Browsing by Author "Bustos, Bernabé I."

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    Assessing the Occurrence and Influence of Cancer Chemotherapy-Related Pharmacogenetic Alleles in the Chilean Population
    (2024) Owen, Gareth Ivor; Córdova-Delgado, Miguel; Bustos, Bernabé I.; Cerpa Castro, Leslie; González Hevia, Pamela Andrea; Morales-Pison, Sebastián; García-Bloj, Benjamín; Garrido, Marcelo; Miquel, Juan Francisco; Quiñones, Luis A.
    Background: Pharmacogenomic knowledge as a biomarker for cancer care has transformed clinical practice, however, as current guidelines are primarily derived from Eurocentric populations, this limits their application in Latin America, particularly among Hispanic or Latino groups. Despite advancements, systemic chemotherapy still poses challenges in drug toxicity and suboptimal response. This study explores pharmacogenetic markers related to anticancer drugs in a Chilean cohort, filling a gap in Latin American research. Notably, the influence of native South American Mapuche-Huilliche ancestry. Methods: To explore pharmacogenetic markers related to anticancer drugs, we utilized an ethnically Admixed Chilean genome-wide association studies (GWAS) dataset of 1095 unrelated individuals. Pharmacogenomic markers were selected from PharmGKB, totaling 36 level 1 and 2 evidence single nucleotide polymorphisms (SNPs) and 571 level 3 SNPs. Comparative analyses involved assessing SNP frequencies across diverse populations from the 1000 Genomes Project. Haplotypes were estimated, and linkage disequilibrium was examined. Ancestry-based association analyses explored relationships between SNPs and Mapuche-Huilliche and European ancestries. Chi-square distribution with p ≤ 0.05 and Bonferroni’s multiple adjustment tests determined statistical differences between allele frequencies. Results: Our study reveals significant disparities in SNP frequency within the Chilean population. Notably, dihydropyrimidine dehydrogenase (DPYD) variants (rs75017182 and rs67376798), linked to an increased risk of severe fluoropyrimidine toxicity, exhibit an exceptionally low frequency (minor allele frequency (MAF) < 0.005). Nudix hydrolase 15 (NUDT15) rs116855232, associated with hematological mercaptopurine toxicity, is relatively common (MAF = 0.062), and is further linked to Mapuche-Huilliche ancestry. Thiopurine methyltransferase enzyme (TPMT), implicated in severe toxicity to mercaptopurines, SNPs rs1142345 and rs1800460 of TMPT gene demonstrate higher MAFs in Admixed Americans and the Chilean population (MAF range 0.031–0.057). Finally, the variant in the UDP-glucuronosyltransferase 1 gene (UGT1A1) rs4148323, correlated with irinotecan neutropenia, exhibits the highest MAF in East Asian (MAF = 0.136) and Chilean (MAF = 0.025) populations, distinguishing them from other investigated populations. Conclusions: This study provides the first comprehensive pharmacogenetic characterization of cancer therapy-related SNPs and highlights significant disparities in SNP frequencies within the Chilean population. Our findings underscore the necessity for inclusive research and personalized therapeutic strategies to ensure the equitable and effective application of precision medicine across diverse global communities.
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    Common variants in ABCG8 and TRAF3 genes confer risk for gallstone disease and gallbladder cancer in admixed Latinos with Mapuche Native American ancestry
    (2018) Bustos, Bernabé I.; Pérez Palma, Eduardo; Buch, Stephan; Azócar, Lorena; Riveras, Eleodoro; Ugarte, Giorgia D.; Toliat, Mohammad; Nürnberg, Peter; Lieb, Wolfgang; Franke, Andre; Hinz, Sebastian; Burmeister, Greta; von Schönfels, Witigo; Schafmayer, Clemens; Völzke, Henry; Völker, Uwe; Homuth, Georg; Lerch, Markus M.; Santos Martín, José Luis; Puschel Illanes, Klaus; Bambs S., Claudia; Gutiérrez Ilabaca, Rodrigo Antonio; Hampe, Jochen; de Ferrari, Giancarlo V.; Miquel, Juan Francisco
    Background Latin Americans and Chilean Amerindians have the highest prevalence of cholesterol gallstone disease (GSD) and gallbladder cancer (GBC) in the world. A handful of loci have been associated with GSD in populations of predominantly European ancestry, however they only explain a small portion of the population-attributable risk of the disease.Methods We performed a genome-wide association study (GWAS) for GSD in 1,095 admixed Latinos with Mapuche Native American Ancestry, followed by a replication analysis of 10 candidate single nucleotide polymorphisms (SNPs) with suggestive genome-wide significance (P<1×10−5) in 1,643 individuals. Disease status was assessed by cholecystectomy or abdominal ultrasonography. Logistic regression analyses were adjusted for age, sex, BMI, Type 2 Diabetes and Amerindian ancestry. Associated variants were further examined in two large GSD European populations and in a Chilean gallbladder cancer (GBC) cohort. We determined the expression levels of a novel GSD-candidate gene in normal and GSD-tissue samples.Results We consistently replicated the ABCG8 gene (rs11887534; P=3.24×10−8, OR=1.74) associated with GSD in admixed Latinos and identified a novel candidate signal within the TRAF3 gene on chromosome 14 (rs12882491; P=1.11×10−7, OR=1.40). ABCG8 and TRAF3 variants also conferred risk to GBC. Gene expression analyses indicated that TRAF3 levels were significantly decreased in the gallbladder (P=0.015) and the duodenal mucosa (P=0.001) of affected GSD individuals compared to healthy controls.Conclusions We confirmed ABCG8 and identified TRAF3 both associated with GSD and GBC in admixed Latinos. Decreased TRAF3 expression levels could enhance gallbladder inflammation as is observed in GSD and GSD-associated GBC.
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    Gallbladder Cancer Risk and Indigenous South American Mapuche Ancestry: Instrumental Variable Analysis Using Ancestry-Informative Markers
    (2023) 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
    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.
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    Variants in ABCG8 and TRAF3 genes confer risk for gallstone disease in admixed Latinos with Mapuche Native American ancestry
    (2019) Bustos, Bernabé I.; Pérez-Palma, Eduardo; Buch, Stephan; Azócar, Lorena; Riveras Hernández, Eleodoro Javier; Ugarte, Giorgia D.; Gutiérrez Ilabaca, Rodrigo Antonio; Nürnberg, Peter; Lieb, Wolfgang; Franke, Andre; Hinz, Sebastian; Burmeister, Greta; Schönfels, Witigo von; Schafmayer, Clemens; Völzke, Henry; Völker, Uwe; Homuth, Georg; Lerch, Markus M.; Santos Martín, José Luis; Puschel Illanes, Klaus; Bambs S., Claudia; Roa Strauch, Juan Carlos Enrique; Toliat, Mohammad; Hampe, Jochen; Ferrari, Giancarlo V. de; Miquel P., Juan Francisco
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    Whole genome sequence of Mapuche-Huilliche Native Americans
    (2018) Vidal Olate, Elena Alejandra; Moyano Yugovic, Tomás Custodio; Bustos, Bernabé I.; Pérez-Palma, Eduardo; Moraga Marín, Carol Mabel; Montecinos López, Alejandro; Azócar López, Lorena Karina; Soto Wilder, Daniela Constanza; Riveras, Eleodoro; Vidal, Mabel; Genova, Alex Di; Puschel Illanes, Klaus; Nürnberg, Peter; Buch, Stephan; Hampe, Jochen; Eyheramendy Duerr, Susana; Miquel Poblete, Juan Francisco; Gutiérrez Ilabaca, Rodrigo Antonio
    Background Whole human genome sequencing initiatives provide a compendium of genetic variants that help us understand population history and the basis of genetic diseases. Current data mostly focuses on Old World populations and information on the genomic structure of Native Americans, especially those from the Southern Cone is scant. Results Here we present a high-quality complete genome sequence of 11 Mapuche-Huilliche individuals (HUI) from Southern Chile (85% genomic and 98% exonic coverage at > 30X), with 96-97% high confidence calls. We found approximately 3.1x106 single nucleotide variants (SNVs) per individual and identified 403,383 (6.9%) of novel SNVs that are not included in current sequencing databases. Analyses of large-scale genomic events detected 680 copy number variants (CNVs) and 4,514 structural variants (SVs), including 398 and 1,910 novel events, respectively. Global ancestry composition of HUI genomes revealed that the cohort represents a marginally admixed population from the Southern Cone, whose genetic component is derived from early Native American ancestors. In addition, we found that HUI genomes display highly divergent and novel variants with potential functional impact that converge in ontological categories essential in cell metabolic processes. Conclusions Mapuche-Huilliche genomes contain a unique set of small- and large-scale genomic variants in functionally linked genes, which may contribute to susceptibility for the development of common complex diseases or traits in admixed Latinos and Native American populations. Our data represents an ancestral reference panel for population-based studies in Native and admixed Latin American populations