Genetic Epidemiology of Polyautoimmunity and Common Autoimmunity in Colombia — Proof of Principle

Introducción: Las enfermedades autoinmunes (EA) son responsables de una gran porción de discapacidad y morbilidad a nivel mundial. Generalmente, las investigaciones científicas se centran en una sola enfermedad, aunque los fenotipos autoinmunes podrían estar representados por efectos pleiotrópicos e...

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Fecha de publicación:: 2016

Institución:: Universidad del Rosario

Repositorio:: Repositorio EdocUR - U. Rosario

Idioma:: spa

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network_acronym_str	EDOCUR2
network_name_str	Repositorio EdocUR - U. Rosario
repository_id_str
dc.title.spa.fl_str_mv	Genetic Epidemiology of Polyautoimmunity and Common Autoimmunity in Colombia — Proof of Principle
title	Genetic Epidemiology of Polyautoimmunity and Common Autoimmunity in Colombia — Proof of Principle
spellingShingle	Genetic Epidemiology of Polyautoimmunity and Common Autoimmunity in Colombia — Proof of Principle Autoinmunidad Poliautoinmunidad Sindrome Autoinmune Multiple Enfermedad Autoinmune Autoinmunidad Familial Incidencia & prevención de la enfermedad Epidemiología Enfermedades autoinmunes Inmunología Autoimmunity Polyautoimmunity Multiple Autoimmune syndrome Familial Autoimmunity Autoimmune disease Ciencias médicas
title_short	Genetic Epidemiology of Polyautoimmunity and Common Autoimmunity in Colombia — Proof of Principle
title_full	Genetic Epidemiology of Polyautoimmunity and Common Autoimmunity in Colombia — Proof of Principle
title_fullStr	Genetic Epidemiology of Polyautoimmunity and Common Autoimmunity in Colombia — Proof of Principle
title_full_unstemmed	Genetic Epidemiology of Polyautoimmunity and Common Autoimmunity in Colombia — Proof of Principle
title_sort	Genetic Epidemiology of Polyautoimmunity and Common Autoimmunity in Colombia — Proof of Principle
dc.contributor.advisor.none.fl_str_mv	Anaya, Juan-Manuel
dc.subject.spa.fl_str_mv	Autoinmunidad Poliautoinmunidad Sindrome Autoinmune Multiple Enfermedad Autoinmune Autoinmunidad Familial
topic	Autoinmunidad Poliautoinmunidad Sindrome Autoinmune Multiple Enfermedad Autoinmune Autoinmunidad Familial Incidencia & prevención de la enfermedad Epidemiología Enfermedades autoinmunes Inmunología Autoimmunity Polyautoimmunity Multiple Autoimmune syndrome Familial Autoimmunity Autoimmune disease Ciencias médicas
dc.subject.ddc.none.fl_str_mv	Incidencia & prevención de la enfermedad
dc.subject.decs.spa.fl_str_mv	Epidemiología Enfermedades autoinmunes Inmunología
dc.subject.keyword.eng.fl_str_mv	Autoimmunity Polyautoimmunity Multiple Autoimmune syndrome Familial Autoimmunity Autoimmune disease
dc.subject.lemb.spa.fl_str_mv	Ciencias médicas
description	Introducción: Las enfermedades autoinmunes (EA) son responsables de una gran porción de discapacidad y morbilidad a nivel mundial. Generalmente, las investigaciones científicas se centran en una sola enfermedad, aunque los fenotipos autoinmunes podrían estar representados por efectos pleiotrópicos en genes no-específicos al presentar mecanismos inmunogenéticos similares. Múltiples casos de una sola enfermedad dentro de familia son evidentes, y aún más sorprendente son los individuos en aquellas familias que sufren de múltiples enfermedades autoinmunes. Este estudio exploró la dinámica de agregación familiar y la segregación en pacientes con EA, poliautoimmunidad (polyA) (presentar por lo menos dos AD) y el síndrome autoinmune múltiple (MAS) (presentar tres o más EA). Por otra parte, se examinó el efecto y la importancia de la homocigosis y la ancestría en individuos afectados colombianos con respecto a desarrollar una EA. Métodos: La agregación y segregación familiar se examinó en familiares de primer grado para un rasgo binario en 210 familias afectadas por EA. La homocigosis se estudió en dos enfoques: (I) Comparación de casos y controles mediante la evaluación del efecto de la homocigosis al nivel de todo el genoma en 453 individuos no relacionados (121 EA tardía, 79 EA temprana, 40 polyA, 30 MAS y 183 individuos control); (II) por un estudio de ligamiento no-paramétrico en parientes afectados en 35 familias con MAS, 49 con polyA, 104 con EA tardía, y 83 con EA temprana. La ancestría se examinó en todos los individuos afectados y sanos colombianos, así como individuos originados a partir de poblaciones de referencia, suponiendo tres grupos ancestrales (k = 3) (i.e., europea, amerindia y africana). El efecto de ancestría para los rasgos estudiados se comparó y analizó mediante regresión logística con respecto a los controles. Todos los individuos y las familias fueron tratados e invitados a participar en el Centro de Investigación de Enfermedades Autoinmunes (CREA) en Medellín y Bogotá, Colombia. Resultados: Este proyecto sugiere que las EA no son rasgos independientes y que el género, la edad y la edad de inicio representan factores que definen y permiten el estudio de la dinámica de los rasgos dentro del grupo familiar. Más allá, los datos de segregación proporcionaron soporte para el papel del componente genético en la etiología de las EAs en las familias de aparición tardía, mientras que para las familias de inicio temprano no se observó un papel claro, tal vez debido a la edad relativamente joven familiar. Los datos también mostraron diferencias en la homocigosidad en relación con los controles para las personas de aparición temprana, mientras que en la inspección de varios marcadores locales se sugiere que la homocigosis se encuentra asociada con la protección/susceptibilidad para la EA temprana, de inicio tardío, polyA y MAS. Por otra parte, la ancestría y la autoinmunidad en muestras de colombianos mostraron cómo el paisaje rasgo autoinmune no es un escenario blanco y negro, sino más bien una colorida mezcla de factores genéticos y ambientales. Todos los marcadores analizados fueron muy informativos con una baja frecuencia del alelo nulo haciéndolos óptimos y fiables para estudios de diversidad genética. Conclusiones: Este estudio asumió a la autoinmunidad como un rasgo más que un fenotipo clínico y como un rasgo continuo que presenta fenotipos extremos. Los datos sugieren que las EAs no son independientes. Por último, una EA individual, definida por síntomas y signos, podría no ser completamente yuxtapuesta con una EA definida por el medio ambiente y genética, lo que hace aún más difícil la tarea de definir y dilucidar los mecanismos de las enfermedades.
publishDate	2016
dc.date.created.none.fl_str_mv	2016-11-28
dc.date.issued.none.fl_str_mv	2016
dc.date.accessioned.none.fl_str_mv	2017-09-03T19:14:28Z
dc.date.available.none.fl_str_mv	2017-09-03T19:14:28Z
dc.type.eng.fl_str_mv	doctoralThesis
dc.type.coar.fl_str_mv	http://purl.org/coar/resource_type/c_db06
dc.type.spa.spa.fl_str_mv	Tesis de doctorado
dc.identifier.doi.none.fl_str_mv	https://doi.org/10.48713/10336_13733
dc.identifier.uri.none.fl_str_mv	http://repository.urosario.edu.co/handle/10336/13733
url	https://doi.org/10.48713/10336_13733 http://repository.urosario.edu.co/handle/10336/13733
dc.language.iso.none.fl_str_mv	spa
language	spa
dc.rights.coar.fl_str_mv	http://purl.org/coar/access_right/c_abf2
dc.rights.acceso.spa.fl_str_mv	Abierto (Texto completo)
dc.rights.cc.spa.fl_str_mv	Atribución-NoComercial-SinDerivadas 2.5 Colombia
dc.rights.uri.none.fl_str_mv	http://creativecommons.org/licenses/by-nc-nd/2.5/co/
rights_invalid_str_mv	Abierto (Texto completo) Atribución-NoComercial-SinDerivadas 2.5 Colombia http://creativecommons.org/licenses/by-nc-nd/2.5/co/ http://purl.org/coar/access_right/c_abf2
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dc.publisher.spa.fl_str_mv	Universidad del Rosario
dc.publisher.department.spa.fl_str_mv	Facultad de Ciencias Naturales y Matemáticas
dc.publisher.program.spa.fl_str_mv	Doctorado en Ciencias Biomédicas
institution	Universidad del Rosario
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spelling	Anaya, Juan-Manuel19474778600Castiblanco Quinche, JohnDoctor en Ciencias Biomédicasd151724e-d3bc-4cff-9dab-92c060ed7ee9-12017-09-03T19:14:28Z2017-09-03T19:14:28Z2016-11-282016Introducción: Las enfermedades autoinmunes (EA) son responsables de una gran porción de discapacidad y morbilidad a nivel mundial. Generalmente, las investigaciones científicas se centran en una sola enfermedad, aunque los fenotipos autoinmunes podrían estar representados por efectos pleiotrópicos en genes no-específicos al presentar mecanismos inmunogenéticos similares. Múltiples casos de una sola enfermedad dentro de familia son evidentes, y aún más sorprendente son los individuos en aquellas familias que sufren de múltiples enfermedades autoinmunes. Este estudio exploró la dinámica de agregación familiar y la segregación en pacientes con EA, poliautoimmunidad (polyA) (presentar por lo menos dos AD) y el síndrome autoinmune múltiple (MAS) (presentar tres o más EA). Por otra parte, se examinó el efecto y la importancia de la homocigosis y la ancestría en individuos afectados colombianos con respecto a desarrollar una EA. Métodos: La agregación y segregación familiar se examinó en familiares de primer grado para un rasgo binario en 210 familias afectadas por EA. La homocigosis se estudió en dos enfoques: (I) Comparación de casos y controles mediante la evaluación del efecto de la homocigosis al nivel de todo el genoma en 453 individuos no relacionados (121 EA tardía, 79 EA temprana, 40 polyA, 30 MAS y 183 individuos control); (II) por un estudio de ligamiento no-paramétrico en parientes afectados en 35 familias con MAS, 49 con polyA, 104 con EA tardía, y 83 con EA temprana. La ancestría se examinó en todos los individuos afectados y sanos colombianos, así como individuos originados a partir de poblaciones de referencia, suponiendo tres grupos ancestrales (k = 3) (i.e., europea, amerindia y africana). El efecto de ancestría para los rasgos estudiados se comparó y analizó mediante regresión logística con respecto a los controles. Todos los individuos y las familias fueron tratados e invitados a participar en el Centro de Investigación de Enfermedades Autoinmunes (CREA) en Medellín y Bogotá, Colombia. Resultados: Este proyecto sugiere que las EA no son rasgos independientes y que el género, la edad y la edad de inicio representan factores que definen y permiten el estudio de la dinámica de los rasgos dentro del grupo familiar. Más allá, los datos de segregación proporcionaron soporte para el papel del componente genético en la etiología de las EAs en las familias de aparición tardía, mientras que para las familias de inicio temprano no se observó un papel claro, tal vez debido a la edad relativamente joven familiar. Los datos también mostraron diferencias en la homocigosidad en relación con los controles para las personas de aparición temprana, mientras que en la inspección de varios marcadores locales se sugiere que la homocigosis se encuentra asociada con la protección/susceptibilidad para la EA temprana, de inicio tardío, polyA y MAS. Por otra parte, la ancestría y la autoinmunidad en muestras de colombianos mostraron cómo el paisaje rasgo autoinmune no es un escenario blanco y negro, sino más bien una colorida mezcla de factores genéticos y ambientales. Todos los marcadores analizados fueron muy informativos con una baja frecuencia del alelo nulo haciéndolos óptimos y fiables para estudios de diversidad genética. Conclusiones: Este estudio asumió a la autoinmunidad como un rasgo más que un fenotipo clínico y como un rasgo continuo que presenta fenotipos extremos. Los datos sugieren que las EAs no son independientes. Por último, una EA individual, definida por síntomas y signos, podría no ser completamente yuxtapuesta con una EA definida por el medio ambiente y genética, lo que hace aún más difícil la tarea de definir y dilucidar los mecanismos de las enfermedades.Background: Autoimmune diseases (AD) are responsible for a substantial amount of disability and morbidity worldwide. Research generally focuses on a single disease, although autoimmune phenotypes could represent pleiotropic outcomes of non-specific disease genes underlying similar immunogenetic mechanisms. While it is apparent that multiple cases of a single disease cluster within families, more striking are the individuals in those families afflicted with multiple autoimmune diseases. This study explored the dynamics of familial aggregation and segregation in AD (i.e., having at least one AD), polyautoimmunity (polyA) (i.e., having at least two ADs) and multiple autoimmune syndrome (MAS) (i.e., having three or more ADs) patients. Moreover, this project examined the effect and importance of homozygosity and whether the ancestry component of Colombian affected individuals is associated with susceptibility/protection to develop an AD. Methods: Familial aggregation was examined for first-degree relatives. Segregation analysis for a binary trait was implemented on 210 single ascertained multiplex AD families. Homozygosity was examined by two approaches: (I) a case – control comparison and evaluation on the effect of homozygosity at the genome-wide level, including 453 genotyped unrelated individuals (121 late-onset AD, 79 early-onset, 40 polyA, 30 MAS and 183 healthy control individuals); and (II) a model-free affected pair linkage approach which included 35 MAS, 49 polyA, 104 late-, and 83 early-onset multiplex families. The admixture effect was examined in all included Colombian affected and healthy individuals, as well as in the individuals originated from reference populations, assuming three ancestral groups (k=3) (i.e., European, Amerindian and African). The ancestry component effect for the studied traits was compared and examined by logistic regression relative to controls. All individuals and families were treated and recruited at the Center for Autoimmune Diseases Research (CREA) from Medellin and Bogota, Colombia, South America. Results: This project provided data supporting that polyA and MAS are not AD independent traits and that gender, age and age of onset represent factors that define and allow the study of the dynamics of the traits within the familial group. Also, segregation data provided evidence for the genetic component role in the etiology of AD in late-onset families, while for early-onset families and perhaps because of their the relatively familial young status, eluded a clear picture of autoimmunity segregation and aggregation. The data also showed homozygosity differences relative to controls for early-onset individuals, while on local inspection several markers suggested homozygosity associated with protection/susceptibility to early-, late-onset, polyA and/or MAS. Moreover, ancestry and autoimmunity in Colombian samples showed how the autoimmune trait landscape is not a black and white scenario but rather a colorful mix of genetic and environmental factors. All markers analyzed were highly informative with a low null allele frequency making them optimal and reliable for genetic diversity studies. Conclusions: This study presumed autoimmunity as a trait rather than a clinical phenotype and tried to approach AD as a continuous trait presenting extreme phenotypes. Data suggested that AD are not independent traits and that gender, age and age of onset represent factors play a role and allow to study of the dynamic of the traits. Finally, a clinical defined individual AD, defined by symptoms and signs, might not be completely juxtaposed to the AD trait defined by environment and genetics, which makes even more difficult the task to define and untangle disease mechanisms.Center for Autoimmune Disease Research (CREA)application/pdfhttps://doi.org/10.48713/10336_13733 http://repository.urosario.edu.co/handle/10336/13733spaUniversidad del RosarioFacultad de Ciencias Naturales y MatemáticasDoctorado en Ciencias BiomédicasAbierto (Texto completo)Atribución-NoComercial-SinDerivadas 2.5 ColombiaEL AUTOR, manifiesta que la obra objeto de la presente autorización es original y la realizó sin violar o usurpar derechos de autor de terceros, por lo tanto la obra es de exclusiva autoría y tiene la titularidad sobre la misma. PARGRAFO: En caso de presentarse cualquier reclamación o acción por parte de un tercero en cuanto a los derechos de autor sobre la obra en cuestión, EL AUTOR, asumirá toda la responsabilidad, y saldrá en defensa de los derechos aquí autorizados; para todos los efectos la universidad actúa como un tercero de buena fe. EL AUTOR, autoriza a LA UNIVERSIDAD DEL ROSARIO, para que en los términos establecidos en la Ley 23 de 1982, Ley 44 de 1993, Decisión andina 351 de 1993, Decreto 460 de 1995 y demás normas generales sobre la materia, utilice y use la obra objeto de la presente autorización. -------------------------------------- POLITICA DE TRATAMIENTO DE DATOS PERSONALES. Declaro que autorizo previa y de forma informada el tratamiento de mis datos personales por parte de LA UNIVERSIDAD DEL ROSARIO para fines académicos y en aplicación de convenios con terceros o servicios conexos con actividades propias de la academia, con estricto cumplimiento de los principios de ley. 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Genetic Epidemiology of Polyautoimmunity and Common Autoimmunity in Colombia — Proof of Principle

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