Cancer is a leading cause of death worldwide. The cancer incidence rate in Chile is 133.7/100,000 inhabitants and it is the second cause of death, after cardiovascular diseases. Most of the antineoplastic drugs are metabolized to be detoxified, and some of them to be activated. Genetic polymorphisms of drug-metabolizing enzymes can induce deep changes in enzyme activity, leading to individual variability in drug efficacy and/or toxicity. The present research describes the presence of genetic polymorphisms in the Chilean population, which might be useful in public health programs for personalized treatment of cancer, and compares these frequencies with those reported for Asian and Caucasian populations, as a contribution to the evaluation of ethnic differences in the response to chemotherapy. We analyzed 23 polymorphisms in a group of 253 unrelated Chilean volunteers from the general population. The results showed that CYP2A6*2, CYP2A6*3, CYP2D6*3, CYP2C19*3, and CYP3A4*17 variant alleles are virtually absent in Chileans. CYP1A1*2A allele frequency (0.37) is similar to that of Caucasians and higher than that reported for Japanese people. Allele frequencies for CYP3A5*3(0.76) and CYP2C9*3(0.04) are similar to those observed in Japanese people. CYP1A1*2C(0.32), CYP1A2*1F(0.77), CYP3A4*1B(0.06), CYP2D6*2(0.41), and MTHFR T(0.52) allele frequencies are higher than the observed either in Caucasian or in Japanese populations. Conversely, CYP2C19*2 allelic frequency (0.12), and genotype frequencies for GSTT1 null (0.11) and GSTM1 null (0.36) are lower than those observed in both populations. Finally, allele frequencies for CYP2A6*4(0.04), CYP2C8*3(0.06), CYP2C9*2(0.06), CYP2D6*4(0.12), CYP2E1*5B(0.14), CYP2E1*6(0.19), and UGT2B7*2(0.40) are intermediate in relation to those described in Caucasian and in Japanese populations, as expected according to the ethnic origin of the Chilean population. In conclusion, our findings support the idea that ethnic variability must be considered in the pharmacogenomic assessment of cancer pharmacotherapy, especially in mixed populations and for drugs with a narrow safety range.

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Background Crohn’s disease (CD) is a chronic inflammatory condition of the gastrointestinal tract. It has been suggested that the cause of CD is due to microbial and environmental factors that induce an imbalance of the immune system in genetically susceptible individuals. The Genetic Environmental Microbial (GEM) Project is a prospective study of asymptomatic first-degree relatives (FDR) of CD patients, recruited to understand the biological and environmental determinants of disease development. Aims Here, we aim to define the relationships between the host inflammation-related proteomics and gut microbiome composition in a cohort of 320 healthy CD FDRs at the time of recruitment. Methods We measured 92 inflammation-related serum proteins using the Olink® ’Inflammation’ proteomics panel. Stool microbial composition was determined by sequencing the V4 region of the 16S rRNA. To assess the relationship between serum protein levels and the relative abundance of microbial taxa, we used a zero-inflated two-part regression model corrected for multiple-comparisons (significant association at p< 2.75 × 10–4). Results We found fifteen serum proteins that were each significantly associated with the relative abundances of one to five genera or families, depending on the analyte. Of particular interest to CD, the relative abundance of both TNF-β and LIGHT (TNFSF14) were negatively associated with the relative abundance of bacteria in the Parabacteroides genus. Both TNF-β and LIGHT are members of the Tumor Necrosis Factor (TNF) family of cytokines with roles in mucosal healing, IgA production, and in control of innate lymphoid cells (ILCs). These processes have been hypothesized to have critical roles in CD pathology. Interestingly, prior work also demonstrates that Parabacteroides distasonis enhanced colitis in a mouse model and was isolated from a gut wall-cavitating microlesion in a patient with severe CD. Other inflammation-related proteins with significant taxa associations include IL-2, IL-33, OSM, 4E_BP1, IL-1α, ARTN, AXIN1, and CDCP1. Conclusions This study highlights the associations between inflammation associated proteomics and gut microbial taxa in asymptomatic FDRs of CD patients. The mechanisms explaining this association will require further analysis. Funding Agencies CCC The Leona M. and Harry B. Helmsley Charitable Trust

218Determinación del polimorfismo de CYP2C9*2 y su relación con la farmacocinética de acenocumarol en voluntarios sanos. Resumen:Antecedentes: La mayoría de los pacientes que reciben tratamientos con anticoagulantes orales por periodos prolongados presentan variabilidad en la respuesta. El acenocumarol es el anticoagulante oral más prescrito en nuestro país, es biotransformado principalmente por CYP2C9 e investigaciones recientes demuestran que la variante CYP2C9*2 es una de las responsables de la variabilidad de respuesta a acenocumarol.Objetivo: Determinar las diferencias en los pará-metros farmacocinéticos de acenocumarol en voluntarios que presentan la variante alélica CYP2C9*2.Métodos: Se estudiaron 24 voluntarios sanos.La detección de genotipos se realizó mediante PCR-RFLP y los parámetros farmacocinéticos se obtuvieron mediante la concentración plasmática de acenocumarol usando un método validado para UPLC-MS/MS.Resultados: Del total de 24 voluntarios,19 tenían el genotipo CYP2C9*1/*1 (wt/wt), 4 tenían genotipo CYP2C9*1/*2 (heterocigoto) y 1 voluntario tenía genotipo de CYP2C9*2/*2 (homocigoto recesivo). Los parámetros farmacocinéticos del acenocumarol no fueron significativamente diferentes entre los individuos con genotipo CYP2C9*2 y CYP2C9*1. Sin embargo, la farmacocinética de acenocumarol del individuo CYP2C9*2/*2 mostró diferencias relevantes con respecto a la observada en el grupo CYP2C9*1/*1 (tmáx aumentó 1,4 veces, ke disminuyó 1,8 veces y t1/2 aumentó 1,7 veces).Conclusión: La farmacocinética de acenocumarol en el individuo con el genotipo CYP2C9*2/*2 refleja una potencial relevancia de este polimorfismo en el tratamiento con acenocumarol. Aim: to determine pharmacokinetics parameters of acenocumarol in volunteers exhibiting the CYP2C9*2 polymorphic variant. Methods:Genotype detection was performed using PCR-RFLP and pharmacokinetics parameters were obtained from the acenocumarol concentrations, using a UPLC-MS/MS validated method. The project was approved by the institutional Ethics Committee of the University of Chile's Faculty of Medicine.Results: 19 out of 24 volunteers had the CYP2C9*1/*1 genotype, 4 the CYP2C9*1/*2 genotype (heterozygous) and 1 subject had the CYP2C9*2/*2 genotype (recessive homozygous). No statistically significant differences between acenocumarol pharmacokinetics parameters of CYP2C9*2 compared to those with normal variant, CYP2C9*1were observed.. However, a single individual with the CYP2C9*2/*2 genotype showed different pharmacokinetics parameters: tmáx and t1/2 were increased 1.4 and 1.7 times, respectively, and kc was 1.8 times lower compared to the group with the CYP2C9*1/*1 genotype. Conclusion:There are clear differences in genotype-dependent acenocoumarol pharmacokinetics in individuals with the CYP2C9*2/*2 genotype, reflecting a potential relevance of this polymorphism in anticoagulation with acenocumarol.Keywords: Pharmacogenetics, CYP2C9*2, anticoagulants, acenocoumarol.Determinación del polimorfismo de CYP2C9*2 y su relación con la farmacocinética de acenocum...

Background Crohn’s disease (CD) is thought to be due to an interaction between environmental factors and the gut microbiome that activates an immune response in genetically susceptible hosts. Epidemiologic studies suggest diet is an important variable in CD development; however, little is known about the mechanism by which diet contributes to pathogenesis. It has recently been shown that diet plays a substantial role in shaping microbiome composition (MC). We hypothesize that specific diet patterns are associated with differences in MC that may be related to CD risk. Aims To characterize associations between diet patterns with MC and fecal calprotectin (FC) in healthy first-degree relatives (FDR’s) of CD patients in the Genetic, Environmental, Microbial (GEM) Project. Methods A validated food frequency questionnaire (FFQ) was used to assess diet for North American FDR’s at recruitment. Each question was summarized as a score based on weekly consumption frequency. The Dirichlet method of unsupervised clustering was used to generate dominant diet clusters. Diet-microbiome associations were assessed using the two-part microbiome model. Stool microbiota at recruitment was characterized by 16s RNA sequencing of V4 region using MiSeq platform. Baseline FC was measured by BUHLMANN ELISA test. Results 2766 FDR’s had FFQ’s at recruitment; mean age 18.52 years, 53% female. The Dirichlet method identified 4 clusters, some of which resembled known diet patterns: Superbowl (mainly organ meats, non-red meat, beer, spirits), High Carbohydrate (HC), Mediterranean (MD) and Western (WD) diets. HC was associated with increased relative abundance of V. veillonella (P=2.68E-4). Both HC and MD were associated with decreased abundance of E. klebsiella (P=2.64E-5 and P=1.02E-5 respectively). WD was associated with decreased abundance of L. dorea (P=5.74E-5), a genus considered high risk for CD. A per question analysis demonstrated significant associations between several taxa and individual foods. Diet clusters were then correlated with FC, and a decrease in FC was observed with MD (estimate -16.96, P=0.012). There were no associations with FC in a per question analysis. Conclusions Dominant dietary patterns and certain individual foods are associated with specific gut MC. As well, MD is inversely associated with FC and therefore has potential use as an intervention for lowering inflammation. Understanding relationships between diet, MC and FC in individuals at high risk for CD would be beneficial in defining new dietary strategies in predictably modulating future risk of CD. Funding Agencies CCCHelmsley Charitable Trust