Thesis (Ph. D.)--York University, 1999. Graduate Programme in Sociology. / Typescript. Includes bibliographical references (leaves 316-336). Also available on the Internet. MODE OF ACCESS via web browser by entering the following URL: http://wwwlib.umi.com/cr/yorku/fullcit?pNQ43440.

Diss. (sammanfattning) Stockholm : Univ., 2004. / Härtill 7 uppsatser.

Diss. (sammanfattning) Uppsala : Univ., 2003. / Härtill 4 uppsatser.

Thesis (M.S.)--University of Michigan, 1972.

Thesis--Arizona State University. / Vita. Includes bibliographical references (leaves [230]-244).

Thesis--Arizona State University. / Vita. Includes bibliographical references (leaves [230]-244).

Thesis (M.S.)--University of Michigan, 1972. / eContent provider-neutral record in process. Description based on print version record.

Diss. (sammanfattning) Göteborg : Göteborgs universitet, 2009. / Härtill 4 uppsatser.

Functional genomics uses high throughput genome-wide technologies to investigate the functional consequences of genetic variants on gene expression and protein products. In the context of disease, using integrative functional genomic approaches to understand the genetic variation which underlies disease susceptibility and aetiology may contribute to better diagnosis, treatment and prevention. This thesis investigated genetic determinants of variation in response to infection by applying a functional genomics approach to investigate three clinical cohorts: patients with severe sepsis, an influenza challenge study and patients with common variable immune deficiency disorders. The transcriptomic response to severe sepsis is reported here for the largest known adult severe sepsis community acquired pneumonia cohort. Two clusters within the cohort, based on gene expression signatures, which have different survival rates and identify individuals with distinct immune responses to sepsis, highlight the value of functional genomics for identifying heterogeneity within patient cohorts. This was further complemented by the resolution of gene expression signatures in healthy individuals following influenza challenge which identified individuals with moderate to severe disease. Shared gene expression signatures between the cohorts highlighted components of the immune response to viral infection important across multiple clinical settings and may assist with the identification of viral infections in the sepsis patients. Gene expression was mapped as a quantitative trait (eQTL). Comparison to data sets for healthy individuals and from innate immune stimulated cells identified regulatory variants specific to the context of sepsis. Whole genome sequencing for a cohort of patients with common variable immune deficiency disorders was performed. This identified novel variants and pathways which may play a role in the underlying immunopathogenesis of disease. Integration with RNA-seq for a small number of patients allowed prioritisation of non-coding variants based on evidence of altered gene expression. Comparison to the sepsis cohort analysis identified key immune related genes involved in rare and common responses to bacterial infection. This thesis has demonstrated the value of integrating multiple functional genomic techniques to further our understanding of the mechanisms underlying variation in the response to infection.

The tyrosine kinase 2 (TYK2) gene was first implicated in autoimmune disease in 2009 when a nonsynonymous single nucleotide polymorphism (nsSNP) in TYK2 was reported to be associated with multiple sclerosis (MS). The immunological function of TYK2, as a kinase involved in signal transduction downstream of numerous different cytokine receptors, further strengthened the candidacy of the gene as an MS-relevant risk factor. More recently, this nsSNP has been associated with several other autoimmune conditions. In addition, another three different SNPs in the region have been found to be associated with a number of autoimmune diseases, sometimes in opposing directions. Considering the complex genetic association pattern that is emerging for the TYK2 region across autoimmune conditions, it was hypothesised that this complexity reflects shared but also distinct pathogenic mechanisms, with the consequences of disease-associated SNPs being unlikely to all be restricted to genotype-dependent effects influencing TYK2. Therefore, the main aim of the work presented in this thesis has been to address this hypothesis by investigating the functional consequences of the disease-associated SNPs in the TYK2 gene region. Using an in vitro cell line system and primary human immune cells, obtained from a genotype-selectable donor cohort, protection at the MS-associated nsSNP was found to correlate with reduced TYK2-mediated signalling downstream of the type I interferon receptor. However, other cytokine signalling pathways were not affected, indicating a greater specificity to the function of TYK2 than has previously been appreciated. For the other SNPs in the region, substantial effects on TYK2 were not observed but immune cell subset-specific correlations with RNA-level expression of other genes in the region were identified. Thus, this is the first study to support the concept that a careful cross-comparative analysis of SNP association patterns in a single genomic region across multiple autoimmune diseases can have significant implications for enabling the delineation of pathways common or specific to different conditions, and this is of particular importance for drug repositioning strategies.