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UBC Theses and Dissertations

Functional analysis of polymorphisms in asthma genes : TSLP and IL1RL1 Akhabir, Loubna


Thymic stromal lymphopoietin (TSLP) and Interleukin 1 receptor-like 1 (IL1RL1) are important for the initiation and maintenance of a Th2 inflammatory environment in the asthmatic lung. TSLP and IL-33, the exclusive IL1RL1 ligand, are secreted by epithelial cells and other immune cells and play essential roles in Th2 polarization, activation and proliferation of immune cells and participate in many asthma cardinal features such as chronic inflammation, airway remodeling and mucus production. TSLP and IL1RL1 are two of the most consistently associated genes in genome-wide association studies of asthma. rs1837253 in TSLP was identified as a putative causal SNP based on consistent association data both from candidate gene and genome-wide association studies; as well as the absence of significant linkage disequilibrium with other single nucleotide polymorphisms (SNPs) in the region. In contrast, there are several asthma-associated IL1RL1 variants and due to the extensive linkage disequilibrium in the region encompassing IL1RL1 and many other genes, potential causal SNP(s) are unknown. In this thesis, I describe the functional analysis of the TSLP SNP rs1837253, the study of SNPs in the IL1RL1 region to identify potentially functional variants by in silico analysis using a lung expression Quantitative Trait Locus dataset and published association data, the functional analysis of the IL1RL1 SNPs: rs1420101 and rs3771180 and finally an analysis of gene expression of TSLP short and long isoforms as well as IL1RL1 receptor and soluble isoforms in relation to clinical phenotypes.

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