Cancers, Vol. 16, Pages 4195: Inbreeding and Gallbladder Cancer Risk: Homozygosity Associations Adjusted for Indigenous American Ancestry, BMI, and Genetic Risk of Gallstone Disease

Cancers, Vol. 16, Pages 4195: Inbreeding and Gallbladder Cancer Risk: Homozygosity Associations Adjusted for Indigenous American Ancestry, BMI, and Genetic Risk of Gallstone Disease

Cancers doi: 10.3390/cancers16244195

Authors: 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 Daniel Carvajal-Hausdorf Héctor Losada Mauricio Almau Plinio Fernández Jordi Olloquequi Pamela Salinas Justo Lorenzo Bermejo

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.