Identifying Inflammatory Markers in Vascular Disease
|dc.identifier.citation||Meikle, F. (2012). Identifying Inflammatory Markers in Vascular Disease (Thesis, Master of Medical Science). University of Otago. Retrieved from http://hdl.handle.net/10523/2140||en|
|dc.description.abstract||Introduction: Cardiovascular disease remains the leading cause of death and disability globally. There has been much interest into the role that inflammation plays in the pathogenesis of cardiovascular disease. The prominent histological feature of AAA is extensive inflammatory infiltration with T cells, B cells, macrophages, neutrophils and natural killer cells as the predominant cells involved in this inflammation. These cells produce inflammatory cytokines, which play a major role in tissue injury by inducing expression of proteolytic enzymes. In this study we have endeavoured to measure inflammatory biomarkers in patients with and without AAA and then assess which genes influence levels of these inflammatory markers. Methods: Participants included 346 with AAA and 380 vascular disease free controls. EDTA plasma samples were collected from all 726 participants and were assessed for the presence of inflammatory biomarkers using Bioplex 27 bead assay. The inflammatory biomarkers assessed included pro-inflammatory cytokines (IL-2, IL-4, IL-5, IL-6, IL-7, IL-8, IL-9, IL-10, IL-15, IL-17, IFN-γ, TNF- α), soluble receptors (IL-1RA), growth factors (G-CSF, GM-CSF, MIP-1α/β) and chemokines (IP-10, Eotaxin, MCP-1). C-reactive protein levels were determined using a specific high-sensitivity C-reactive protein (hsCRP) assay (Roche, Tina-quant high sensitivity [latex] assay). Separate genome wide association study (GWAS) was performed for IL-6, hsCRP and Eotaxin by comparing the upper with lower tertile for each marker. The genome wide data for each primary cohort participant had previously been generated using the Affymetrix SNP6.0 GeneChip® platform. Results: The important demographic predictors of AAA were identified as age, hypertension, dyslipidaemia and smoking history. Univariate analysis showed significantly elevated levels of hsCRP, IL-6, IL-8, IP-10, IL-1RA, VEGF and Eotaxin in the AAA group compared to controls (p<0.002). HsCRP, IL-6 and Eotaxin remained significantly associated with AAA within a multivariate model, which included the demographic risk factors of AAA. Within the genetic analysis those participants with high Eotaxin and hsCRP levels had 27 highly significant genes (p<1x10-4) identified, those with high IL-6 had 13 highly significant genes. These genes had associations with processes implicated in vascular disease including smooth muscle cell growth and differentiation (NRG1), apoptosis signalling (USP7, MAP2K6), cell adhesion (FLRT3), smooth muscle migration (CHN2), regulation of vascular tone (SLC28A3), and endothelial signalling and vascular function (APOLD1). Conclusion: This study replicated those associations between traditional risk factors, hsCRP, IL-6 and AAA. Eotaxin, on the other hand, has not previously been studied in relation to AAA, and thus may represent a novel indicator of AAA. Some of the most highly significant genes that were associated with elevated levels of hsCRP, IL-6 or Eotaxin had previously been noted to play a role in inflammation or vascular disease. There were a considerable number of genes that had previously been noted to play a role in inflammation or vascular disease. It is possible that this study has generated genetic associations with AAA that might be validated in separate populations in future studies.|
|dc.publisher||University of Otago|
|dc.rights||All items in OUR Archive are provided for private study and research purposes and are protected by copyright with all rights reserved unless otherwise indicated.|
|dc.title||Identifying Inflammatory Markers in Vascular Disease|
|thesis.degree.discipline||Vascular Research Department|
|thesis.degree.name||Master of Medical Science|
|thesis.degree.grantor||University of Otago|
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