The stratification potential of a novel epigenetic biomarker in rheumatoid arthritis

Duncan, Caitlin (2021) The stratification potential of a novel epigenetic biomarker in rheumatoid arthritis. PhD thesis, University of Glasgow.

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Abstract

Rheumatoid arthritis (RA) is a chronic autoimmune disease of the joints, that affects 0.5-1% of the population globally. While primarily affecting the joints, systemic inflammation impacts other organs and the disease has a significant socioeconomic burden. While there are a wide range of medications to pharmacologically manage RA, it is a largely heterogeneous disease and the current treatment strategy does not consider the heterogeneity between patients. As such, precision medicine approaches to treatment are desired. A 5-loop chromosome conformation signature (CCS) was identified that had 90% specificity at predicting non-response to methotrexate (MTX) in early RA. These epigenetic biomarkers offer a novel strategy for improving patient care, and provide insight into disease pathogenesis.

The aim of the work presented in this thesis was to further characterise this novel epigenetic biomarker. Investigation of this biomarker also offered the opportunity to hypothesise about underlying pathogenesis. A combination of molecular analysis of patient samples, and in-silico methodologies were applied to investigate these aims.

In the first instance, the CCS was validated as a biomarker for identifying MTX responders using bioinformatic tools. Preliminary work was also carried out to identify the optimal method for detecting chromosome loops from the signature in the lab. Quantitative PCR was thoroughly explored, but excluded as a reliable and robust method of loop detection for our signature of interest. It was also found that the CCS was MTX specific, and alternative signatures would be required for prediction of response to other csDMARDs. Further validation of the signature, using an independent clinical cohort, revealed that specific loops from the CCS held stratification potential while others did not. In-silico investigations revealed different epigenetic landscapes exist between loops associated with responders and non-responders to MTX. Specifically, data suggests loops associated with responders exist in an environment which enhances gene transcription, while loops associated with non-responders have an environment indicating potential for gene repression. Differences in chromatin architecture, revealed through a discovery microarray, have indicated that 3D epigenetic endotypes exist within the early RA population. Further investigations suggested each endotype have different, unique pathways that are highly regulated. Furthermore, results revealed that there is a stable RA chromatin signature that exists, which highlights the importance of the 3D epigenome underpinning disease.

In summation, this body of work has shown CCS to be promising biomarker for the stratification of the early RA population. Furthermore, thorough investigation of this signature highlighted novel pathways that may be involved in disease pathogenesis. This work has exciting potential to contribute to improved RA treatment in the future.

Item Type: Thesis (PhD)
Qualification Level: Doctoral
Subjects: Q Science > QR Microbiology > QR180 Immunology
Colleges/Schools: College of Medical Veterinary and Life Sciences > Institute of Infection Immunity and Inflammation
Supervisor's Name: Goodyear, Professor Carl and McInnes, Professor Iain and Hunter, Dr. Ewan
Date of Award: 2021
Depositing User: Theses Team
Unique ID: glathesis:2021-82492
Copyright: Copyright of this thesis is held by the author.
Date Deposited: 08 Oct 2021 08:50
Last Modified: 12 Oct 2021 08:02
Thesis DOI: 10.5525/gla.thesis.82492
URI: http://theses.gla.ac.uk/id/eprint/82492

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