Candidate Sequence Variants for Polyautoimmunity and Multiple Autoimmune Syndrome from a Colombian Genetic Isolate: Implications for Population Genetics

Autoimmunity is an immunological disorder whereby patients have lost immunological tolerance to self-antigen. It has extreme financial and socioeconomic burden with costs of over 100 billion dollars in the USA alone, and an estimated prevalence of 9.4%, and evidence indicates that this estimate has increased at a rate of 5% per year for the past 3 years. These phenotypes can be manifested in more severe forms through polyautoimmunity, whereby patients are carrying 2 or more autoimmune conditions. In addition to that, there is also the most extreme phenotype of autoimmunity known as the Multiple Autoimmune Syndrome (MAS), consisting of cases where patients have 3 or more autoimmune diseases. These extreme phenotypes are extremely important for genetic research as will be elaborated upon in this thesis. For more than 20 years, pedigrees from the world’s largest known genetic isolate, from the Paisa region of Colombia have been ascertained and thoroughly followed by Dr. Juan-Manuel Anaya and Dr. Mauricio Arcos-Burgos. This population has maintained its status as a genetic isolate since the 16th century, during the early colonization by the Spanish Conquistadors. In this thesis, our attempts in identifying potential candidate variants potentially underpinning the genetic etiology of autoimmune conditions in this population is facilitated by the fact that families are derived from individuals carrying extreme phenotypes, from familial cohorts where genetic homogeneity is maximized. Candidates are identified in both sporadic as well as familial cases. This is primarily achieved through combination of linkage analysis and association tests for both rare and common variants, derived from variant-calling pipelines and that had undergone quality control, filtering and functional annotation, via bioinformatic anlayses. Genes harbouring variants with significant evidence of linkage and association were primarily involved in negative regulation of apoptosis, phagocytosis, regulation of endopeptidase activity, response to lipopolysaccharides and plasminogen urokinase receptor activity. These findings, that were obtained by utilizing the combinations of statistical as well as network-based analyses have relevant potential implications in autoimmunity, and can be further supported with additional studies