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Chapter 1 Introduction THE ROLE OF GENES AND ENVIRONMENT ON FETAL GROWTH Thesis presented for the degree of Doctor of Philosophy in the Faculty of Population Health Sciences, University College London Dr Sara Louise Hillman 1 SIGNED DECLARATION I, Sara Louise Hillman 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. 2 ACKNOWLEDGEMENTS I want to thank my supervisor, Dr David Williams, for the opportunity given to me to pursue this PhD. I am enormously grateful for his unwavering support and guidance. Under his tutelage I have developed so much as a clinical academic and I hope this work is just the beginning of an extremely productive partnership. I am also grateful to my secondary supervisor, Professor Donald Peebles; his sense and reasoning have kept the work focussed and his support has been much appreciated. I was fortunate enough to be awarded funding for the project from Wellbeing of Women through a Research Training Fellowship. I am also grateful to the UCL Biomedical Centre who provided seed money to get the project underway and the BMA Joan Dawking award, who continue to fund this work. There are several people I need to mention that made the project possible. I am indebted to their expertise and kindness. At, UCL, special mention must be made of Dr Mike Okorie who taught me flow mediated dilation and Dr Chiara Bacchelli and Dr Louise Ocaka who made exome sequencing a possibility. I also want to thank the team at the Blizard, especially Dr Melissa Smart and Chris Matthews, who got me up to speed on DNA methylation and helped tremendously with the practicalities of running and analysing my samples. I must thank the patients and families that agreed to take part in the study. I also want to thank the staff at UCH; the midwives in MFAU and FMU who helped me recruit; the staff on Labour Ward who helped me collect samples and the doctors who assisted me; Dr Melissa Whitten, Dr Tamara Kubba and Dr Anna Jeffery Smith. Finally I want to thank my family; my husband Guy who is my rock and a pillar of support; our girls, Molly and Isla, who have broadened our world more than we thought possible and ‘the mums’ who have made having twins and completing a PhD a possibility. I could not have done it without you all. X 3 ABSTRACT Fetal growth is influenced by the in utero environment and genetic factors inherited from both parents. Poor fetal growth leading to low birth weight is associated with insulin resistance and type-2 diabetes in later life. The fetal programming of adult disease hypothesis suggests that growth-restricted fetuses make enduring physiological adaptations that predispose to diabetes in later life. The fetal insulin hypothesis suggests that poor fetal growth and diabetes are two phenotypes of genetically determined insulin resistance. Under these circumstances, an insulin resistant fetus cannot optimise insulin-mediated growth and is predisposed to diabetes in later life. Environmental and genetic influences come together through epigenetic modifications, for example DNA methylation, that alter gene expression without altering the nucleotide sequence. The first aim of this thesis was to investigate whether men who fathered pregnancies complicated by fetal growth restriction had an insulin resistant phenotype at the time of the index pregnancy. A case-control study showed that men who fathered growth- restricted offspring have pre-clinical insulin resistance and are more likely to smoke than fathers of normal grown offspring. This observation supports the concept that an insulin resistant genotype inherited from a father could manifest as poor fetal growth in offspring. I then investigated the mechanisms through which paternal insulin resistance might be inherited by a growth-restricted fetus. I studied DNA extracted from the cord blood of growth-restricted offspring using whole exome sequencing to identify novel gene variants and those known to be associated with type-2 diabetes. I validated findings with Sanger sequencing and Taqman genotyping in all family members. Using the Illumina Human 450 BeadChip, I found marked differences in genome wide DNA methylation of fetal cord blood and placental samples from growth restricted compared with normal grown offspring. Future work is aimed at investigating the functional consequences of genetic and epigenetic differences to identify targets for treatment and prophylaxis against fetal growth restriction and diabetes. 4 TABLE OF CONTENTS SIGNED DECLARATION………………………………………..……………………..2 ACKNOWLEDMENTS……………………………………….…………………….......3 ABSTRACT……………………………………………………..……………….…….4 TABLE OF CONTENTS………………………...…………………………………….…5 LIST OF FIGURES…………………………………………………………………......9 LIST OF TABLES…………………………...…………………………….………......11 ABBREVIATIONS…………………..…………………………….…...………….…..13 CHAPTER 1: INTRODUCTION……………………………………….15 1.1 Fetal Growth .................................................................................................... ………….16 1.2 Consequences of poor fetal growth ................................................................................. 16 1.3 Fetal Growth Restriction ................................................................................................. 17 1.4 Evidence of a genetic influence on fetal growth ............................................................ 19 1.5 Monogenic diabetes, birth weight and T2DM risk ....................................................... 20 1.6 Role of fetal insulin in growth ......................................................................................... 21 1.7 The fetal insulin hypothesis ............................................................................................. 22 1.8 Genetic influence of T2DM risk alleles .......................................................................... 26 1.9 Birth weight Genome Wide Association Studies (GWAS) ........................................... 31 1.10 Candidate approach linking T2DM risk alleles and birth weight ............................. 32 1.11 The paternal influence on fetal growth ...................................................................... 33 1.12 Environmental influence on fetal growth .................................................................... 34 1.13 Environmental influence on gene expression through epigenetic change ................ 37 1.14 Epigenetics and Diet – an example of environment influencing genes ...................... 38 1.15 Placental methylation..................................................................................................... 39 1.16 DNA methylation in relation to placental diseases ..................................................... 41 4 1.17 DNA methylation in umbilical cord blood ................................................................... 41 1.18 Animal models that support a role for DNA methylation in FGR ............................ 42 1.19 Trans-generational epigenetic inheritance .................................................................. 43 1.20 Genetic-epigenetic interactions in T2DM .................................................................... 45 1.21 Rationale for study ......................................................................................................... 46 1.22 Hypothesis ....................................................................................................................... 47 1.23 Thesis Aims ..................................................................................................................... 48 CHAPTER 2: RESEARCH METHODS AND MATERIALS……….………..49 2.1 Phenotype study ............................................................................................................... 50 2.2 Feasibility of recruitment ................................................................................................ 52 2.3 Recruitment criteria......................................................................................................... 53 2.4 Diagnosis of fetal growth restriction .............................................................................. 53 2.5 Exclusion criteria ............................................................................................................. 54 2.6 Study protocol .................................................................................................................. 54 2.7 Homeostasis model assessment (HOMA) measurement ............................................... 58 2.8 Endothelial function measurement ................................................................................. 59 2.9 Pulse wave velocity ........................................................................................................... 61 2.10 Sample collection, handling and storage ...................................................................... 62 2.11 Fetal samples .................................................................................................................. 63 2.12 DNA extraction ............................................................................................................... 64 2.13 Whole exome sequencing ............................................................................................... 66 2.14 Validation of exome data ............................................................................................... 72 2.15 DNA methylation ...........................................................................................................
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