Development of a small panel of SNPs to infer ancestry in Chileans that distinguishes Aymara and Mapuche components

BACKGROUND: Current South American populations trace their origins mainly to three continental ancestries, i.e. European, Amerindian and African. Individual variation in relative proportions of each of these ancestries may be confounded with socio-economic factors due to population stratification. Therefore, ancestry is a potential confounder variable that should be considered in epidemiologic studies and in public health plans. However, there are few studies that have assessed the ancestry of the current admixed Chilean population. This is partly due to the high cost of genome-scale technologies commonly used to estimate ancestry. In this study we have designed a small panel of SNPs to accurately assess ancestry in the largest sampling to date of the Chilean mestizo population (n = 3349) from eight cities. Our panel is also able to distinguish between the two main Amerindian components of Chileans: Aymara from the north and Mapuche from the south. RESULTS: A panel of 150 ancestry-informative markers (AIMs) of SNP type was selected to maximize ancestry informativeness and genome coverage. Of these, 147 were successfully genotyped by KASPar assays in 2843 samples, with an average missing rate of 0.012, and a 0.95 concordance with microarray data. The ancestries estimated with the panel of AIMs had relative high correlations (0.88 for European, 0.91 for Amerindian, 0.70 for Aymara, and 0.68 for Mapuche components) with those obtained with AXIOM LAT1 array. The country's average ancestry was 0.53 ± 0.14 European, 0.04 ± 0.04 African, and 0.42 ± 0.14 Amerindian, disaggregated into 0.18 ± 0.15 Aymara and 0.25 ± 0.13 Mapuche. However, Mapuche ancestry was highest in the south (40.03%) and Aymara in the north (35.61%) as expected from the historical location of these ethnic groups. We make our results available through an online app and demonstrate how it can be used to adjust for ancestry when testing association between incidence of a disease and nongenetic risk factors. CONCLUSIONS: We have conducted the most extensive sampling, across many different cities, of current Chilean population. Ancestry varied significantly by latitude and human development. The panel of AIMs is available to the community for estimating ancestry at low cost in Chileans and other populations with similar ancestry.

Estimando el efecto del cambio climático sobre el riesgo de la enfermedad de Chagas en Chile por medio del número reproductivo / Effects of climate change on reproductive number of Chagas disease

Background: Reproductive number (R0)-maps estimate risk zones of vector-borne diseases and geographical distribution changes under climate change. Aim: To map R0 aiming to estimate the epidemiological risk of Chagas disease in Chile, its distribution and possible changes due to the global climate change. Material and Methods: We used a relationship between R0 and entomological parameters of vectors as function of environmental variables, to map the risk of Chagas disease in Chile, under current and projected future environmental conditions. Results: We obtained a geographical R0 estimation of Chagas disease in Chile. The highest R0averages correspond to the Central-Northern regions of Chile. T. cruzi transmission area could increase in the future due to climate changes. Independent of the future condition, both for optimistic and pessimistic climate change scenarios, the area of potential risk for Chagas disease transmission would increase. The estimated R0 values suggest that, if a control of T. infestans is not maintained, Chagas disease endemic status will persist or increase, independently of the climate change scenarios. Conclusions: Mapping R0 values is an effective method to assess the risk of Chagas disease. The eventual increase in the transmission area of the disease is worrisome.

Farmacogenética, tabaco, alcohol y su efecto sobre el riesgo de desarrollar cáncer / Pharmacogenetics, tobacco, alcohol and its effect on the risk development cancer

El cáncer es la segunda causa de muerte en el mundo, según datos de la Organización Mundial de la Salud (OMS) en el año 2015 ocasionó 8,8 millones de muertes. Dentro de los factores de riesgo para el desarrollo de cáncer se encuentran el tabaquismo y el consumo de alcohol. En Chile el 33,6% de la población fuma y un 21,2 % de los jóvenes. El consumo de alcohol en la población chilena es de 74,5 % y en los jóvenes de un 12,2 %. Entre los factores fisiológicos que influyen en el desarrollo de cáncer, el factor genético juega un rol relevante, habiéndose demostrado que la presencia de polimorfismos genéticos alteran la capacidad del organismo de eliminar contaminantes y aumentan el riesgo de desarrollar cáncer. Lo mismo ocurre con polimorfismos que impiden la reparación de ADN debido a daños producidos por efecto de contaminantes ambientales como el humo de cigarrillo. El objetivo de esta revisión es analizar el estado del arte de la relación entre farmacogenética, tabaco y alcohol como factores de riesgo para el desarrollo de cáncer. Los resultados sugieren que la presencia de po limorfismos que alteran la función de enzimas de biotransformación fase I (CYP1A1, CYP1E1) y fase II (GST), además de polimorfismos en enzimas de reparación del ADN (ERCC1/ERCC2) aumentan el riesgo de cáncer inducido por el hábito tabáquico y alcohólico. Esta asociación es importante, si consideramos que en la población chilena el hábito de fumar y beber alcohol es altamente prevalente.

Cancer is the second leading cause of death in the world, causing 8.8 million deaths in 2015 according to the World Health Organization (WHO). Risk factors for cancer include smoking and alcohol con sumption. In Chile, 33.6% of the population and 21.2% of young people smokes. Alcohol consump tion in the Chilean population is 74.5% and 12.2% in young people. Among the physiological factors that influence the development of cancer, the genetic factor plays a relevant role. It has been shown that the presence of genetic polymorphisms that alter the ability of the body to eliminate contami nants increase the risk of developing cancer. The same applies to polymorphisms that prevent DNA repair due to damage caused by environmental pollutants such as cigarette smoke. The objective of this review is to analyze the state of the art of the relationship between pharmacogenetics, smoking, and alcohol consumption as risk factors for the development of cancer. In conclusion, the results suggest that the presence of polymorphisms that alter the function of biotransformation enzymes phase I (CYP1A1, CYP1E1) and phase II (GST), as well as polymorphisms in DNA repair enzymes (ERCC1 / ERCC2), increase the risk of cancer induced by smoking and alcohol consumption. This association is important considering that smoking and drinking alcohol are highly prevalent among the Chilean population.

El polimorfismo rs12979860 C> T en el gen Interferón lambda 4 no está asociado a riesgo de fibrosis hepática en pacientes chilenos con hepatitis crónica por virus C / Interferon Lambda 4 RS12979860 C> T polymorphism is not associated with liver fibrosis in patients with hepatitis C

Background. Host genetic predispositions may be important determinants of liver fibrosis in patients with chronic hepatitis C (CHC). The association between Interferon-L 4 (IFNL4) rs12979860 C>T polymorphism and risk of liver fibrosis in CHC is contradictory. Aim: To evaluate the impact of IFNL4 rs12979860 polymorphism on the risk of fibrosis in patients with CHC. Material and Methods: One hundred fifty patients with CHC aged 50 ± 11 years (89 females) were genotyped for IFNL4 rs12979860 using real time PCR. Fibrosis present in liver biopsies was assessed using the METAVIR score, comparing patients with either no fibrosis, mild fibrosis, or intermediate fibrosis (F0+F1+F2, n = 96), with patients with severe fibrosis or cirrhosis (F3+F4, n = 54). Results: In F0-F2 patients the distribution of rs12979860 genotypes was 22 CC, 57 CT and 17 TT, whereas in patients F3-F4 the distribution was 10, 29 and 15, respectively. No association between IFNL4 rs12979860 genotype and risk of fibrosis was observed in uni or multivariate analyses. Conclusions: IFNL4 rs12979860 C>T polymorphism is not associated with risk of liver fibrosis in this group of patients with CHC.

Aplicación de grafos acíclicos dirigidos en la evaluación de un set mínimo de ajuste de confusores: un complemento al modelamiento estadístico en estudios epidemiológicos observacionales / Directed acyclic graphs in statistical modelling of epidemiological studies

Background: Confusion in observational epidemiological studies distorts the relationship between exposure and event. "Step by step" regression models, diverts the decision to a statistical algorithm with little causal basis. Directed Acyclic Graphs (DAGs), qualitatively and visually assess the confusion. They can complement the decision on confounder control during statistical modeling. Aim: To evaluate the minimum set of confounders to be controlled in a cause-effect relationship with the use of "step-by-step regression" and DAGs, in a study of arsenic exposure. Material and Methods: We worked with data from Cáceres et al., 2010 in 66 individuals from northern Chile. The interindividual variability in the urinary excretion of dimethyl arsenic acid attributable to the GSTT1 polymorphism was estimated. A causal DAG was constructed using DAGitty v2.3 with the list of variables. A multiple linear regression model with the step-by-step backwards methodology was carried out. Results: The causal diagram included 12 non-causal open pathways. The minimum adjustment set corresponded to the variables "sex", "body mass index" and "fish and seafood ingest". Confusion retention of the multivariate model included normal and overweight status, gender and the interaction between "water intake" and GSTT1. Conclusions: The use of DAG prior to the modeling would allow a more comprehensive, coherent and biologically plausible analysis of causal relationships in public health.

Assessing the risk zones of Chagas' disease in Chile, in a world marked by global climatic change

BACKGROUND Vector transmission of Trypanosoma cruzi appears to be interrupted in Chile; however, data show increasing incidence of Chagas' disease, raising concerns that there may be a reemerging problem. OBJECTIVE To estimate the actual risk in a changing world it is necessary to consider the historical vector distribution and correlate this distribution with the presence of cases and climate change. METHODS Potential distribution models of Triatoma infestans and Chagas disease were performed using Maxent, a machine-learning method. FINDINGS Climate change appears to play a major role in the reemergence of Chagas' disease and T. infestans in Chile. The distribution of both T. infestans and Chagas' disease correlated with maximum temperature, and the precipitation during the driest month. The overlap of Chagas' disease and T. infestans distribution areas was high. The distribution of T. infestans, under two global change scenarios, showed a minimal reduction tendency in suitable areas. MAIN CONCLUSION The impact of temperature and precipitation on the distribution of T. infestans, as shown by the models, indicates the need for aggressive control efforts; the current control measures, including T. infestans control campaigns, should be maintained with the same intensity as they have at present, avoiding sylvatic foci, intrusions, and recolonisation of human dwellings.

Tasa de cesáreas según la clasificación de Robson: análisis comparativo entre dos hospitales universitarios / Tasa de cesáreas según la clasificación de Robson: análisis comparativo entre dos hospitales universitarios

RESUMEN Introducción y objetivos: La ejecución de cesáreas para la interrupción del embarazo y su tasa óptima de utilización ha sido un tema controversial desde sus inicios. En esta línea Robsons y Cols proponen una clasificación para evaluar y comparar de manera eficaz las prácticas realizadas en las distintas instituciones de salud. El objetivo de este trabajo fue comparar la tasa de cesáreas realizadas durante el año 2017 tanto en el Hospital Clínico Universidad de Chile (HCUCH) como en el Hospital base San José de Osorno (HBSJO), y de esta forma, describir sus diferencias estadísticas. Métodos: Los resultados se obtuvieron mediante la recopilación de datos del libro de pabellones disponible en ambos departamentos. Resultados: Se observó una diferencia significativa en la interrupción del embarazo vía alta, la que alcanzó un 55,7% en el HCUCH, en contraste con un 35,7% en el HBSJO. En el HCUCH, el 87,8% de la totalidad de los partos correspondieron a mujeres con embarazos de bajo riesgo, realizándose cesárea en el 52,9% de ellas. En el HBSJO en cambio, las cifras fueron de un 74,6% y 32,2% respectivamente. En las únicas categorías en las cuales no existió una diferencia estadísticamente significativa en cuanto a la tasa de cesáreas realizadas fueron las distocias de presentación y los embarazos gemelares, alcanzando un a tasa de 100% en embarazos gemelares en el HBSJO. Las hipótesis que explican estas diferencias radican principalmente en la organización administrativa y a la población atendida en cada hospital. Conclusiones: Los distintos centros asistenciales de nuestro país se rigen por distintas formas de funcionamiento. Esto explica entre otras cosas, la diferencia estadísticamente significativa que se produce al comparar la tasa de cesárea del HCUCH con el HBSJO. Hacemos un llamado en este trabajo a utilizar el método de clasificación de Robson para facilitar la supervisión y la comparación crítica de estos índices en los hospitales.

ABSTRACT Introduction and objectives: The caesarean section execution for the interruption of pregnancy and its optimal rate of use, has been a controversial issue since its inception. In this line Robsons and Cols propose a classification to standardize and effectively compare the practices carried out in the different health institutions. The aim of this study was to compare the rate of cesareans performed during 2017 both at the "University Clinical Hospital of Chile" (HCUCH) and at the "San José de Osorno Hospital" (HBSJO), and in this way, describe their statistical differences. Methods: The results were obtained by collecting data from the pavilion book available in both departments. Results: There was a significant difference in the cesarean rate between both hospitals. This difference reached 55.7% in the HCUCH, in contrast to 35.7% in the HBSJO. In the HCUCH, 87.8% of all the deliveries corresponded to women with low risk pregnancies, with cesarean sections performed in 52.9% of them. On the other hand, in the HBSJO the values were 74.6% and 32.2% respectively. The only categories in which there was no statistically significant difference in the rate of cesarean sections performed, were pregnancies with dystocia presentation and twin pregnancies, reaching a 100% of surgical intervention in this last group. The hypotheses that explain these differences lie mainly in the administrative organization and the population served in each hospital. Conclusions: The different healthcare centers in our country are governed by different ways of functioning. This explains, among other things, the statistically significant difference that occurs when comparing the cesarean rate of the HCUCH and the HBSJO. We encourage in this study to use Robson's classification method to facilitate the supervision and critical comparison of these indices in hospitals.

Caracterización epidemiológica de mordeduras en personas, según registro de atención de urgencia: Provincia de Los Andes, Chile / Epidemiological characterization of bites on people, as emergency care record: Province of Los Andes, Chile

Background: Bites constitute a public health problem worldwide. Aim: To characterize epidemiologically bites by animals happened in the province of Los Andes (2005-2007). Method: Descriptive, retrospective epidemiological study. Studied variables: Bitten person (BP), accident by bite, biting animal and bite. It was not feasible to obtain more updated information by law of patient protection. Results: 2,360 BP were assisted in the emergency unit of San Juan de Dios Hospital and Rio Blanco clinic. An annual average rate of 729 BP/100,000 inhabitants and 1.99 daily average was recorded. The male gender was most affected (53.5%) and the age group from 6 to 10 years old. (Rate: .521/100,000). Most frequent topographic location was the lower limb, except in children under 5 year olds in whom predominated head and neck. The biting animal according to frequency was: the dog (67.1%) spider (7.1%) and cat (3.9%). The animal property was 35.6% known and 30.7% own. The most frequent problems were: nonspecific allergy; toxic effect by spider bites and among the infections, the disease made by cat’s scratch stands out. Regarding the record system, the biting animal complaint was applied to 47.6% of the BP and the 92.8% of the recorded information was incomplete. Conclusions: Bites reported higher rates in the province of Los Andes than the average of the country (729 versus 188/100,000), standing out the higher magnitude in 6 to 10 year-old-children. It is noticed that the record is low and incomplete. In this province, no bite control programs or updated studies have been carried out.

Introducción: Las mordeduras constituyen un problema de salud pública mundial. Objetivo: Caracterizar epidemiológicamente las mordeduras por animales ocurridos en la provincia de Los Andes (2005-2007). Método: Estudio epidemiológico descriptivo retrospectivo. Variables estudiadas: Persona mordida (PM), accidente por mordedura, animal mordedor y mordedura. No fue factible obtener información más actualizada por ley de protección del paciente. Resultados: Se atendieron 2.360 PM en los Servicios de Urgencia del Hospital San Juan de Dios y Clínica Río Blanco. Se registró una tasa anual promedio de 729 PM/100.000 hbts. y promedio diario 1,99. El género más afectado fue el masculino (53,5%), y el grupo etario de 6 a 10 años (tasa:1.521/100.000). La ubicación topográfica más frecuente fue extremidad inferior, excepto en niños bajo 5 años de edad en quienes predominó cabeza-cuello. El animal mordedor según frecuencia fue: perro (67,1%) araña (7,1%) y gato (3,9%). La propiedad del animal fue 35,6% conocida y 30,7% propios. Las complicaciones más frecuentes fueron alergia no específica, efecto tóxico por mordedura de arañas y entre las infecciones destaca la enfermedad por rasguño de gato. La notificación de animal mordedor se aplicó a 47,6% de las PM; 92,8% de la información contenida estaba incompleta. Conclusiones: Las mordeduras en la Provincia de Los Andes presentaron tasas mayores que el promedio país (729 versus 188/100.000), destacando la mayor magnitud en niños de 6 a10 años. En la provincia no se han realizado programas de control de mordeduras o estudios actualizados.

¿Qué dicen los números de la evolución temporal de la enfermedad de Chagas? / What do the numbers tell us about the temporal evolution of Chagas’ disease?

Chagas disease remains highly prevalent in Chile, especially between the regions of Arica and Parinacota, and Coquimbo. Since 1999 it is considered that in Chile the vector transmission was interrupted. Under this premise, the epidemiological dynamics should be changing. We analyzed the evolution of the prevalence of Chagas’ disease analyzing 64,995 xenodiagnosis performed in the laboratory of Parasitology of the Faculty of Medicine of the University of Chile between 1949 and 2014. The evolution of the mortalities and incidences from the databases of the Ministry of Health in the periods in which it was analyzed. The rates of domiciliary infestation and the number of vector insects sent to the Public Health Institute and its trypano-triatomine indices were also analyzed. The prevalence of Chagas’ disease in inhabitants of risk areas remained stable in this period as well as mortality. The incidence rate shows a progressive increase with a tendency towards stabilization. A significant decrease in sampling effort was found, declining by two orders of magnitude, especially since 2000. The progressive increase in morbidity had no clear relation to the interruption of the vector chain nor to the greater diagnostic effort occurred in 2009, since it was evident from before. While home infestation declines, reports of intrusion of solitary individuals and wild foci of T. infestans have increased. Trypano-triatomine indices were maintained with high values in all vector species. This study shows a worrying situation, for while on the one hand the interruption of the vector transmission and improvement in the research systems is emphasized, the concern for this disease seems to be decreasing with less diagnostic efforts and lower education at the higher level, and by the other hand the numbers show that the problem if it is not increasing, at least maintains its careless historical magnitude.

Resumen Introducción: La enfermedad de Chagas sigue siendo altamente prevalente en Chile, especialmente entre las regiones de Arica y Parinacota y de Coquimbo. Desde 1999 se considera que en Chile se encuentra interrumpida la transmisión vectorial. Bajo esta premisa, la dinámica epidemiológica se debiera estar modificando. Objetivo: Analizar la evolución temporal de la enfermedad de Chagas en Chile Material y Métodos: Analizamos la evolución de la prevalencia de la enfermedad de Chagas a través del análisis de resultados de 64.995 xenodiagnós-ticos realizados en el laboratorio de Parasitología de la Facultad de Medicina de la Universidad de Chile, entre 1949 y 2014. Se estudió la evolución de las mortalidades e incidencias disponibles en las bases de datos del Ministerio de Salud en los períodos en que fue posible. Se analizaron las tasas de infestación domiciliaria y el número de insectos vectores enviados al Instituto de Salud Pública y sus índices tripano-tratominos. Resultados: La prevalencia de la enfermedad de Chagas en habitantes de zonas de riesgo se mantuvo estable en este período, al igual que la mortalidad. La tasa de incidencia muestra un incremento progresivo con tendencia a la estabilización. Se encontró un significativo decrecimiento del esfuerzo de muestreo, decayendo dos órdenes de magnitud, especialmente desde 2000. El aumento progresivo de la morbilidad no tiene clara relación con el corte de la cadena vectorial ni con el mayor esfuerzo diagnóstico ocurrido en 2009, ya que era evidente desde antes. Mientras que la infestación domiciliaria disminuye, han aumentado los reportes de intromisión de individuos solitarios y los focos silvestres de T. infestans. Los índices tripano triatominos se mantienen con valores altos en todas las especies vectores. Discusión: Este estudio muestra una situación preocupante, ya que mientras por una parte se destaca el corte de la transmisión vectorial y mejora en los sistemas de pesquisa, la preocupación por esta enfermedad parece ir decreciendo con menores esfuerzos diagnósticos y menor enseñanza a nivel superior, y por otra parte los números muestran que el problema si es que no está aumentando, al menos mantiene su descuidada magnitud histórica.

Sensibilidad y Especificidad Clínica del Indice Mandibular Canino y del Ancho Mesiodistal del Diente Canino Para Estimar el Sexo: Ajuste de un Modelo Predictivo / Clinical Sensitivity and Specificity of Mandibular Canine Index and Mesiodistal Canine Width to Estimate Sex: Adjustment of a Predictive Model

Los dientes son un excelente material de investigación en personas vivas y cadáveres, en el ámbito antropológico, genético, odontológico y forense, por sus características (dureza, resistencia al ataque químico, fuego y descomposición). El diente canino mandibular es el menos afectado por enfermedad periodontal, menos extraído, más resistente a traumas severos y el que presenta mayor dimorfismo sexual. Se puede usar para la estimación de sexo, calculando el Índice Mandibular Canino (IMC). El propósito de este estudio es determinar la certeza del IMC en la estimación de sexo respecto al ancho mesiodistal del canino. El estudio fue realizado en 150 sujetos (H:M= 65:85), entre 18­24 años. El ancho mesiodistal del canino y la distancia canina fueron medidos en los modelos obtenidos y el IMC fue calculado. Se calculó la sensibilidad y especificidad para cada uno de los índices en cuestión. El IMC tuvo una sensibilidad del 33,85 % y una especificidad de 75,29 % en la estimación de sexo. El ancho mesiodistal del canino tuvo una sensibilidad de 66,15 % y una especificidad de 84,71 %. El ancho mesiodistal del canino tiene mayor sensibilidad y especificidad que el IMC en la estimación médicolegal de sexo.

Teeth are an excellent research material in living persons and in corpses, in the anthropological, genetic, dental and forensic fields, because of their characteristics (hardness, resistance to chemical attack, fire and decay). Mandibular canine teeth are the least affected by periodontal disease, the least extracted teeth, are more resistant to severe trauma and have a greater sexual dimorphism. They can be used for sex estimation, through the Mandibular Canine Index (MCI). The purpose of this study is to determine the accuracy of the MCI in sex estimation, compared to the mesiodistal canine width method. The study was conducted on 150 subjects (M:F= 65:85), aged 18­24. The mesiodistal width of canine and the intercanine distance were measured on the obtained models, and the MCI was calculated. The sensitivity and specificity for each of the two indexes were also calculated. MCI had a sensitivity of 33.85% and a specificity of 75.29 % in sex estimation. The mesiodistal width of canine had a sensitivity of 66.15 % and a specificity of 84.71 %. The mesiodistal width of canine has a higher sensitivity and specificity than the MCI in the medicolegal estimation of sex.

Influence of CYP3A4/5 polymorphisms in the pharmacokinetics of levonorgestrel: a pilot study / Influencia de polimorfismos genéticos de CYP3A4/5 en la farmacocinética de levonorgestrel: estudio piloto

Introduction.Levonorgestrel a synthetic progestagen used for endometriosis, dysmenorrhea and emergency contraception, is quickly and completely absorbed in the digestive tract. levonorgestrel is predominantly metabolised through hepatic routes that utilise the CYP3A system (CYP3A4 and CYP3A5). Objective.This study aimed to evaluate the association between variant alleles of CYP3A4*1B and CYP3A5*3 polymorphisms and the pharmacokinetics of levonorgestrel. Materials and methods. A group of 17 adult female healthy volunteers who signed an informed consent were genotyped for CYP3A4 and CYP3A5 through PCR-RFLP. Volunteers were submitted to pharmacokinetic analysis where, after a 12-hour overnight fast, they received a single oral dose of 0.75 mg of levonorgestrel. Serial blood samples were obtained (0 to 24 hours), and levonorgestrel concentrations were determined by UPLC-MS/MS to determine pharmacokinetic parameters. The procedures employed herein were performed according to the Declaration of Helsinki and Good Clinical Practices standards. Results. Observed genotype frequencies in the studied group for CYP3A4*1B were 11.8% for *1B/*1B, 5.8% for *1/*1B and 82.4% for *1/*1. CYP3A5*3 frequencies were 70.5% for *3/*3, 23.5% for *1/*3 and 6.5% for *1/*1. A high pharmacokinetic variability between volunteers was observed, but no statistical association of pharmacokinetic parameters was found within the studied CYP3A4/5 polymorphisms. Conclusions. Genetic polymorphisms could be important factors in determining inter-patient variability in plasma levonorgestrel concentrations, which in this study were not significantly associated with the presence of CYP3A4*1B and CYP3A5*3 polymorphisms. Therefore, due to the significant inter-patient variability that we observed during the course of this study, it is necessary to carry out studies with larger number of volunteers.

Introducción. El levonorgestrel, un progestágeno sintético usado para endometriosis, dismenorrea y anticoncepción de emergencia, es rápida y completamente absorbido en el tubo digestivo. Su metabolismo es principalmente hepático, mediante las enzimas CYP3A4 y CYP3A5. Objetivo. El presente estudio tuvo como objetivo evaluar la asociación entre la farmacocinética de levonorgestrel y las variantes alélicas de CYP3A4*1B y CYP3A5*3. Materiales y métodos. En un grupo de 17 mujeres adultas sanas, que firmaron un consentimiento informado, se practicó genotipificación para CYP3A4*1B y CYP3A5*3 mediante PCR. Posteriormente, las voluntarias fueron sometidas a un estudio farmacocinético donde, luego de 12 horas de ayuno, recibieron una dosis de 0,75 mg de levonorgestrel. Se extrajeron muestras sanguíneas seriadas (0 a 24 horas) y se determinaron las concentraciones de levonorgestrel mediante un método validado de UPLC-ms/ms, para luego obtener los parámetros farmacocinéticos. Todos los procedimientos consideraron los aspectos éticos de la Declaración de Helsinki y las buenas prácticas clínicas. Resultados. Las frecuencias genotípicas observadas para el grupo de estudio fueron 11,8 % para *1B/*1B; 5,8 % para *1/*1B, y 82,4 % para *1/*1 de CYP3A4*1B. Para CYP3A5*3, las frecuencias genotípicas fueron 70,5 % para *3/*3; 23,5 % para *1/*3, y 6,5 % para *1/*1. Se observa una interesante variabilidad entre las voluntarias que sugiere una relación con las variantes genéticas CYP3A, pero que no permite establecer una asociación estadísticamente significativa, presumiblemente debido al bajo número de individuos homocigotos mutados de CYP3A4 y silvestres de CYP3A5. Conclusiones. Los polimorfismos genéticos podrían ser factores relevantes en la determinación de la variabilidad entre pacientes en las concentraciones plasmáticas de levonorgestrel, lo cual, sin embargo, no pudo ser establecido estadísticamente en este estudio. Por lo tanto, resulta necesario continuar este tipo de estudios con mayor número de voluntarios para establecer una asociación entre la variabilidad observada y la presencia de estos polimorfismos.

Variantes genéticas de CYP2A6 y su relación con la dependencia tabáquica y el hábito de fumar en una muestra individuos chilenos: Un estudio piloto / Relation of genetic variants of CYP2A6 with tobacco dependence and smoking habit in Chilean subjects: A pilot study

Background: Genetic and metabolic factors associated with nicotine metabolism may be related to smoking behavior. Aim: To assess the prevalence of allelic and genotype variants of CYP2A6 in a sample of Chilean subjects and to evaluate their relationship with smoking and tobacco dependence. Material and Methods: The genotype frequencies for *2, *3 and *4 of CYP2A6*1 (wild type) gene were determined by polymerase chain reaction (PCR) in 54 volunteers. Addiction to tobacco was evaluated using the Fagerstrom Test. The association between the presence of allelic variants of CYP2A6 and smoking and tobacco dependence was evaluated with chi square test. Results: The prevalence of *1, *2 (wt/*2), *3 (wt/*3 or *31*3) and *4 (del/del) were 92.6%, 3.7%, 0% y 3.7%, respectively. No significant association was observed between being a carrier of a variant genotype of CYP2A6 and smoking or tobacco dependence. Conclusions: In this sample of Chilean individuals we did not find a relation between any CYP2A6 genotype with smoking or tobacco dependence.

Determinación del polimorfismo de CYP2C9*2 y su relación con la farmacocinética de acenocumarol en voluntarios sanos / Relation of cy2c9*2 polymorphism and acenocumarol pharmacokynetics in healthy volunteers

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 parámetros 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.

Background: Most of the patients receiving anticoagulant therapy for extended periods show variability in their clinical response. Acenocumarol, the most commonly prescribed oral anticoagulant in our country, is biotransformed mainly through CYP2C9 and recent research shows that CYP2C9*2 variant is partly responsible for the variable response to ace-nocumarol. 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 phar-macokinetics 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.

Caracterización epidemiológica y evolución del cáncer de mama en Arica y Parinacota, Chile 1997-2007 / Epidemiological characterization and evolution of breast cancer patients in the Arica and Parinacota region in Chile, 1997-2007

Objetivo Caracterizar epidemiológicamente el cáncer de mama y su evolución en la Región de Arica y Parinacota para el decenio 1997- 2007, Chile Método Se realizó un estudio descriptivo de tendencia. Se revisaron las historias clínicas de 306 casos pesquisados, consultantes del Policlínico de Oncología Mamaria del Hospital en Red Dr. Juan Noé Crevani. Se realizó un análisis descriptivo univariado de cada variable estudiada y se evaluó la tendencia de la incidencia y mortalidad de cáncer de mama. Resultados De los 306 casos estudiados durante el periodo, el 51,3 por ciento tuvo entre 46 y 65 años de edad, siendo el 13,9 por ciento de origen Aymara. El 70,2 por ciento de las pacientes eran menopáusicas, 98,4 por ciento sin tratamiento hormonal. El 12 por ciento refirió tener antecedentes familiares, de los cuales la hermana fue lo más frecuente. El 84,1 por ciento tuvo el diagnostico de carcinoma ductal infiltrante, un 32,8 por ciento de estos en etapa IIA. De todos los casos, el 31,6 por ciento presentó metástasis múltiple, con 74,7 por ciento en un rango de edad entre of 56 a 94 años. El análisis de la serie indica una tendencia creciente de nuevos casos y una moderada tendencia a la diminución de la tasa de mortalidad. Conclusiones La Región de Arica y Parinacota de Chile, muestra una tendencia creciente absoluta y relativa de nuevos casos de cáncer de mama durante el decenio estudiado. Por otra parte, la tasa mortalidad tendió a la disminución en el periodo. Ambos situaciones se explicarían en parte por el diagnóstico precoz y las políticas de salud implementados.

Objective Epidemiologically characterizing breast cancer in the Arica and Parinacota region in Chile and its evolution during 1997-2007. Method A descriptive, cross-sectional study was performed. All clinical histories for 306 cases of breast cancer were reviewed. All patients were detected through the Arica Juan Noé Crevani Hospital's Oncological Mammary Polyclinic from 1997 to 2007. A descriptive data analysis was made, followed by a tendency analysis. Results 51.3 percent of the 306 cases studied were aged 46 to 65 years, 13.9 percent being of Aymara ethnic origin. 70.2 percent of the women involved in the study were climacteric, 98.4 percent being without hormonal treatment. 12 percent referred to having a family background of cancer, the sister being the most frequently referred to relative. 84.1 percent had a histological diagnosis of infiltrating ductal carcinoma, stage IIA being the most frequently occurring one (32.8 percent). 31.6 percent presented multiple metastases, 74.7 percent of this group being aged 56 to 94. Time series analysis indicated an increasing incidence rate and decreasing mortality rate. Conclusions The Arica and Parinacota region of Chile presented an increasing tendency for new cases of breast cancer during the period being studied which was concentrated during the early stages of evolution. These findings could be explained by the early detection of breast cancer and the implementation of public health policy.

Study of Cytochrome P450 2E1 and its allele Variants in Liver Injury of Nondiabetic, Nonalcoholic Steatohepatitis Obese Women

CYP2E1 enzyme is related to nonalcoholic steatohepatitis (NASH) due to its ability for reactive oxygen species production, which can be influenced by polymorphisms in the gene. The aim of this study was to investigate hepatic levels, activity, and polymorphisms of the CYP2E1 gene to correlate it with clinical and histological features in 48 female obese NASH patients. Subjects were divided into three groups: (i) normal; (ii) steatosis; and (iii) steatohepatitis. CYP2E1 protein level was assayed in microsomes from liver biopsies, and in vivo chlorzoxazone hydroxylation was determined by HPLC. Genomic DNA was isolated for genotype analysis through PCR. The results showed that liver CYP2E1 content was significantly higher in the steatohepatitis (45 percent; p=0.024) and steatosis (22 percent; p=0.032) group compared with normal group. Chlorzoxazone hydroxylase activity showed significant enhancement in the steatohepatitis group (15 percent, p=0.027) compared with the normal group. c2 rare allele of RsallPstl polymorphisms but no C allele of Dral polymorphism was positively associated with CHZ hydroxylation, which in turn is correlated with liver CYP2E1 content (r=0.59; p=0.026). In conclusion, c2 allele is positively associated with liver injury in NASH. This allele may determine a higher transcriptional activity of the gene, with consequent enhancement in pro-oxidant activity of CYP2E1 thus affording liver toxicity.

Consumo precoz de tabaco y alcohol como factores modificadores del riesgo de uso de marihuana / Early tobacco and alcohol consumption as modifying risk factors on marijuana use

OBJETIVO: Evaluar la relación entre consumo precoz de tabaco y alcohol y el riesgo de consumir marihuana en escolares. MÉTODOS: Estudio transversal con datos del IV Estudio Nacional de Consumo de Drogas en Población Escolar, año 2001. Se analizó 54,001 escolares de ocho a 20 años de edad. Como variables predictoras se consideró el autoreporte de consumo de tabaco y alcohol, la edad de inicio de consumo de tabaco y/o alcohol, y la intensidad de uso del tabaco. Como variable resultado se utilizó el autoreporte de uso de marihuana y la edad de inicio de consumo de ésta. Para el análisis de los datos se utilizó regresión de Poisson y regresión de Weibull. RESULTADOS: Los escolares presentaron alta prevalencia de consumo de tabaco, alcohol y marihuana (77 por ciento, 79 por ciento y 23 por ciento respectivamente). El consumo de tabaco en presencia de consumo de alcohol fue un factor de riesgo de uso de marihuana (RP=10.4; IC 95 por ciento: 8.9;12.2). El inicio tardío de consumo de tabaco (HR=0.85; IC 95 por ciento: 0.84;0.86) y alcohol (HR=0.90; IC 95 por ciento: 0.89;0.91) resultó ser un factor protector del uso de marihuana. La probabilidad de consumo de marihuana fue mayor en quienes fumaban todos o casi todos los días en relación a quienes fumaban sólo los fines de semana (RP=3.11; IC 95 por ciento: 2.96;3.26 vs. RP=1.70; IC 95 por ciento: 1.58;1.83). CONCLUSIONES: El riesgo de consumo de marihuana se asoció significativamente con la edad de inicio de consumo de tabaco, la frecuencia de consumo de tabaco y el consumo simultáneo de alcohol. Las estrategias de prevención deberían orientarse a evitar el consumo precoz de tabaco en escolares.

OBJECTIVE: To assess the relationship between early tobacco and alcohol use and the risk of marijuana consumption among schoolchildren. METHODS: A cross-sectional study comprising data from the Fourth National Study on Drug Use in the Chilean School Population (2001). There were studied 54,001 schoolchildren aged between eight and 20 years. Predictors were self-reported tobacco and alcohol use (ever users), age at initiation of tobacco and/or alcohol use, and intensity of tobacco use. The study outcome was self-reported marijuana use (ever users versus never users) and age at initiation of marijuana use. Poisson regression and Weibull regression were used for data analysis. RESULTS: Lifetime prevalence of tobacco use was high: 77 percent, alcohol 79 percent, and marijuana 23 percent. Tobacco consumption increased the likelihood of marijuana use (PR=10.4; 95 percent CI: 8.9;12.2). Later initiation of tobacco (HR=0.85; 95 percent CI: 0.84;0.86) and alcohol (HR=0.90; 95 percent CI: 0.89;0.91) decreased the risk of marijuana use. Marijuana use was higher in heavy smokers compared to light smokers (PR=3.11; 95 percent CI: 2.96;3.26 versus PR=1.70; 95 percent CI: 1.58;1.83). CONCLUSIONS: Tobacco use is strongly associated with marijuana use, which is significantly associated with the age at initiation of tobacco use, intensity of tobacco use and concurrent use of alcohol. Prevention strategies should target prevention of adolescent early tobacco use.

OBJETIVO: Avaliar a relação entre consumo precoce de tabaco e álcool e o risco de consumir maconha por escolares. MÉTODOS: Estudo transversal com dados do IV Estudio Nacional de Consumo de Drogas en Población Escolar, ano 2001 no Chile. Analisaram-se 54.001 escolares de oito a 20 anos de idade. As variáveis preditoras consideradas foram: consumo de tabaco e álcool, a idade de início de consumo de tabaco e/ou álcool e a intensidade de uso de tabaco. Uso de maconha e idade de início do consumo foram as variáveis de desfecho. Para a análise dos dados se utilizou regressão de Poisson e regressão de Weibull. RESULTADOS: Os escolares apresentaram alta prevalência de consumo de tabaco, álcool maconha (77 por cento, 79 por cento e 23 por cento, respectivamente). O consumo de tabaco na presença de consumo de álcool foi um fator de risco de uso de maconha (RP=10,4; IC 95 por cento: 8,9;12,2). O início tardio de consumo de tabaco (HR=0,85; IC 95 por cento: 0,84;0,86) e álcool (HR=0,90; IC 95 por cento: 0,89;0,91) resultou ser um fator protetor do uso de maconha. A probabilidade de consumo de maconha foi maior naqueles que fumavam diariamente ou quase, em relação àqueles que fumavam somente aos fins de semana (RP=3,11; IC 95 por cento: 2,96;3,26 vs. RP=1,70; IC 95 por cento: 1,58;1,83). CONCLUSÕES: O risco de consumo de maconha se associou significativamente à idade de início de consumo de tabaco, à freqüência de consumo de tabaco e ao consumo simultâneo de álcool. As estratégias de prevenção deveriam proteger os escolares do consumo precoce de tabaco.

Variantes alélicas de CYP1A1 y GSTM1 como biomarcadores de susceptibilidad a cáncer gástrico: influencia de los hábitos tabáquico y alcohólico / Cytochrome P4501A1 (CYP1A1), glutathione S transferase M1 (GSTM1) polymorphisms and their association with smoking and alcohol consumption as gastric cancer susceptibility biomarkers

Background: Gastric cancer (GaC) is the second cause of death by cancer in the world and one of the first causes in Chile. However, the burden of this disease shows remarkable worldwide variation probably explained by environmental and genetic factors. The role of susceptibility low penetrance genes and environmental and dietary factors in the etiology of gastric cancer is not well-known. Aim: To analyze the possible association between CaG susceptibility, genetic (CYP1A1 and GSTM1 polymorphisms) and environmental (tobacco and alcohol) factors. Patients and Methods: In a case-control study, we included 73 patients with a pathologically diagnosed GaC and 263 controls. DNA was extracted from peripheral blood to detect allele variants for CYP1A1 and GSTM1, using polymerase chain reactions and digestion with restriction enzymes. Results: There was a clear association of smoking and alcohol ingestion with GaC with odds ratios (OR) of 2.54 (95 percent confidence intervals (CI) of 1.45-4.46 and OR of 3.36 (95 percent CI 1.76-6.41), respectively. Polymorphic variants of CYP1A1 and GSTM1 had no association with GaC. However, the m2 variant of CYP1A1 significantly modifies the risk induced by tobacco or alcohol (OR 13.65; 95 percent CI 3.15-59.05 y 8.37; 95 percent CI 1.86-37.64, respectively). Conclusions: Subjects that carry the m2 allelic variant of CYP1A1 and are exposed to tobacco smoke or alcohol have a significantly higher risk of developing gastric cancer.

Famacogénica del cáncer: Estudio de variaciones genéticamente determinadas en la susceptibilidad a cáncer por exposición a xenobióticos / Cancer pharmacogenetics: Study of genetically determined variations on cancer susceptibility due to xenobiotic exposure

Pharmacogenetics is the study of genetically determined variations in the response to drugs and toxic agents, and their implications on disease. Recently, the discipline has acquired great relevancy due to the development of non-invasive molecular techniques that identify genetic variants in human beings. There is also a need to explain the individual differences in susceptibility to drug actions and disease risk. Genetic variants can modify the magnitude of a pharmacologic effect, toxicity threshold, secondary effects and drug interactions. There are approximately thirty families of drug-metabolizing enzymes with genetic variants that cause functional alterations and variations in pharmacologic activity. We summarize the general knowledge about genetic variants of biotransformation enzymes, their relationship with cancer risk and the role of ethnicity. Cancer pharmacogenetics is another promising and exciting research area that will explain why people with an almost identical group of genes, have a different susceptibility to cancer, whose etiology has genetic and environmental components.