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Coding and Non-Coding Circulating Rnas Associated with the Presence and Rapid Expansion of Abdominal Aortic Aneurysms Vikram Murlidhar Iyer BA, MBBS (Hons)

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Coding and Non-Coding Circulating Rnas Associated with the Presence and Rapid Expansion of Abdominal Aortic Aneurysms Vikram Murlidhar Iyer BA, MBBS (Hons) 1 Coding and non-coding circulating RNAs associated with the presence and rapid expansion of abdominal aortic aneurysms Vikram Murlidhar Iyer BA, MBBS (Hons) A thesis submitted for the degree of Master of Philosophy at The University of Queensland in 2018 Faculty of Medicine 2 Abstract Introduction Abdominal aortic aneurysms (AAA) are pathological dilatations of the abdominal aorta. AAA may progressively enlarge and eventually rupture; ruptured AAA has a high mortality and morbidity even with timely surgical intervention. AAA diagnosis is usually made using imaging modalities such as duplex ultrasonography (USS) or computed tomography (CT). While there has been increasing interest in medical management of AAA, no treatment other than surgery has been found to adequately treat the condition. Non-coding RNAs such as microRNAs, which regulate gene expression at the post-transcriptional level, are increasingly being investigated for their use as diagnostic and prognostic biomarkers as well as therapeutic targets in AAA. One barrier to their clinical utility is a lack of specificity for AAA compared to other cardiovascular diseases such as ischaemic heart disease (IHD) and peripheral artery disease (PAD). This study aimed to identify circulating non-coding RNAs associated with AAA presence and growth, as well as to investigate their downstream targets to provide insights into their pathophysiological roles in AAA development and progression. Methods A two-stage prospective case-control study was conducted using participants recruited to the Vascular Database and Peripheral Vascular Biobank at James Cook University. To identify circulating non-coding and coding RNAs associated with AAA presence, serum and whole blood samples from 36 age- and sex-matched participants, comprising 12 cases with AAA, 12 cases with PAD, and 12 healthy controls, were used. AAA was excluded using USS or CT imaging for the PAD and healthy control groups, and PAD was excluded using ankle-brachial pressure indices (ABPI) for the AAA and healthy control groups. Demographic details, comorbidities and medications were recorded for all participants. Using a commercially-available and validated RNA extraction kit, total RNA was extracted from the serum and blood samples and analysed for expression of 800 non-coding RNAs using the Human miRNA v3 Assay Panel on nanoString Technologies’ nCounter Analysis System for serum miRNA, and the Illumina HiSeq 2500 platform for coding RNA from blood cells. Results were analysed using nanoString Technologies’ nSolver Analysis Tool and DESeq2 Bioconductor v3.5 tool, with statistical analyses performed using the appropriate categorical, parametric and non-parametric tests in SPSS v23. A 3 larger cohort of 107 cases with AAA was then recruited to validate the findings from the initial serum analysis using the same methods. Downstream coding RNA (mRNA) target and pathways analysis was conducted for differentially-expressed miRNAs using online prediction tools. To identify circulating non-coding RNAs associated with AAA growth, serum samples were identified from 106 AAA cases who underwent 12-monthly serial CT assessments over a 12 – 24- month period. Maximum orthogonal AAA diameter was recorded in millimetres (mm) from each CT using a semi-automated protocol whose inter- and intra-observer reproducibility has been previously established. Annual AAA growth was calculated from these measurements using a linear mixed effects model. Clinical detail recording, RNA extraction, analysis, and statistical methods were performed as described previously. Results Six miRNAs from serum, and two coding RNAs from blood cells were identified as significantly differentially-expressed in the AAA group compared to the PAD and healthy control groups in the discovery phase. After validation in a larger AAA cohort, only one miRNA in serum (let-7b-5p) remained significantly differentially-expressed. let-7b-5p was 1.388-fold upregulated in the serum of the AAA cohort compared to the healthy control group, and 0.761-fold downregulated in the PAD cohort (p<0.001). Receiver operator characteristic (ROC) curve analysis demonstrated an area under the curve (AUC) of 0.918 for let-7b-5p for diagnosing AAA compared to the other two groups, marking it as a potential biomarker for AAA diagnosis. Downstream target and pathways analysis revealed biologically plausible mRNA targets for let-7b-5p, including one of the two identified differentially-expressed coding RNAs (SUB1) in whole blood of AAA patients, functionally implicating let-7b-5p in AAA development. The AAA growth cohort was divided by median annual AAA growth rate in mm into two equal groups. Serum miR-1268a was significantly downregulated in the fast-growing AAA group compared to the slow-growing AAA group (0.707-fold, p = 0.043). ROC curve analysis demonstrated an AUC of 0.618 for miR-1268a for diagnosing fast-growing AAA, indicating this miRNA is not suitable in isolation as a biomarker for AAA growth. However, downstream targets and pathways analysis revealed biologically plausible mRNA targets of miR-1268a, functionally implicating it in AAA progression. 4 Conclusion In this study, one circulating miRNA in serum (let-7b-5p) was associated with AAA diagnosis, while another miRNA (miR-1268a) was associated with fast-growing AAA. let-7b-5p demonstrates promise as a biomarker for AAA diagnosis, while miR-1268a was not suitably sensitive or specific for independent biomarker use to predict AAA progression. The downstream targets and pathways associated with these miRNAs potentially implicate them in AAA pathogenesis and progression. Further larger focussed studies are required to validate these findings. Word count: 778. Character count: 4,662 (excl. spaces). 5 Declaration by author This thesis is composed of my original work, and contains no material previously published or written by another person except where due reference has been made in the text. I have clearly stated the contribution by others to jointly-authored works that I have included in my thesis. I have clearly stated the contribution of others to my thesis as a whole, including statistical assistance, survey design, data analysis, significant technical procedures, professional editorial advice, financial support and any other original research work used or reported in my thesis. The content of my thesis is the result of work I have carried out since the commencement of my higher degree by research candidature and does not include a substantial part of work that has been submitted to qualify for the award of any other degree or diploma in any university or other tertiary institution. I have clearly stated which parts of my thesis, if any, have been submitted to qualify for another award. I acknowledge that an electronic copy of my thesis must be lodged with the University Library and, subject to the policy and procedures of The University of Queensland, the thesis be made available for research and study in accordance with the Copyright Act 1968 unless a period of embargo has been approved by the Dean of the Graduate School. I acknowledge that copyright of all material contained in my thesis resides with the copyright holder(s) of that material. Where appropriate I have obtained copyright permission from the copyright holder to reproduce material in this thesis and have sought permission from co-authors for any jointly authored works included in the thesis. 6 Publications during candidature Peer-reviewed review articles: Golledge J, Biros E, Bingley J, Iyer V, Krishna SM. Epigenetics and peripheral artery disease. Curr Atheroscler Rep. 2016 Apr;18(4):15. Iyer V, Rowbotham S, Biros E, Bingley J, Golledge J. A systematic review investigating the association of microRNAs with human abdominal aortic aneurysms. Atherosclerosis. 2017 Jun;261:78-89. Publications included in this thesis None. Manuscripts included in this thesis None. 7 Contributions by others to the thesis Project conception and design: Professor Jonathan Golledge, Professor Philip Walker, Dr John Bingley, Dr Erik Biros, Dr Smriti Krishna, Dr Joseph Moxon. Participant selection and recruitment: Ms Jenna Pinchbeck, Ms Georgina Anderson, Ms Lisan Yip, Mr Cedric Hensman. Sample identification: Ms Sharon Lazzaroni, Dr Susan Morton. Non-routine technical work: Ms Sharon Lazzaroni, Dr Susan Morton, Dr Erik Biros, Mr Thomas Watkins. Analysis and interpretation of scientific data: Dr Matt Field, Dr Erik Biros, Dr Smriti Krishna, Professor Jonathan Golledge, Dr Joseph Moxon, Mr Thomas Watkins, Associate Professor John Miles. Critical revision of manuscript: Professor Jonathan Golledge, Dr John Bingley. Statement of parts of the thesis submitted to qualify for the award of another degree None. Research involving human or animal subjects This research project was approved by the Human Research Ethics Committees (HREC) of the Royal Brisbane and Womens’ Hospital (Ref. HREC/14/QRBW/284), the Townsville Hospital and Health Service (Ref. HREC/12/QTHS/202, and HREC/13/QTHS/125), and the Medical Research Ethics Committee (MREC) of the University of Queensland (Approval No. 2016000552). Approval letters may be found in Appendix A. 8 Acknowledgements This project would not have been possible without the excellent guidance offered by my supervisors. Dr John Bingley and Prof Jonathan Golledge have been very supportive and approachable, and I look forward to working with them again in the future. I must also mention the late Prof Philip Walker, who was my original principal supervisor prior to his
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