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Aspects Genotypiques Et Phenotypiques Des Dyslipidemies

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Aspects Genotypiques Et Phenotypiques Des Dyslipidemies N° 244 - 2014 Année 2014 THESE UNIVERSITE LYON 1 – UNIVERSITE CLAUDE BERNARD Ecole Doctorale Interdisciplinaire Sciences-Santé Diplôme de Doctorat Spécialité Biochimie par Mathilde Charcosset Di Filippo Aspects génotypiques et phénotypiques des dyslipidémies primitives rares affectant le métabolisme des lipoprotéines riches en triglycérides Soutenue le 20 novembre 2014 Directeur de Thèse : Professeur Philippe MOULIN Co-encadrant : Docteur Agnès SASSOLAS JURY Monsieur le Professeur Philippe MOULIN Directeur de thèse Madame le Professeur Laurence DUVILLARD Rapporteur Monsieur le Professeur Jean Marc LACORTE Rapporteur Monsieur le Docteur Philippe LESNIK Examinateur Monsieur le Professeur René VALERO Examinateur Monsieur le Docteur Hubert VIDAL Examinateur UNIVERSITE CLAUDE BERNARD - LYON 1 Président de l’Université M. François-Noël GILLY Vice-président du Conseil d’Administration M. le Professeur Hamda BEN HADID Vice-président du Conseil des Etudes et de la Vie Universitaire M. le Professeur Philippe LALLE Vice-président du Conseil Scientifique M. le Professeur Germain GILLET Directeur Général des Services M. Alain HELLEU COMPOSANTES SANTE Faculté de Médecine Lyon Est – Claude Bernard Directeur : M. le Professeur J. ETIENNE Faculté de Médecine et de Maïeutique Lyon Sud – Charles Mérieux Directeur : Mme la Professeure C. BURILLON Faculté d’Odontologie Directeur : M. le Professeur D. BOURGEOIS Institut des Sciences Pharmaceutiques et Biologiques Directeur : Mme la Professeure C. VINCIGUERRA Institut des Sciences et Techniques de la Réadaptation Directeur : M. le Professeur Y. MATILLON Département de formation et Centre de Recherche en Biologie Directeur : Mme. la Professeure A-M. SCHOTT Humaine COMPOSANTES ET DEPARTEMENTS DE SCIENCES ET TECHNOLOGIE Faculté des Sciences et Technologies Directeur : M. F. DE MARCHI Département Biologie Directeur : M. le Professeur F. FLEURY Département Chimie Biochimie Directeur : Mme Caroline FELIX Département GEP Directeur : M. Hassan HAMMOURI Département Informatique Directeur : M. le Professeur S. AKKOUCHE Département Mathématiques Directeur : M. Georges TOMANOV Département Mécanique Directeur : M. le Professeur H. BEN HADID Département Physique Directeur : M. Jean-Claude PLENET UFR Sciences et Techniques des Activités Physiques et Sportives Directeur : M. Y.VANPOULLE Observatoire des Sciences de l’Univers de Lyon Directeur : M. B. GUIDERDONI Polytech Lyon Directeur : M. P. FOURNIER Ecole Supérieure de Chimie Physique Electronique Directeur : M. G. PIGNAULT Institut Universitaire de Technologie de Lyon 1 Directeur : M. C. VITON Ecole Supérieure du Professorat et de l’Education Directeur : M. A. MOUGNIOTTE Institut de Science Financière et d'Assurances Directeur : M. N. LEBOISNE 1 REMERCIEMENTS Les travaux présentés dans ce mémoire ont été réalisés dans l’unité INSERM 1060 CarMeN (Cardiovasculaire Metabolisme Diabétologie Nutrition) dirigée par le Dr Hubert Vidal au sein de l’Equipe INgénierie et FOnction des LIpides & lipoProtéines (INFOLIP) animée par le Pr Philippe Moulin et le Pr Michel Lagarde et dans l’U.F. Dyslipidémies- Cardiobiologie, Laboratoire de Biologie Médicale MultiSites du CHU de Lyon, Groupe Hospitalier Est, Centre de Biologie, dirigée jusqu’en 2013 par le Dr Agnès Sassolas. Je tiens donc vous remercier de m’avoir donné l’opportunité d’effectuer cette thèse. Je remercie tout particulièrement le Dr Agnès Sassolas, vous êtes à l’initiative de ce travail. Vous m’avez encadrée et accompagnée au cours de ces années passées à vos côtés qui ont été d’une richesse incroyable autant sur le plan des connaissances scientifiques qu’humaines. Vous avez su me guider durant les difficultés professionnelles et les épreuves de la vie. Je vous remercie de la confiance que vous m’avez accordée. Veuillez recevoir par ce travail ma profonde admiration, ma sincère gratitude et mon amitié. Je remercie bien évidemment le Pr Philippe Moulin d’avoir accepté de diriger ce travail de thèse. Vos conseils et votre disponibilité sans faille ont permis l’aboutissement de ce projet. Je ne ferai pas d’autre thèse mais serai heureuse de pouvoir continuer à travailler avec vous. Merci pour votre aide et votre soutien bienveillant. Veuillez recevoir le témoignage de ma reconnaissance et de mon profond respect. Je remercie le Pr Laurence Duvillard et le Pr Jean Marc Lacorte pour avoir pris le temps d’apporter votre regard d’expert en lipidologie et de m’avoir fait l’honneur d’être rapporteurs. Merci d’avoir si aimablement accepté de juger ce travail. Veuillez croire à ma plus grande estime. Je remercie le Dr Philippe Lesnik pour l’intérêt porté à ce travail et pour avoir accepté de participer à mon jury de thèse. Veuillez croire en mon plus profond respect. Je remercie le Pr René Valéro d’avoir accepté de juger ce travail. J’espère que nous pourrons continuer à collaborer via l’exploration de patients. Soyez assuré de ma reconnaissance. Je remercie le Dr Hubert Vidal d’avoir accepté de juger ce travail et pour votre accueil toujours chaleureux. J’espère pouvoir continuer mes travaux de recherche au sein de l’unité. Soyez assuré de mon profond respect. Je remercie toutes les personnes qui ont été indispensables à la réalisation de ce travail, fruit d’une collaboration multidisciplinaire (biologie, hépatogastroentérologie, endocrinologie, …), chercheurs et personnels hospitaliers : - le Pr Alain Lachaux et le Dr Noël Peretti : pour votre collaboration et votre investissement pour ce travail. Vous m’avez donné l’opportunité d’étudier les hypocholestérolémies familiales, maladies extrêmement rares, grâce à votre recrutement de patients. Je souhaite que notre collaboration se poursuive au-delà de ce travail. - les Drs Sybil Charrière, Christophe Marçais et Cyrielle Caussy pour votre implication sur l’étude des hypertriglycéridémies, ainsi que les médecins de l’unité d’Endocrinologie adulte (Drs Laure Groisne, Myriam Moret, …) - le Dr Marie Elisabeth Samson Bouma, pour ton investissement dans l’étude des patients présentant une hypocholestérolémie ainsi que tous les médecins qui ont contribué au recrutement des patients français, italiens, néérlandais, … 2 - le Dr Dominique Bozon pour vos connaissances dans le domaine de la biologie moléculaire (les mutations les plus exotiques ne vous resistent pas), pour vos précieux conseils et également pour votre intiation au Criollo… - les équipes qui s’occupent des plateaux de Biologie Moléculaire et de NGS : merci aux biologistes (Véronique, Gilles, …) et techniciens : votre investissement dans ces structures est indispensable. Je remercie bien évidemment toute l’équipe Dyslipidémies : Sabrina, Martine, Chantal, Véronique, Séverine, Marjorie, Muriel. Vous avez contribué à ce travail, directement ou indirectement. J’apprecie votre soutien quotidien, votre gentillesse et votre bienveillance à mon égard, je sais que je peux compter sur vous. Une dédicace particulière également à Oriane Marmontel, qui m’ « assiste » maintenant depuis un an : tu prends ton travail quotidien à cœur et tu t’es lancée également dans l’aventure de LA thèse de sciences… Courage ! Une pensée également pour l’équipe cardiobiologie, notre histoire ensemble commence juste… C’est dans la difficulté que l’union fait la force, Maitre GLIMS en est la preuve. Je remercie également le Pr Robert Rousson : votre phrase préférée « et ta thèse ? » m’a incitée à finaliser ce travail. Maintenant, je redoute la phrase suivante… Merci également à tous mes collègues biologistes du CR de Biochimie encore en activité ou déjà partis à la retraite. Une pensée pour toute l’équipe du PTPP avec laquelle j’ai passé quelques années entre pannes, rapports d’intervention, contrôles de qualités… et fou-rires. J’ai beaucoup appris avec vous et passé de bons moments. Enfin, un grand merci à Véronique R (ma voisine de bureau, ou de chocolaterie plutôt), Isa, Régine, Oriane (encore), Laurence … Nos pauses déjeuner (et chocolat), souvent studieuses mais toujours amicales sont indispensables, merci pour votre soutien et votre amitié. A Christian, Lucas et Angelina Je vous dois tous ces moments de Bonheur. Christian, merci pour ton soutien indeféctible. Lucas, Angelina, vous êtes mes rayons de soleil. Je sais maintenant ce que je serais sans vous, vous êtes mes trésors, vous êtes ma vie. Promis, la thèse c’est finit (finit la biblio dans la voiture, sur la plage, dans le jardin, les parcs, la nuit), maintenant vivent les vacances sans articles ! Recevez ici tout mon amour. A mes parents, ma sœur Gaëlle et mon frère Rémi, ma famille et ma belle-famille Vous m’avez toujours soutenue et encouragée dans mes choix. Je ne sais comment vous remercier pour votre aide. Recevez toute mon affection. A tous mes amis, et paticulièrement Sandrine et nos footings (il va falloir qu’on sy remette, ça me manque !), Jérôme Claire et leur tribu (mes pingouins de Valence préférés), Céline et Marielle et leurs petites familles, David N (dit Dr Di Nabetto)… Merci à tous pour votre amitié. A ceux qui ne sont plus là et qui ont tellement compté… 3 Aspects génotypiques et phénotypiques des dyslipidémies primitives rares affectant le métabolisme des lipoprotéines riches en triglycérides Les anomalies du métabolisme des lipoprotéines riches en triglycérides (LRTG), les chylomicrons et les VLDL exposent à des hypocholestérolémies lors d’un défaut de sécrétion et à des hypertriglycéridémies (HTG) majeures entraînant un risque athéromateux et de pancréatites aigües lors de l’altération de leur clairance. Nous avons diagnostiqué des patients présentant un défaut génétique
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