Inbreeding and Gallbladder Cancer Risk: Homozygosity Associations Adjusted for Indigenous American Ancestry, BMI, and Genetic Risk of Gallstone Disease
Journal
Cancers
ISSN
2072-6694
Date Issued
2024-12-17
Author(s)
Francisco Ceballos
Felix Boekstegers
Dominique Scherer
Carol Barahona Ponce
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
Héctor Losada
Mauricio Almau
Plinio Fernández
Jordi Olloquequi
Pamela Salinas
Justo Lorenzo Bermejo
Type
journal-article
Abstract
<jats:p>Latin Americans have a rich genetic make-up that translates into heterogeneous fractions of the autosomal genome in runs of homozygosity (FROH) and heterogeneous types and proportions of indigenous American ancestry. While autozygosity has been linked to several human diseases, very little is known about the relationship between inbreeding, genetic ancestry, and cancer risk in Latin Americans. Chile has one of the highest incidences of gallbladder cancer (GBC) in the world, and we investigated the association between inbreeding, GBC, gallstone disease (GSD), and body mass index (BMI) in 4029 genetically admixed Chileans. We calculated individual FROH above 1.5 Mb and weighted polygenic risk scores for GSD, and applied multiple logistic regression to assess the association between homozygosity and GBC risk. We found that homozygosity was due to a heterogeneous mixture of genetic drift and consanguinity in the study population. Although we found no association between homozygosity and overall GBC risk, we detected interactions of FROH with sex, age, and genetic risk of GSD that affected GBC risk. Specifically, the increase in GBC risk per 1% FROH was 19% in men (p-value = 0.002), 30% in those under 60 years of age (p-value = 0.001), and 12% in those with a genetic risk of GSD above the median (p-value = 0.01). The present study highlighted the complex interplay between inbreeding, genetic ancestry, and genetic risk of GSD in the development of GBC. The applied methodology and our findings underscored the importance of considering the population-specific genetic architecture, along with sex- and age-specific effects, when investigating the genetic basis of complex traits in Latin Americans.</jats:p>
Subjects
american ancestry
;
bmi
;
gallbladder cancer
;
inbreeding
;
runs of homozygosity
;
adult
;
aged
;
allele
;
article
;
body mass
;
cancer risk
;
chile
;
chilean
;
cholecystectomy
;
cholelithiasis
;
depression
;
female
;
genetic association
;
genetic drift
;
genetic risk
;
genetic risk score
;
genotype
;
genotyping
;
homozygosity
;
human
;
human experiment
;
inbreeding
;
male