Browsing by Author "Azócar, Lorena"

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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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    Genetic and functional identification of the likely causative variant for cholesterol gallstone disease at the ABCG5/8 lithogenic locus
    (2013) Von Kampen, Oliver; Buch, Stephan; Nothnagel, Michael; Azócar, Lorena; Molina, Héctor; Brosch, Mario; Erhart, Wiebke; Von Schöenfels, Witigo; Egberts, Jan; Seeger, Marcus; Miquel P., Juan Francisco; Puschel Illanes, Klaus
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    Prediction of Extraintestinal Manifestations in Inflammatory Bowel Disease Using Clinical and Genetic Variables with Machine Learning in a Latin IBD Group
    (2025) Pérez Jeldres, Tamara de Lourdes; Reyes Pérez, Paula; González Hormazábal, Patricio; Avendaño Soriano, Cristóbal Raimundo; Segovia Melero, Roberto; Azócar, Lorena; Verónica Silva; Andrés de la Vega; Arriagada, Elizabeth; Hernández, Elisa; Aguilar, Nataly; Pavez Ovalle, Carolina Denisse; Hernández Rocha, Cristián Antonio; Candia Balboa, Roberto Andrés; Miquel Poblete, Juan Francisco; Álvarez Lobos, Manuel Marcelo; Valdés, Ivania; Medina Rivera, Alejandra; Bustamante, María Leonor
    Extraintestinal manifestations (EIMs) significantly increase morbidity in inflammatory bowel disease (IBD) patients. In this study, we examined clinical and genetic factors associated with EIMs in 414 Latin IBD patients, utilizing machine learning for predictive modeling. In our IBD group (314 ulcerative colitis (UC) and 100 Crohn’s disease (CD) patients), EIM presence was assessed. Clinical differences between patients with and without EIMs were analyzed using Chi-square and Mann–Whitney U tests. Based on the genetic data of 232 patients, we identified variants linked to EIMs, and the polygenic risk score (PRS) was calculated. A machine learning approach based on logistic regression (LR), random forest (RF), and gradient boosting (GB) models was employed for predicting EIMs. EIMs were present in 29% (120/414) of patients. EIM patients were older (52 vs. 45 years, p = 0.01) and were more likely to have a family history of IBD (p = 0.02) or use anti-TNF therapy (p = 0.01). EIMs were more common in patients with CD than in those with UC without reaching statistical significance (p = 0.06). Four genetic variants were associated with EIM risk (rs9936833, rs4410871, rs3132680, and rs3823417). While the PRS showed limited predictive power (AUC = 0.69), the LR, GB, and RF models demonstrated good predictive capabilities. Approximately one-third of IBD patients experienced EIMs. Significant risk factors included genetic variants, family history, age, and anti-TNF therapy, with predictive models effectively identifying EIM risk.
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    Salmonella enterica serovar Typhi and gallbladder cancer : a case control study and meta-analysis
    (2016) Koshiol, Jill; Wozniak Banchero, Aniela; Cook, María Paz; Adaniel, Christina; Acevedo, Johanna; Azócar, Lorena; Roa Strauch, Juan Carlos Enrique; Miquel P., Juan Francisco; Ferreccio Readi, Catterina; Díaz, Alfonso; Molina, Héctor; Miranda, Carolina; Castillo, Claudia
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    Transcriptomic profiles reveal differences in zinc metabolism, inflammation, and tight junction proteins in duodenum from cholesterol gallstone subjects
    (2020) Riveras Hernández, Eleodoro Javier; Azócar, Lorena; Moyano, Tomás C.; Ocares, Marcia; Molina, Héctor; Romero, Diego; Roa Strauch, Juan Carlos Enrique; Valbuena Mora, José Rafael; Gutiérrez, Rodrigo A.; Miquel P., Juan Francisco
    Cholesterol Gallstone Disease (GSD) is a common multifactorial disorder characterized by crystallization and aggregation of biliary cholesterol in the gallbladder. The global prevalence of GSD is similar to 10-20% in the adult population but rises to 28% in Chile (17% among men and 30% among women). The small intestine may play a role in GSD pathogenesis, but the molecular mechanisms have not been clarified. Our aim was to identify the role of the small intestine in GSD pathogenesis. Duodenal biopsy samples were obtained from patients with GSD and healthy volunteers. GSD status was defined by abdominal ultrasonography. We performed a transcriptome study in a discovery cohort using Illumina HiSeq. 2500, and qPCR, immunohistochemistry and immunofluorescence were used to validate differentially expressed genes among additional case-control cohorts. 548 differentially expressed genes between GSD and control subjects were identified. Enriched biological processes related to cellular response to zinc, and immune and antimicrobial responses were observed in GSD patients. We validated lower transcript levels of metallothionein, NPC1L1 and tight junction genes and higher transcript levels of genes involved in immune and antimicrobial pathways in GSD patients. Interestingly, serum zinc and phytosterol to cholesterol precursor ratios were lower in GSD patients. A significant association was observed between serum zinc and phytosterol levels. Our results support a model where proximal small intestine plays a key role in GSD pathogenesis. Zinc supplementation, modulation of proximal microbiota and/or intestinal barrier may be novel targets for strategies to prevent GSD.