Identification and Verification of Differentially Methylated Regions in Cell-Free DNA as a Peripheral Biomarker for Bicuspid Aortic Valve Aortopathy

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dc.contributor.advisorGreenway, Steven C.
dc.contributor.advisorFedak, Paul
dc.contributor.authorMaredia, Ashna Karimbhai
dc.contributor.committeememberBathe, Oliver F.
dc.contributor.committeememberBraun, Andrew P.
dc.date2020-02
dc.date.accessioned2020-01-10T16:55:58Z
dc.date.available2020-01-10T16:55:58Z
dc.date.issued2020-01-08
dc.description.abstractBicuspid aortic valve (BAV) is a common congenital cardiac malformation associated with aortopathy for which the progression of aortic dilation is difficult to predict at present. BAV aortopathy has been linked to genetic factors and abnormal hemodynamic flow with regions of elevated wall shear stress (WSS) on the ascending aorta. The dying vascular smooth muscle cells release fragmented DNA into the circulation and this cell-free DNA (cfDNA) could be leveraged as a biomarker for aortopathy. Identification of tissue-specific differentially methylated regions (DMRs) in DNA provides a potential mechanism to identify cfDNA arising from the ascending aorta. The objective is to identify aorta-specific DMRs in the cfDNA of BAV patients as a biomarker for the severity of the aortopathy. We hypothesize that BAV-associated aortopathy leads to increased cell death and increased release of aorta-specific cfDNA correlating with the severity of aortopathy as defined by aortic cell death, elastin degradation and dysregulation of ECM proteins. BAV patient aortic wall samples corresponding to areas of elevated and normal WSS were collected and stained for cell death. Regions of elevated aortic WSS showed greater cell death when compared to regions of normal aortic WSS (p=0.00006). We established a bioinformatic pipeline for the identification of aorta-specific DMRs and they were verified with BAV patient cfDNA. The levels of aorta specific cfDNA of the DMRs on Chr 11, 18 and 22 of BAV patients had a significant correlation with levels of cell death in elevated aortic WSS regions. However, there was no correlation with elastin thickness, ECM concentrations of matrix metalloproteinases (MMP) types 1, 2 and 3, tissue inhibitor of metalloproteinases-1 and transforming growth factor-β1. Further work needs to be done in order to identify more specific aortic DMRs that have stronger correlation to the severity of BAV aortopathy markers with larger cohorts for biomarker validation. The identification of a peripheral biomarker that correlates with tissue disease will be an important advance in the non-invasive diagnosis of BAV-associated aortopathy and potentially help guide clinical decision-making regarding the need for surgical intervention.en_US
dc.identifier.citationMaredia, A. K. (2020). Identification and Verification of Differentially Methylated Regions in Cell-Free DNA as a Peripheral Biomarker for Bicuspid Aortic Valve Aortopathy (Master's thesis, University of Calgary, Calgary, Canada). Retrieved from https://prism.ucalgary.ca.en_US
dc.identifier.doihttp://dx.doi.org/10.11575/PRISM/37430
dc.identifier.urihttp://hdl.handle.net/1880/111457
dc.language.isoengen_US
dc.publisher.facultyCumming School of Medicineen_US
dc.publisher.institutionUniversity of Calgaryen
dc.rightsUniversity of Calgary graduate students retain copyright ownership and moral rights for their thesis. You may use this material in any way that is permitted by the Copyright Act or through licensing that has been assigned to the document. For uses that are not allowable under copyright legislation or licensing, you are required to seek permission.en_US
dc.subjectBicuspid aortic valveen_US
dc.subjectAortopathyen_US
dc.subjectBiomarkeren_US
dc.subjectnon-invasiveen_US
dc.subjectcell-free DNAen_US
dc.subjectdifferentially methylated regionen_US
dc.subjectmethylationen_US
dc.subjectcell deathen_US
dc.subjectwall shear stressen_US
dc.subject.classificationBioinformaticsen_US
dc.subject.classificationBiology--Cellen_US
dc.subject.classificationBiology--Molecularen_US
dc.subject.classificationBiochemistryen_US
dc.titleIdentification and Verification of Differentially Methylated Regions in Cell-Free DNA as a Peripheral Biomarker for Bicuspid Aortic Valve Aortopathyen_US
dc.typemaster thesisen_US
thesis.degree.disciplineMedicine – Medical Sciencesen_US
thesis.degree.grantorUniversity of Calgaryen_US
thesis.degree.nameMaster of Science (MSc)en_US
ucalgary.item.requestcopytrueen_US
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