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Title: Characterising lymphocyte mediated mechanisms of genetic risk in rheumatoid arthritis
Authors: Clark, Alexander David
Issue Date: 2020
Publisher: Newcastle University
Abstract: Rheumatoid arthritis (RA) is an immune-mediated inflammatory disease of the synovial joints with a global prevalence of 1%, causing pain, work instability and disability. The condition’s genetic aetiology is complex, and genome-wide association studies have highlighted over 100 susceptibility loci. The vast majority of implicated variants are noncoding, posing a major challenge in defining genetic mechanisms of cell-mediated immune dysregulation. The precise contribution to this process of epigenetic factors at a cellular level, such as the addition of methyl groups to DNA, also remains to be deciphered. By conducting comprehensive molecular profiling of circulating immune cells from early arthritis patients, my project aimed to elucidate mechanisms of genetic risk and prioritise causal disease genes in RA. To address this, genomewide DNA methylation, transcriptome and genotype data were available from peripheral blood CD4+ T cells and B cells of treatment-naïve early arthritis patients. Firstly, a comparison of DNA methylation between patients with early RA and those with other arthropathies was undertaken. Subsequently, the capacity of RA-associated variants to influence DNA methylation by mapping methylation quantitative trait loci (meQTLs) was confirmed. Here, it was observed that disease variants preferentially modified DNA methylation at sites mapping to lymphocyte enhancers and regions flanking transcription start sites, as well as positions bound by the NFκB transcription factor. By integrating transcriptomic data and employing a statistical approach to infer causality, loci were identified at which genetically conferred modifications in DNA methylation regulate transcription of genes including FCRL3, ANKRD55, IL6ST, and JAZF1 in CD4+ T cells. Finally, in vitro assays were used to validate meQTLs at loci of interest, and to confirm regulatory mechanisms. This work highlights genes and pathways of potential relevance to lymphocyte-mediated pathology in early RA and, potentially, other immune mediated diseases. It has implications for the functional interpretation of genome/epigenome-wide association studies.
Description: Ph. D. Thesis
Appears in Collections:Translational and Clinical Research Institute

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