Ischaemic stroke rates are expected to rise significantly in the next decades due to an aging population. This increases the demand for new stroke biomarkers for early detection of patients at risk and new targets for treatment. It has been hypothesized that epigenetics may be important in the aetiology of stroke. The study consisted of three types of investigation: analysis of candidate gene polymorphism, candidate gene methylation analysis and epigenome-wide methylation analysis (EWAS) of pooled stroke and control samples. The stroke types studied were large vessel disease (LVD), small vessel disease (SVD) and cardioembolic stroke (CE). DNA from peripheral blood samples was used for EWAS and methylation analysis. Significant increases in rare allele frequency were observed in the EHMT2 and DNMT3B genes for all stroke cases; MBD2, DNMT3B and DNMT3L polymorphisms were associated with LVD. IL10, SOD3, LINE1 and PITX2 were significantly hypomethylated in LVD. IL10 and ALOX15 were hypomethylated in CE compared to controls. Methylation levels of following genes were associated with age (LINE1, IL10, MTHFR, TNFα, and PITX2), gender (SOD3 and LINE1), total cholesterol level (SOD3) and systolic blood pressure (IL10). HDAC9 genetic polymorphism was associated with the MTHFR methylation level. A distinctive methylation pattern for each stroke subtype was found by EWAS. The CE pool was hypomethylated at genome, chromosome and gene level, while LVD and SVD pools had regions with higher and lower methylation levels compared to the controls. GNAS was identified as new candidate gene by EWAS. The results suggested that genetic polymorphism and DNA methylation levels of candidate genes were associated with ischaemic stroke. Stroke subtypes had distinct methylation profiles suggesting differences in underlying aetiology. Variations in methylation levels detected in this study could lead to identification of specific biomarkers. Replication on a large number of subjects is required before final conclusions can be drawn.
| Identifer | oai:union.ndltd.org:bl.uk/oai:ethos.bl.uk:582717 |
| Date | January 2013 |
| Creators | Pogoryelova, Oksana |
| Publisher | University of Aberdeen |
| Source Sets | Ethos UK |
| Detected Language | English |
| Type | Electronic Thesis or Dissertation |
| Source | http://digitool.abdn.ac.uk:80/webclient/DeliveryManager?pid=201969 |
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