doctoralThesis
Genetic Epidemiology of Polyautoimmunity and Common Autoimmunity in Colombia — Proof of Principle
Fecha
2016Autor
Castiblanco Quinche, John
Institución
Resumen
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.