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Title: A profile of differential DNA methylation in sporadic human prion disease blood : precedent, implications and clinical promise
Author: Dabin, Luke Child
ISNI:       0000 0004 8507 5158
Awarding Body: UCL (University College London)
Current Institution: University College London (University of London)
Date of Award: 2019
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Sporadic Creutzfeldt-Jakob Disease (sCJD) is a rare but devastating neurodegenerative disorder characterised by misfolding, propagation and deposition of the prion protein in the brain, leading to neuronal death and rapid cognitive and functional decline. As there is no obvious genetic cause of sCJD, the epigenetic status of sCJD patients may clarify spontaneous prion disease aetiology or reveal biomarkers of the disease. Blood from patients was profiled to document genome-wide differential DNA methylation. 38 loci were identified as being differentially methylated in sCJD blood, including two which associated with disease severity as measured by the MRC Scale score. Of 7 loci considered for replication, 5 showed similar effects in a second cohort of patients, but not in patients of Alzheimer's disease, iatrogenic CJD, or inherited prion disease, suggesting these effects are specific to the sporadic form of CJD. Notably hypomethylation at a site in the promoter of AIM2, an inflammasome component, retained its association with disease severity. Hypomethylation of FKBP5, a gene known to regulate the cellular response to cortisol, prompted further investigation which revealed that circulating cortisol is indeed elevated in sCJD patients. Profiling of frontal cortex-derived DNA showed that differential methylation observed in blood is absent from the brain methylome. Machine learning classification of sCJD based on genome-wide methylation data was able to classify sCJD and healthy control status with an accuracy of 87.04%. This is an appreciable level of accuracy but importantly sets precedence for further classification of prion patients in more complex clinical and research settings, as well as assisting differential diagnosis of less conventional rapid dementias.
Supervisor: Mead, S. ; Vire, E. Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available