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Genetic Regulation of the Host Response to Cardiac Surgery and Cardiopulmonary Bypass

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Genetic Regulation of the Host Response to Cardiac Surgery and Cardiopulmonary Bypass Genetic regulation of the host response to cardiac surgery and cardiopulmonary bypass E.M.SVOREN MBBS, FRCA, EDIC. 1 | P a g e Statement of originality I, Eduardo M Svoren, confirm that the research included within this thesis is my own work or that where it has been carried out in collaboration with, or supported by others, that this is duly acknowledged below and my contribution indicated. Previously published material is also acknowledged below. I attest that I have exercised reasonable care to ensure that the work is original, and does not to the best of my knowledge break any UK law, infringe any third party’s copyright or other Intellectual Property Right, or contain any confidential material. I accept that the College has the right to use plagiarism detection software to check the electronic version of the thesis. I confirm that this thesis has not been previously submitted for the award of a degree by this or any other university. The copyright of this thesis rests with the author and no quotation from it or information derived from it may be published without the prior written consent of the author. Signature: Date: Contributors I am very grateful to the research nurses, Ms Alice Purdy and Eli McAlees, for their collaboration in patient recruitment and blood sampling. Both genome-wide expression array and genotyping arrays (Illumina R™) were processed at the Wellcome Trust Sanger Institute, Cambridge. Peter Hamburg and Emma Davenport collaborated in the eQTL analysis. 2 | P a g e Acknowledgments To Professor Charles Hinds whose support and encouragement made possible what I had considered for many years a dream. From the first discussion that I had with him over undertaking research for the accomplishment of this thesis, several years passed by and my personal circumstances changed, including obtaining a completion certificate in Anaesthesia and becoming consultant in neuro-anaesthesia and neuro-critical care. This did not happen without hurdles and the occasional disappointment. However, Professor Hinds always had words of encouragement and some good old-fashioned advice, both invaluable in achieving the completion of this chapter of my life. I would like to thank Dr Julian Knight who patiently tolerated my lack of laboratory experience and whose intellectual input through stimulating informal discussions, corrections and advice provided me with the tools and the right frame of mind to accomplish this investigation. Peter Hamburg and Emma Davencroft collaborated in the eQTL analysis. I couldn’t have progressed with the analysis without their help. To Sandra Sims for her help in “how to do things” and many late afternoon conversations over a cup of coffee.To Leona for her positive outlook. Finally, to Juanita and Aliyah for keeping my sanity and pushing me forward. Awards and funding Intensive Care Society (Young Investigator Award) (£10,000) HCA International. Bench fees (£19,500) Collaborative Work University College of London (UCL). Genotyping cost (£20,000) 3 | P a g e To the memory of Professor Nelly Coarasa. 4 | P a g e Abstract There is significant variation between individual patients in the magnitude and pattern of their systemic response to cardiac surgery. Poor outcomes in these patients have been associated with a dysfunctional host response. This thesis seeks to define such variability at the level of gene expression by sequential analysis of transcription before and after surgery for a low risk group of patients undergoing elective cardiac surgery and cardiopulmonary bypass (CPB) patients using expression microarray profiling. To that aim, we analysed sequential global gene expression patterns in circulating peripheral blood leukocytes. We also investigated the role of DNA sequence variation in modulating the observed changes in gene expression. This approach allowed us to identify important genetic modulators and novel biological pathways and gain new insights into the mechanisms that regulate the host response to surgery. 5 | P a g e Background: Despite advances in surgical, anaesthetic and cardio-protective techniques, cardiac surgery continues to be associated with a considerable risk of postoperative complications and significant mortality (2% to 8%)4-6. Moreover, patients undergoing elective cardiac surgery are increasingly elderly, with more severe cardiac disease and multiple co-morbidities8. Much of this morbidity and mortality is related to a dysfunctional host inflammation that can predispose to nosocomial infection and multiorgan failure in as many as 10% of cases, of which up to 40% can be fatal 9. Specific complications which are often attributable, at least in part to a dysfunctional inflammatory response, include acute lung injury and acute respiratory distress syndrome (ARDS) in 1 to 2% of patients, renal impairment (8%), cognitive impairment (up to 65%), cerebrovascular accident (1.5 to 5.2%) and myocardial injury (7 to 15%)10-13. The host response to cardiac surgery is triggered by a number of distinct events, including the initiation of cardiopulmonary bypass (CPB) during which blood is exposed to foreign material, ischaemia/reperfusion of vital organs such as the heart and lungs, the re-warming period and surgical tissue injury2. This response involves the triggering of innate immune pathways, a systemic inflammatory response and immune compromise that can predispose to infectious complications and organ failures14. The ability to successfully regulate the propagation and resolution of this inflammatory response is now considered to be one of the principal determinants of individual patient outcome following cardiac surgery15, 16 and involves an orchestrated pattern of changes in gene expression that is designed to protect the host and promote recovery17. Current understanding predicts that individual differences in this response are mediated by DNA sequence variation and modulation of gene expression by epigenetic changes. The evolution of the host response is orchestrated by multiple genes, the activity of which must be sequentially regulated in a coordinated manner to produce a reaction commensurate with the trigger. Differences in gene expression between individuals have been shown to be heritable and to be regulated to a significant degree by underlying genetic diversity at the DNA sequence level. Expression quantitative trait studies involving genome-wide expression profiling have demonstrated that genes involved in immunity and inflammation show particularly strong evidence of modulation by genetic diversity18. Recent advances in our understanding of gene function have highlighted the importance of a diverse array of regulatory mechanisms, including cis and trans effects19. 6 | P a g e Aims and objective of this research: My hypothesis is that individual differences in the host response to cardiac surgery, as reflected by temporal changes in gene expression, are modulated by DNA sequence variation. I will be using the insult of cardiac surgery as a “probe” to unmask large effect sizes of genes that would not be detectable by other means. The aims of this proposal, therefore, are: 1. To define sequential, genome-wide patterns of differential gene expression and their individual variability post cardiac surgery. 2. To identify important, novel biological pathways involved in the host response to cardiac surgery. 3. To define the role of DNA sequence variation in modulating gene expression following cardiac surgery. 7 | P a g e Chapter -1. Cardiac surgery...............................................................................16 1-1 Introduction 1-2 Elective cardiac surgery as a model of the host response to injury 1-3 The host response to cardiac surgery 1-4 Renal dysfunction 1-5 Neurological dysfunction 1-6 Post-operative bleeding 1-7 Atrial fibrillation(AF) 1-8 Lung dysfunction Chapter- 2. Genomics in sepsis and cardiac surgery.......................................25 2-1 Introduction 2-2 Basic principles 2-3 DNA sequence variation and complications after cardiac surgery.......33 2-3-1 Renal dysfunction 2-3-2 Neurological dysfunction 2-3-3 Lung dysfunction 2-3-4 Post-operative bleeding 2-3-5 Atrial fibrillation (AF) 2-3-6 Adverse myocardial outcomes and grafts patency after cardiac surgery 2-4 DNA sequence variation and sepsis.......................................................44 2-4-1 Malaria 2-4-2 Leprosy 2-4-3 HIV 8 | P a g e 2-5 DNA sequence variation and sepsis in the critically ill patient...........48 2-5-1 Cytokines 2-5-2 Tumour necrosis factor 2-5-3 Interleukin-1 2-5-4 Interleukin-6 2-5-5 Interferon - (INF-) 2-5-6 Toll-like receptors (TLRs) 2-5-7 Mannose-binding lectin 2-5-8 Cell wall recognition molecules: BPI, LPB and CD14 2-5-9 Immunoglobulin receptors 2-5-10 Heat shock proteins 2-5-11 Plasminogen activator inhibitor-1 2-5-12 Protein C 2-5-13 Angiotensin-converting enzyme (ACE) 2-6 Gene expression..........................................................................................66 2-6-1 Introduction 2-6-2 Gene expression in sepsis 2-6-3 Gene expression studies in cardiovascular surgery 2-6-4 Sequential gene expression profiles following elective cardiac surgery involving cardiopulmonary bypass (CPB) 2-6-5 Methods: Experimental details and design of the investigation 2-6-6 Results 2-6-7 Discussion 2-6-8 Limitations 2-6-9 Conclusions 9 | P a g e Chapter-3 Expression quantitative trait eQTL..................................................106 3-1 Introduction 3-2 Methods 3-2-1 Genotyping 3-2-2 Data analysis 3-3 Results3-4 Pathways present only
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