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Epistatic Interactions and Epigenetic Modifications for Molecular Stratification of Chronic Diseases Ting Xie

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Epistatic Interactions and Epigenetic Modifications for Molecular Stratification of Chronic Diseases Ting Xie Epistatic interactions and epigenetic modifications for molecular stratification of chronic diseases Ting Xie To cite this version: Ting Xie. Epistatic interactions and epigenetic modifications for molecular stratification of chronic dis- eases. Human health and pathology. Université de Lorraine, 2017. English. NNT : 2017LORR0339. tel-01835056 HAL Id: tel-01835056 https://tel.archives-ouvertes.fr/tel-01835056 Submitted on 11 Jul 2018 HAL is a multi-disciplinary open access L’archive ouverte pluridisciplinaire HAL, est archive for the deposit and dissemination of sci- destinée au dépôt et à la diffusion de documents entific research documents, whether they are pub- scientifiques de niveau recherche, publiés ou non, lished or not. The documents may come from émanant des établissements d’enseignement et de teaching and research institutions in France or recherche français ou étrangers, des laboratoires abroad, or from public or private research centers. publics ou privés. AVERTISSEMENT Ce document est le fruit d'un long travail approuvé par le jury de soutenance et mis à disposition de l'ensemble de la communauté universitaire élargie. Il est soumis à la propriété intellectuelle de l'auteur. Ceci implique une obligation de citation et de référencement lors de l’utilisation de ce document. D'autre part, toute contrefaçon, plagiat, reproduction illicite encourt une poursuite pénale. Contact : [email protected] LIENS Code de la Propriété Intellectuelle. articles L 122. 4 Code de la Propriété Intellectuelle. articles L 335.2- L 335.10 http://www.cfcopies.com/V2/leg/leg_droi.php http://www.culture.gouv.fr/culture/infos-pratiques/droits/protection.htm Ecole Doctorale BioSE (Biologie- Santé- Environnement) Thèse Présentée et soutenue publiquement pour l’obtention du titre de DOCTEUR DE l’UNIVERSITE DE LORRAINE Mention: « Sciences de la Vie et de la Santé » Par: Ting XIE Interactions épistatiques et modifications épigénétiques pour la stratification moléculaire des maladies chroniques Epistatic interactions and epigenetic modifications for molecular stratification of chronic diseases. Le 19 Décembre 2017 Membres du jury: Rapporteurs : Prof Nikolaos DRAKOULIS National & Kapodistrian University of Athens, Faculty of Pharmacy, Athens Prof. Dr. Belgin SUSLEYICI Marmara University, Faculty of Science and Letters, Department of Molecular Biology, Istanbul Examinateurs : Prof Jochen SCHNEIDER Luxembourg Centre for Systems Biomedicine - Université du Luxembourg, Luxembourg Prof Jean-Louis MERLIN Faculté de Pharmacie, Université de Lorraine, Nancy Dr Maria STATHOPOULOU IR2, INSERM U1122; IGE-PCV, Université de Lorraine, Nancy (co-directrice de thèse) Dr Sofia SIEST DR1, INSERM U1122; IGE-PCV, Université de Lorraine, Nancy (directrice de thèse) Université de Lorraine - UMR INSERM U1122; IGE-PCV - Faculté de Pharmacie - 30, rue Lionnois - 54000 Nancy – France 1 Acknowledgement Many persons contributed to this thesis in different ways, and I am grateful to all of them. My biggest thank is for my major supervisor, Dr Sophie VISVIKIS-SIEST, Director of the UMR INSERM U1122; IGE-PCV, who gave me the opportunity to work with her and her team, and gave me a very exciting project. Without her help and support, this project would not have been possible. I would like also to thank my co-supervisor, Dr Maria STATHOPOULOU for being helpful for correction of my thesis manuscript, and patiently explained the scientific problems with her rigorous scientific spirit during my research. I would like to express my sincere thanks to members of my thesis committee, Prof Nikolaos DRAKOULIS, Prof Belgin SÜSLEYİCİ DUMAN, Prof Jochen SCHNEIDER and Dr Jean-Louis MERLIN for having accepted to evaluate my Ph.D. I would like to thank all of my colleagues in U1122; IGE-PCV team, present and past: Brigitte, Patricia, Christine, Sébastien, Alex-Ander, Alexandros, Jerome, Vesna, Samina, Dwaine and Lauren. I would like to thank the ‘Region Lorraine’ for having awarded me a three-year scholarship, which enabled me to carry out this project. I would like also to thank Randox Laboratories Ltd, the "Agence Nationale de la Recherche, programme d'Investissements d'avenir"(grant number ANR-15RHU-0004) and the Operational Programme “FEDER-FSE Lorraine et Massif des Vosges 2014-2020” for their help in the realisation of the projects And finally, I would like to extend my deepest gratitude to my family: my parents Aiguo XIE and Lianyu SUN, and so on. They always have provided unwavering love and encouragement. Thank you for believing in me. 2 Table of contents Acknowledgement ......................................................................................................... 2 Abbreviations ................................................................................................................. 6 List of tables ................................................................................................................... 9 List of figures ................................................................................................................ 11 List of publications ....................................................................................................... 12 List of original publications ...................................................................................... 13 List of review publications ....................................................................................... 14 Other publications ................................................................................................... 14 Présentation synthétique de la thèse .......................................................................... 16 Situation du sujet ..................................................................................................... 17 Résultats obtenus - discussion ................................................................................. 20 Conclusions et perspectives ..................................................................................... 28 Foreword ...................................................................................................................... 30 Introduction ................................................................................................................. 33 Chronic diseases ....................................................................................................... 34 Cardiovascular diseases ........................................................................................... 35 The major CVD risk factors ....................................................................................... 35 Age and gender .................................................................................................... 36 Family inheritance ................................................................................................ 36 Tobacco ................................................................................................................ 37 Hypertension ........................................................................................................ 39 Obesity ................................................................................................................. 39 Dyslipidemia and blood lipids .............................................................................. 40 Major depressive disorder (MDD) ........................................................................... 43 The risk factors for MDD .......................................................................................... 44 Osteoporosis ............................................................................................................ 45 Alzheimer’s disease AD .......................................................................................... 46 Common biomarkers ................................................................................................ 47 3 Comorbidities ........................................................................................................... 48 Epistasis .................................................................................................................... 50 Epigenetics ............................................................................................................... 51 The targeted candidate biomarkers ......................................................................... 53 Vascular endothelial growth factor (VEGF) .......................................................... 54 Apolipoprotein E (ApoE) ...................................................................................... 58 Lipolysis-stimulated lipoprotein receptor (LSR) ................................................... 58 Personalised medicine ............................................................................................. 59 Pharmacogenomics .................................................................................................. 60 Materials and Methods ................................................................................................ 66 Populations .............................................................................................................. 67 STANISLAS Family Study ....................................................................................... 67 Cilento study ........................................................................................................ 67 LifeLines Cohort Study and Biobank (LLs) ...........................................................
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