Browsing by Author "Boekstegers, Felix"
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- ItemDevelopment and internal validation of a multifactorial risk prediction model for gallbladder cancer in a high-incidence country(2023) Boekstegers, Felix; Scherer, Dominique; Barahona Ponce, Carol; Marcelain, Katherine; Garate-Calderon, Valentina; Waldenberger, Melanie; Morales, Erik; Rojas, Armando; Munoz, Cesar; Retamales, Javier; de Toro, Gonzalo; Barajas, Olga; Rivera, Maria Teresa; Cortes, Analia; Loader, Denisse; Saavedra, Javiera; Gutierrez, Lorena; Ortega, Alejandro; Bertran, Maria Enriqueta; Bartolotti, Leonardo; Gabler, Fernando; Campos, Monica; Alvarado, Juan; Moisan, Fabricio; Spencer, Loreto; Nervi, Bruno; Carvajal-Hausdorf, Daniel; Losada, Hector; Almau, Mauricio; Fernandez, Plinio; Olloquequi, Jordi; Fuentes-Guajardo, Macarena; Gonzalez-Jose, Rolando; Bortolini, Maria Catira; Acuna-Alonzo, Victor; Gallo, Carla; Linares, Andres Ruiz; Rothhammer, Francisco; Lorenzo Bermejo, JustoSince 2006, Chile has been implementing a gallbladder cancer (GBC) prevention program based on prophylactic cholecystectomy for gallstone patients aged 35 to 49 years. The effectiveness of this prevention program has not yet been comprehensively evaluated. We conducted a retrospective study of 473 Chilean GBC patients and 2137 population-based controls to develop and internally validate three GBC risk prediction models. The Baseline Model accounted for gallstones while adjusting for sex and birth year. Enhanced Model I also included the non-genetic risk factors: body mass index, educational level, Mapuche surnames, number of children and family history of GBC. Enhanced Model II further included Mapuche ancestry and the genotype for rs17209837. Multiple Cox regression was applied to assess the predictive performance, quantified by the area under the precision-recall curve (AUC-PRC) and the number of cholecystectomies needed (NCN) to prevent one case of GBC at age 70 years. The AUC-PRC for the Baseline Model (0.44%, 95%CI 0.42-0.46) increased by 0.22 (95%CI 0.15-0.29) when non-genetic factors were included, and by 0.25 (95%CI 0.20-0.30) when incorporating non-genetic and genetic factors. The overall NCN for Chileans with gallstones (115, 95%CI 104-131) decreased to 92 (95%CI 60-128) for Chileans with a higher risk than the median according to Enhanced Model I, and to 80 (95%CI 59-110) according to Enhanced Model II. In conclusion, age, sex and gallstones are strong risk factors for GBC, but consideration of other non-genetic factors and individual genotype data improves risk prediction and may optimize allocation of financial resources and surgical capacity.
- ItemGallbladder 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 LorenzoA 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.
- ItemIdentification of Circulating lncRNAs Associated with Gallbladder Cancer Risk by Tissue-Based Preselection, Cis-eQTL Validation, and Analysis of Association with Genotype-Based Expression(2022) Blandino, Alice; Scherer, Dominique; Rounge, Trine B.; Umu, Sinan U.; Boekstegers, Felix; Barahona Ponce, Carol; Marcelain, Katherine; Garate-Calderon, Valentina; Waldenberger, Melanie; Morales, Erik; Rojas, Armando; Munoz, Cesar; Retamales, Javier; de Toro, Gonzalo; Barajas, Olga; Rivera, Maria Teresa; Cortes, Analia; Loader, Denisse; Saavedra, Javiera; Gutierrez, Lorena; Ortega, Alejandro; Bertran, Maria Enriqueta; Gabler, Fernando; Campos, Monica; Alvarado, Juan; Moisan, Fabrizio; Spencer, Loreto; Nervi, Bruno; Carvajal-Hausdorf, Daniel E.; Losada, Hector; Almau, Mauricio; Fernandez, Plinio; Gallegos, Ivan; Olloquequi, Jordi; Fuentes-Guajardo, Macarena; Gonzalez-Jose, Rolando; Bortolini, Maria Catira; Gallo, Carla; Linares, Andres Ruiz; Rothhammer, Francisco; Lorenzo Bermejo, JustoSimple Summary Gallbladder cancer (GBC) is an aggressive disease with poor prognosis that urgently needs risk biomarkers for prevention. Long noncoding RNAs (lncRNAs) have been linked to various types of cancer and have good potential as circulating biomarkers. Prediction of lncRNA expression based on genotype data may contribute to quantify individual GBC risk even without direct lncRNA expression measurement. In this study, we investigate the relationship between GBC risk and genotype-based expression of circulating lncRNAs. Long noncoding RNAs (lncRNAs) play key roles in cell processes and are good candidates for cancer risk prediction. Few studies have investigated the association between individual genotypes and lncRNA expression. Here we integrate three separate datasets with information on lncRNA expression only, both lncRNA expression and genotype, and genotype information only to identify circulating lncRNAs associated with the risk of gallbladder cancer (GBC) using robust linear and logistic regression techniques. In the first dataset, we preselect lncRNAs based on expression changes along the sequence "gallstones -> dysplasia -> GBC". In the second dataset, we validate associations between genetic variants and serum expression levels of the preselected lncRNAs (cis-lncRNA-eQTLs) and build lncRNA expression prediction models. In the third dataset, we predict serum lncRNA expression based on individual genotypes and assess the association between genotype-based expression and GBC risk. AC084082.3 and LINC00662 showed increasing expression levels (p-value = 0.009), while C22orf34 expression decreased in the sequence from gallstones to GBC (p-value = 0.04). We identified and validated two cis-LINC00662-eQTLs (r(2) = 0.26) and three cis-C22orf34-eQTLs (r(2) = 0.24). Only LINC00662 showed a genotyped-based serum expression associated with GBC risk (OR = 1.25 per log2 expression unit, 95% CI 1.04-1.52, p-value = 0.02). Our results suggest that preselection of lncRNAs based on tissue samples and exploitation of cis-lncRNA-eQTLs may facilitate the identification of circulating noncoding RNAs linked to cancer risk.
- ItemPRDM15 Is Associated with Risk of Chronic Obstructive Pulmonary Disease in a Rural Population in Chile(KARGER, 2020) Hosgood, H. Dean, III; Diaz Pena, Roberto; Blansky, Deanna; Jaime, Sergio; Parra, Viviana; Boekstegers, Felix; Bermejo, Justo Lorenzo; Garcia Valero, Jose; Montes, Juan F.; Valdivia, Gonzalo; Miravitlles, Marc; Agusti, Alvar; Silva, Rafael S.; Olloquequi, JordiBackground: Genome-wide association studies (GWAS) have accelerated our understanding of the genetic underpinnings of chronic obstructive pulmonary disease (COPD); however, GWAS populations have typically consisted of European descent, with similar to 1% of Latin American ancestry. Objective: To overcome this limitation, we conducted a GWAS in a rural Chilean population with increased COPD risk to investigate genetic variation of COPD risk in this understudied minority population. Method: We carried out a case-control study of 214 COPD patients (defined by the GOLD criteria) and 193 healthy controls in Talca, Chile. DNA was extracted from venous blood and genotyped on the Illumina Global Screening Array (n = 754,159 markers). After exclusion based on Hardy-Weinberg equilibrium (p <= 0.001), call rates (<95%), and minor allele frequencies (<0.5%) in controls, 455,564 markers were available for logistic regression. Results: PRDM15 rs1054761 C allele (p = 2.22 x 10(-7)) was associated with decreased COPD risk. Three PRDM15 SNPs located on chromosome 21 were significantly associated with COPD risk (p < 10(-6)). Two of these SNPs, rs1054761 and rs4075967, were located on a noncoding transcript variant region of the gene. Conclusion: PRDM15 overexpression may play a role in the B-cell dysregulation in COPD pathogenesis. To the best of our knowledge, the association between PRDM15 and COPD risk was not previously found in GWAS studies in largely European populations, highlighting the importance of investigating novel variants associated with COPD risk among ethnically diverse populations.
- ItemSubtypes of Native American ancestry and leading causes of death: Mapuche ancestry-specific associations with gallbladder cancer risk in Chile(2017) Bermejo, Justo Lorenzo; Boekstegers, Felix; González Silos, Rosa; Marcelain, Katherine; Báez Benavides, Pablo; Barahona Ponce, Carol; Müller, Bettina; Ferreccio Readi, Catterina; Koshiol, Jill; Fischer, Christine