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The Genetic Architecture of Secretory PLA2 (Spla2) Genes and Their Impact on Spla2 Activity/Mass and Association with CHD Risk

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The Genetic Architecture of Secretory PLA2 (Spla2) Genes and Their Impact on Spla2 Activity/Mass and Association with CHD Risk The Genetic Architecture of Secretory PLA2 (sPLA2) Genes and their Impact on sPLA2 Activity/Mass and Association with CHD Risk Holly Jane Exeter University College London A thesis submitted in accordance with the regulations of the University College London for the degree of Doctor of Philosophy Centre for Cardiovascular Genetics UCL Institute of Cardiovascular Science 1 For Mum and Dad 2 Declaration I, Holly Jane Exeter confirm that the work presented in this thesis is my own. Where information has been derived from other sources, I confirm that this has been indicated in the thesis. In relation to specific chapters I would like to clarify my role: In Chapter 3 I was responsible for identifying SNPs of interest from the results of previously genotyped studies. I was then responsible for the in depth literature and bioinformatics study undertaken for PLA2G2A, sPLA2-IIA and the SNPs of interest. I designed the primers for all cloning and EMSA work and carried out all of the cloning experiments, luciferase assays, TaqMan Gene Expression assays and EMSAs according to the methods described. I also carried out the statistical work relating to the luciferase assay experiments. In Chapter 4 I was responsible for genotyping 2 of the studies in the final meta-analysis; IMPROVE and CYPRUS. I used the PRISMA guidelines to compile an in depth literature search of the sPLA2 inhibitor, varespladib. I was part of the core group of investigators who met to discuss the results and direction of the study (participants of the MR study are at the end of the thesis). In Chapter 5 I was responsible for identifying SNPs of interest from the results of previously genotyped studies. I was then responsible for the in depth literature and bioinformatics study undertaken for PLA2G5, sPLA2-V and the SNPs of interest. I genotyped SNPs as indicated in Table 5.1. In Chapter 6 I was responsible for identifying the SNP of interest from the results of previously genotyped and published studies. I was then responsible for the in depth literature and bioinformatics study undertaken for PLA2G10, sPLA2-X and the SNP of interest. With Jutta Palmen I designed the RFLP protocol for genotyping rs4003228 and rs4003232. With Dr Montse Guardiola I was responsible for genotyping rs4003232 and rs4003228 in all studies. Regarding the Advanced Study of Aortic Pathology (ASAP) (the Karolinska Institute, Sweden). All analysis was carried out by Dr. Lasse Folkersen, based on ideas conceived by myself, Prof. Philippa Talmud, Dr. Michael Holmes and Dr. Lasse Folkersen. Holly J. Exeter 3 Acknowledgements There are many people who deserve my thanks and acknowledgement for their roles in this thesis. First I would like to express my sincere and heartfelt thanks to my supervisor, Philippa Talmud. Your honesty and openness throughout this process have been vital and your faith in me and excellent guidance has driven me to bring out the best in myself. Thank you. I would also like to convey my gratitude to Professor Steve Humphries, whose generously given time and expertise have been invaluable, and to Professor Aroon Hingorani for his encouragement and advice throughout. The research carried out in this thesis was funded by the British Heart Foundation and I am extremely grateful to them for the financial support that they have provided as well as their keen interest in the progress of this work. CVG is not an everyday lab. It has been a pleasure to be part of such a diverse and exciting group, but more than that I have had enormous fun and made some fantastic friends. The camaraderie between all staff is fantastic and the depth of expertise on every kind of subject has meant that I have never been short of conversation or someone willing to help! Special thanks have to go to those that have shared the PhD office with me; Melissa, Donald, Klelia, Angus and Marta, you made it a pleasure to come to work and have provided tea and sympathy and shared laughs and excitement in equal measure! To those in the RA office, Jacquie, Jay, Wendy, Ros, Phil, Dauda and KaWah, you have all been instrumental in helping me to problem solve and learn new skills as well as providing a warm and friendly environment to come and work with. Thanks to all of you. Of all the group at CVG I need to single out Jutta Palmen who has been a great friend and an outstanding mentor in the lab. Her patience has allowed me to steadily build my confidence in my abilities and vastly improve my lab skills. I have experienced many ups and downs during the course of my thesis, but I have consistently been able to trust Jutta and Philippa especially to support and guide me to find the right solutions. Thanks are extended also to those who I have collaborated with closely throughout my studies; Dr Michael Holmes, Dr Lasse Folkersen, Dr Jackie Cooper and Dr Montse Guardiola. Jackie and Michael for their statistical expertise, Lasse for access to and analysis of his groups’ study, the Advanced Study of Aortic Pathology (ASAP) and Montse for her collaboration on the PLA2G10 genotyping data. These individuals and their contributions are indicated throughout the thesis. 4 Outside of science I have the most amazing group of friends. The support and tolerance they have provided me with over many years, but especially during my PhD studies, has been fantastic; Hannah, Emily, EJ, Averil, Carla, Jasmine, Danielle and Mellissa, you’re all brilliant! My special thanks and gratitude go to my oldest friend Lauren, who has lifted and motivated me on more occasions than I can say. Thank you to all of you for listening (and for being amazing dance partners!). Thanks to my dear family, all of you, my aunts, uncles, cousins, Grandma, Nan, Granddad and Granddad, you have all had an indefinable influence on my life and I greatly appreciate all that you have done for me. Alice and Charlie, my superb siblings(!) You put up with me day in and day out and have lived through all of my many stressful moments! Your tolerance is hugely appreciated and your capacity to make me laugh (intentionally or not!) and cheer me up has been greatly needed! We are an awesome trio! Finally, I would not be anything without the limitless love and support of my wonderful parents. Mum and Dad, your help and encouragement have shaped me and led me to believe that I could be whatever I wanted to be. There is no way for me to fully express my gratitude for your love and commitment- both emotional and financial over all these years, but I hope I’ve made you proud. Thank you both for being you! 5 Abstract Secretory phospholipase A2 group (sPLA2) enzymes hydrolyze the sn-2 ester bond of phospholipids, producing lysophospholipids and free fatty acids. SPLA2s have been identified as biomarkers of atherosclerosis in observational and animal studies. The aim of this study was to identify functional variants in PLA2G2A and, to a lesser extent, PLA2G5 and PLA2G10 (sPLA2 encoding genes). These variants could then serve as tools to examine their contribution to sPLA2-activity, since this is a composite measure of sPLA2- IIA,-V and –X, and associations with CHD risk/CHD traits. Two PLA2G2A SNPs were identified as being associated with sPLA2-IIA mass/sPLA2 activity. Luciferase assays, EMSA and RNA expression were used to examine their allelic differences. Rs3767221G showed 55% lower luciferase activity compared to rs3767221T -35 (p = 1.22×10 ), and stronger EMSA∼ binding of a nuclear protein compared to the T-allele. For rs11573156 C >G there were no luciferase or EMSA allelic differences. For rs11573156 there was no differential allelic lymphocyte cDNA expression for exons 5-6, but G-allele carriers (n = 7) showed a trend to lower exon 1-2 expression versus CC individuals. In the ASAP study (n = 223), a SNP acting as a proxy for rs11573156 (r2 = 0.91) on the expression array showed allelic difference of 25% in liver expression of total PLA2G2A (1.67×10-17). -5 However, exon 2 specific expression∼ was greatly reduced (4.5×10 ) compared to exons 3-6 (10-10 to 10-20), implying allele-specific exon 2 skipping as the functional basis of rs11573156 association. Rs11573156 was used as a genetic tool in a large Mendelian randomisation (MR) collaboration to establish the causality of sPLA2-IIA for CHD. While the sPLA2-IIA mass was strongly associated with CHD events, rs11573156 was not associated with outcome. Similar approaches were taken for studying PLA2G5 and PLA2G10, using eQTL data and smaller meta-analyses. Both PLA2G2A SNPs are functional. Using rs11573156 as a genetic instrument, MR suggested that sPLA2-IIA is not causally associated with CHD. Based on initial meta- analyses, neither PLA2G5 nor PLA2G10 appeared to be associated significantly with sPLA2 activity in cardiovascular related tissues. This conclusion is consistent with the outcome of the recent Phase III trial for the sPLA2 inhibitor varespladib, which was terminated due to lack of efficacy since the drug was shown to be having no significant effect on the reduction of secondary cardiovascular events. 6 Contributors to the Mendelian Randomisation Study of sPLA2-IIA and CHD Michael V Holmes, MRCP, MSc Fabrizio Veglia, PhD Tabassome Simon, MD, PhD Lesca M. Holdt, MD, PhD Lasse Folkersen, PhD, Frank Beutner, MD, PhD Folkert W Asselbergs, MD, PhD Ron T Gansevoort, MD, PhD Montse Guardiola, PhD Gerjan J Navis, MD, PhD Jackie A Cooper, MSc Irene Mateo Leach, PhD Jutta Palmen, Lutz P. Breitling, MD Jaroslav A Hubacek, DSc, PhD Hermann Brenner, MD, MPH Kathryn F Carruthers, MPhil Dhayana Dallmeier, MD Benjamin D Horne, PhD, MPH Anders Franco-Cereceda, MD, PhD Kimberly D.
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