The complex genetics of multiple sclerosis

Cox, Mathew B.

Title: The complex genetics of multiple sclerosis
Creator: Cox, Mathew B.
Relation: University of Newcastle Research Higher Degree Thesis
Resource Type: thesis
Date: 2013
Description: Research Doctorate - Doctor of Philosophy (PhD) (Medical Genetics)
Description: Multiple sclerosis (MS) is an autoimmune disorder directed against the central nervous system (CNS). While it is known that lymphocytes can cross the blood brain barrier from the periphery, resulting in inflammatory lesions in the brain and spinal cord, the underlying aetiology of MS remains unknown. Current evidence suggests that the risk of developing MS is a result of both genetic and environmental factors. At least 57 genetic loci have been confirmed to be associated with MS, with DRB1*1501 showing the strongest effect. Alone these associated genes do not explain all of the predicted genetic contribution that underlies MS. Environmental factors, including low levels of vitamin D and smoking, have also been associated with an increased risk of developing MS, and together with genetic risk factors are thought to contribute significantly to the likelihood of developing disease. The aim of this study was to investigate variation in the transcriptome and genome of MS patients, to identify genes, and pathways that interact with environmental factors that could potentially explain the risk of developing MS. In this thesis, several levels of genetic investigation were undertaken which were then correlated with potential factors that interact with the environment. Initially a whole-genome gene expression study comparing MS cases against healthy controls was undertaken which revealed a predominance of genes involved in the immune system. Interestingly, four of the dysregulated genes form part of the plasminogen activation pathway, including MMP9, which is thought to be involved in the break-down of the blood brain barrier. To investigate potential causes of this dysregulation in the plasminogen activation pathway, I performed a candidate gene SNP association study, investigating 17 common variants within these four genes, in over 4500 samples. There was no association of any variant investigated and MS risk, nor did genotype correlate with gene expression. The role of miRNA and its association with gene expression in MS was undertaken where I identified an expression profile, unique to MS compared to healthy controls. Two of the miRNAs, miR-17 and miR-20a which were significantly under-expressed in MS were further investigated, and found to target genes involved in T cell activation. It appears from this study that the dysregulation of miRNAs observed in this study may result in increased T cell activation, as seen in MS. Finally, a candidate gene SNP association study was performed to investigate two common variants in the vitamin D receptor gene (VDR). We identified some evidence of association of one variant in VDR with increased risk of MS. A second variant in VDR in combination with DRB1*1501, revealed a non-significant trend for an increased risk of MS. The results presented in this thesis highlight the autoimmune nature of MS. Genes involved in the immune system are dysregulated in MS patients, and miRNAs that are able to regulate T cell activation genes are also dysregulated. Interestingly, we identified altered gene expression which may play a role in the breakdown of the blood brain barrier. We also identified a potential interaction between genetic factors associated with increased risk of MS.
Subject: multiple sclerosis; genetics; gene expression; SNP genotyping; miRNA; thesis by publication
Identifier: http://hdl.handle.net/1959.13/1039292
Identifier: uon:13635
Language: eng
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