado and Fabricio Mois{\'a}n and Loreto Spencer and Bruno Nervi and Daniel Carvajal and H{\'e}ctor Losada and Mauricio Almau and Plinio Fern{\'a}ndez and Jordi Olloquequi and Carter, \{Alice R.\} and \{Miquel Poblete\}, \{Juan Francisco\} and Bustos, \{Bernabe Ignacio\} and \{Fuentes Guajardo\}, Macarena and Rolando Gonzalez-Jose and Bortolini, \{Maria C{\'a}tira\} and Victor Acu{\~n}a-Alonzo and Carla Gallo and \{Ruiz Linares\}, Andres and Francisco Rothhammer and \{Lorenzo Bermejo\}, Justo",

note = "Publisher Copyright: {\textcopyright} 2023 by the authors.",

year = "2023",

month = aug,

doi = "10.3390/cancers15164033",

language = "Ingl{\'e}s",

volume = "15",

journal = "Cancers",

issn = "2072-6694",

number = "16",

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Zollner, L, Boekstegers, F, Barahona Ponce, C, Scherer, D, Marcelain, K, Gárate-Calderón, V, Waldenberger, M, Morales, E, Rojas, A, Munoz, C, Retamales, J, De Toro, G, Kortmann, AV, Barajas, O, Rivera, MT, Cortés, A, Loader, D, Saavedra, J, Gutiérrez, L, Ortega, A, Bertrán, ME, Bartolotti, L, Gabler, F, Campos, M, Alvarado, J, Moisán, F, Spencer, L, Nervi, B, Carvajal, D, Losada, H, Almau, M, Fernández, P, Olloquequi, J, Carter, AR, Miquel Poblete, JF, Bustos, BI, Fuentes Guajardo, M, Gonzalez-Jose, R, Bortolini, MC, Acuña-Alonzo, V, Gallo, C, Ruiz Linares, A, Rothhammer, F & Lorenzo Bermejo, J 2023, 'Gallbladder Cancer Risk and Indigenous South American Mapuche Ancestry: Instrumental Variable Analysis Using Ancestry-Informative Markers', Cancers, vol. 15, no. 16, 4033. https://doi.org/10.3390/cancers15164033

TY - JOUR

T1 - Gallbladder Cancer Risk and Indigenous South American Mapuche Ancestry

T2 - Instrumental Variable Analysis Using Ancestry-Informative Markers

AU - Zollner, Linda

AU - Boekstegers, Felix

AU - Barahona Ponce, Carol

AU - Scherer, Dominique

AU - Marcelain, Katherine

AU - Gárate-Calderón, Valentina

AU - Waldenberger, Melanie

AU - Morales, Erik

AU - Rojas, Armando

AU - Munoz, César

AU - Retamales, Javier

AU - De Toro, Gonzalo

AU - Kortmann, Allan Vera

AU - Barajas, Olga

AU - Rivera, María Teresa

AU - Cortés, Analía

AU - Loader, Denisse

AU - Saavedra, Javiera

AU - Gutiérrez, Lorena

AU - Ortega, Alejandro

AU - Bertrán, Maria Enriqueta

AU - Bartolotti, Leonardo

AU - Gabler, Fernando

AU - Campos, Mónica

AU - Alvarado, Juan

AU - Moisán, Fabricio

AU - Spencer, Loreto

AU - Nervi, Bruno

AU - Carvajal, Daniel

AU - Losada, Héctor

AU - Almau, Mauricio

AU - Fernández, Plinio

AU - Olloquequi, Jordi

AU - Carter, Alice R.

AU - Miquel Poblete, Juan Francisco

AU - Bustos, Bernabe Ignacio

AU - Fuentes Guajardo, Macarena

AU - Gonzalez-Jose, Rolando

AU - Bortolini, Maria Cátira

AU - Acuña-Alonzo, Victor

AU - Gallo, Carla

AU - Ruiz Linares, Andres

AU - Rothhammer, Francisco

AU - Lorenzo Bermejo, Justo

PY - 2023/8

Y1 - 2023/8

N2 - 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.

AB - 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.

KW - Mendelian randomization

KW - ancestry-informative markers

KW - causal inference

KW - gallbladder cancer

KW - gallstone disease

KW - genetic admixture

KW - indigenous South American Mapuche ancestry

KW - instrumental variables

UR - https://www.scopus.com/pages/publications/85168872244

U2 - 10.3390/cancers15164033

DO - 10.3390/cancers15164033

M3 - Artículo

AN - SCOPUS:85168872244

SN - 2072-6694

VL - 15

JO - Cancers

JF - Cancers

IS - 16

M1 - 4033

ER -

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

Abstract

UN SDGs

Keywords

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