The differential expression of microrna in abdominal aortic aneurysms
thesisposted on 06.11.2014, 11:54 by Philip William Stather
Abdominal aortic aneurysms (AAA) account for 5,251 deaths per year in the UK (2010). Their current incidence in the NHS AAA screening programme is 1.8%, however the vast majority are small. These patients therefore undergo surveillance prior to the need for surgical intervention. Biomarkers for AAA have been extensively studied, with a meta-analysis, conducted herein, identifying a significant association between several biomarkers and AAA (upregulation of matrix metalloproteinase-2, matrix metalloproteinase-9, tissue inhibitor of matrix metalloproteinase-1, interleukin-6, interleukin-10, tumour necrosis factor-α, osteoprotegerin, osteopontin, interferon-γ, intercellular adhesion molecule-1, vascular cell adhesion protein-1, D-dimer, C-reactive protein, alpha-1 antitrypsin, fibrinogen, triglycerides, and lipoprotein(a), and downregulation of apolipoprotein-A and high density lipoprotein). However, the sensitivity and specificity of these biomarkers is poor, therefore this thesis aimed to look at the expression of microRNAs (miRNAs) in AAA, hitherto previously unstudied. MiRNAs are short, non-coding RNA sequences which are transcribed from DNA, however they are not translated into protein. They exert their effect by attaching to messenger RNA (mRNA) and causing repression of translation into protein, and deadenylation, thus causing mRNA degradation. MiRNAs are capable of interacting with over 60% of known genes. The studies within this thesis have undertaken a case control discovery and validation study into miRNAs in AAA, identifying a significant upregulation of 29 miRNAs within the discovery study, 4 of which were validated in blood (let-7e, miR-15a, miR-196b, miR-411), and miR-196b being further validated in plasma. There was however no miRNA dysregulation found in aortic tissue. In addition, these 4 miRNAs were found to have significant interactions with previously studied AAA biomarkers identified through earlier systematic review and meta-analysis. The 4 miRNAs identified within this thesis were similarly dysregulated in patients with peripheral arterial disease, therefore they may be dysregulated due to generalised atherosclerosis rather than AAA, and must be interpreted with caution.