Molecular Strategies to Distinguish Key Subphenotypes in Sarcoidosis
AuthorCasanova, Nancy Gonzalez
AdvisorGarcia, Joe G. N.
MetadataShow full item record
PublisherThe University of Arizona.
RightsCopyright © is held by the author. Digital access to this material is made possible by the University Libraries, University of Arizona. Further transmission, reproduction, presentation (such as public display or performance) of protected items is prohibited except with permission of the author.
AbstractSarcoidosis is a multisystemic disease of unknown etiology and unpredictable course, characterized by histopathological conglomerates of inflammatory cells defined as granulomas. These lesions however are non-pathognomonic, and in the absence of an identifiable etiologic agent, there are not specific diagnostic test for sarcoidosis. Despite the variable course of sarcoidosis, the lungs are affected in 90 percent of the cases. Approximately 25-30% of sarcoidosis patients progress to a complicated phenotype with progressive disease, leading to pulmonary fibrosis and organ dysfunction with increased mortality. These cases are in desperate need for biomarkers, conventional sarcoidosis biomarkers have proven to be insufficiently sensitive for implementation in routine clinical care. In this dissertation, I focused on the use of alternate strategies for biomarkers development utilizing genomic base approaches based on high-throughput molecular assays to characterize genotype, gene expression, and epigenetics that define sarcoidosis subphenotypes. Our results demonstrated that the integration of expression quantitative loci (eQTL) studies increase the power of Genome-wide association studies (GWAS). We identified SNPs that were associated to complicated sarcoidosis in African Americans (AA) and in European Americans (EA), and then we validated these SNPs by Massarray. Furthermore, at the transcript level, we identified the Peripheral Mononuclear Cells (PBMCs) responses to TNF-α exposure, a cytokine involved in the initiation of granulomas and progression of fibrosis in sarcoidosis and identified a differential dysregulation in pathways unique to complicated sarcoidosis. At the transcriptome level, we profiled microdisected granulomas from lung and lymph nodes, and identified a hub of genes that were dysregulated only in sarcoidosis in both compartments. Additionally, we compared the genomic profile of these granulomas in Sarcoidosis vs Tuberculosis (TB) and Coccidioidomycosis. We corroborated that some genes previously suggested as potential sarcoidosis markers were also present in fungal or mycobacterium granulomas, pointing to a common mechanistic origin. We also demonstrated a strong similarity at the transcriptional level between Sarcoidosis and TB. The contribution of the epigenetic mechanisms to the clinical presentation of sarcoidosis was assessed through DNA methylation analysis, complicated sarcoidosis reveled a hypo-methylated pattern in genes within HLA complex while the miRNA analysis derived a molecular signature consisting of 17 protein-coding genes, potentially regulated by 8 miRNAs dysregulated in complicated sarcoidosis.
Degree ProgramGraduate College