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2018 Chen Lingyan 1448129 This electronic thesis or dissertation has been downloaded from the King’s Research Portal at https://kclpure.kcl.ac.uk/portal/ Genetics and Epigenetics in Systemic Lupus Erythematosus Chen, Lingyan Awarding institution: King's College London The copyright of this thesis rests with the author and no quotation from it or information derived from it may be published without proper acknowledgement. END USER LICENCE AGREEMENT Unless another licence is stated on the immediately following page this work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International licence. https://creativecommons.org/licenses/by-nc-nd/4.0/ You are free to copy, distribute and transmit the work Under the following conditions: Attribution: You must attribute the work in the manner specified by the author (but not in any way that suggests that they endorse you or your use of the work). Non Commercial: You may not use this work for commercial purposes. No Derivative Works - You may not alter, transform, or build upon this work. Any of these conditions can be waived if you receive permission from the author. Your fair dealings and other rights are in no way affected by the above. Take down policy If you believe that this document breaches copyright please contact [email protected] providing details, and we will remove access to the work immediately and investigate your claim. Download date: 03. Oct. 2021 GENETICS AND EPIGENETICS IN SYSTEMIC LUPUS ERYTHEMATOSUS Lingyan CHEN Department of Medical & Molecular Genetics Faculty of Life Sciences & Medicine King’s College London This thesis is submitted for the degree of DoCtor of Philosophy (PhD) 1 To my parents 2 DeClaration The work described in this thesis was carried out within the Vyse Immunogenetics Group in the Department of Medical and Molecular Genetics at King’s College London under the supervision of Professor Timothy James Vyse and Dr David Lester Morris and between the years of October 2014 and March 2018. I hereby declare that except where specific reference is made to the work of others, the contents of this thesis are original and have not been submitted in whole or in part for consideration for any other degree or qualification in this, or any other University. This thesis is the result of my own work and includes nothing which is the outcome of work done in collaboration, except where specifically indicated in the text. Lingyan Chen March 2018 3 AbstraCt Systemic lupus erythematosus (SLE) is a chronic inflammatory autoimmune disease associated with a wide range of clinical features involving different organs and the prognosis is also highly variable. It is a complex genetic trait in which more than 80 susceptibility loci show robust genetic association with disease risk. Firstly, I preformed eQTL mapping, incorporating co-localization analysis of GWAS in the functional immune cells, in order to identify likely causal genes. The results indicate that eQTLs present in a diverse set of immune cells, encompassing both the innate and adaptive immune responses for more than half of the loci. I then integrated genetics, epigenetics and gene expression to delineate the regulatory map of SLE risk loci across human cells and tissues. Using GARFIELD and GoShifter, I demonstrated that SLE genetic associations displayed a marked enrichment pattern for areas of open chromatin in blood, including B cells, T cells, monocytes, and NK cells. Moreover, I found that a large proportion (66%) of the SLE eQTLs showed to overlap with areas of open chromatin, denoting extensive local coordination of genetic influences on gene expression and epigenetics. SLE patients with renal involvement have more severe clinical outcomes and an increased mortality risk. By calculating the genetic risk score (GRS) using a list of SNPs that are reported to be significantly associated with SLE, I found a significant correlation between GRS and patients with renal involvement – the higher the GRS, the higher probability of getting renal disease. The GRS also correlated inversely with age of SLE onset. As part of the functional study of post-GWAS, I investigated the protein expression of selected SLE-susceptibility gene products, namely Ikaros family members and OX40L, in a range of immune cells, using multi-parameter flow cytometry. The results reveal some cellular specificity in gene expression in disease. In particular, IKZF3 expression on activated regulatory T cell subsets was decreased, while OX40L expression on B cell subsets was increased in SLE. In summary, I combined eQTLs and epigenomes to identify the functional tissues and causal genes. In addition, I measured the expression of OX40L and Ikraos family to help understand the cell effects at protein level. Finally, I found that the genetic risk factors that influence the severity of SLE are through a quantitative way but not qualitative way, suggesting that the GRS approach may become a useful factor in predicting outcome in this clinically heterogeneous disease. 4 Acknowledgements I would firstly like to express my utmost gratitude to my supervisors Professor Tim Vyse and Dr. David Morris for giving me the opportunity to undertake this PhD and for their very helpful guidance, teaching and encouragement over the last four years. Their support has been invaluable, so thank you a million. It has been a great pleasure to work with them. I am also very grateful to China Scholarship Council (CSC) for funding this PhD Scholarship. I thank my collaborators in the Professor Julian Knight’s Group in Oxford University, Dr. Phe De Jager’s Group in Broad Institute, and Dr. Kerrin Small’s Group in King’s College London. I would like to acknowledge the Biomedical Research Centre Flow Cytometry Core and personally thank Dr. Susanne Heck and her team for their patience and kind suggestions throughout the flow cytometry project. I would like to thank my thesis committee: Dr Kerrin Small, Dr Alan Hodgkinson, and Dr Mike Weale, for their very helpful suggestions throughout my PhD. This thesis would not have been achievable without the help of my colleagues both past and present in the Immunogenetics group. Thank you so much. In particular, I would like to thank Chris for his encouragement and sincere help everytime I needed. To Pindy, I thank for his very patient teaching in the flow cytometry experiment. To Amy, Ulla, and Andrea, Su, Sarah, and Susan, I thank for all their kind considerations and support throughout my PhD – wishing you all the best for the future. I would like to thank my flatmates – Mengying and Linxi, for providing me a very warm and nice home in London. Thanks to my friends who play badminton with me to help me out of stress. Thanks to my sister and brothers for their support (especially financially) throughout my PhD. I am so blessed to have such loving and kind family in my life. Above all else I would like to thank my wonderful parents who have always believed in me and supported my decisions all the time. They are completely special to me. I dedicate this PhD thesis to them. 5 Publications Chen, L., Morris, D. L. & Vyse, T. J. Genetic advances in systemic lupus erythematosus: an update. Sep 2017 In : Current Opinion in Rheumatology. 29, 5, p. 423-433 Odhams, C. A., Cortini, A., Chen, L., Roberts, A. L., Viñuela, A., Buil, A., Small, K. S., Dermitzakis, E. T., Morris, D. L., Vyse, T. J. & Cunninghame Graham, D. S. Mapping eQTLs with RNA-Seq Reveals Novel Susceptibility Genes, Non-Coding RNAs, and Alternative-Splicing Events in Systemic Lupus Erythematosus. 5 Jan 2017 In : Human Molecular Genetics. 26, 5, p. 1003-1017 Morris, D. L, Sheng, Y., Zhang, Y. , Wang, Y. F. , Zhu, Z. , Tombleson, P. , Chen, L. , Cunninghame Graham, D. S. , Bentham, J. , Roberts, A. L. , Chen, R. , Zuo, X. , Wang, T. , Wen, L. , Yang, C. , Liu, L. , Yang, L. , Li, F. , Huang, Y. , Yin, X. & 12 others. Genome- wide association meta-analysis in Chinese and European individuals identifies ten new loci associated with systemic lupus erythematosus. 11 Jul 2016 In : Nature Genetics. Bentham, J., Morris, D. L., Cunninghame Graham, D. S., Pinder, C. L., Tombleson, P., Behrens, T. W., Martín, J., Fairfax, B. P., Knight, J. C., Chen, L., Replogle, J., Syvänen, A. C., Rönnblom, L., Graham, R. R., Wither, J. E., Rioux, J. D., Alarcón-Riquelme, M. E. & Vyse, T. J. Genetic association analyses implicate aberrant regulation of innate and adaptive immunity genes in the pathogenesis of systemic lupus erythematosus. 1 Dec 2015 In : Nature Genetics. 47, 12, p. 1457-1464 6 Table of Contents DECLARATION ................................................................................................................................................... 3 ABSTRACT ........................................................................................................................................................ 4 ACKNOWLEDGEMENTS ....................................................................................................................................... 5 PUBLICATIONS .................................................................................................................................................. 6 TABLE OF CONTENTS .......................................................................................................................................... 7 TABLE OF FIGURES ........................................................................................................................................... 11 TABLE OF TABLES ...........................................................................................................................................
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