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Une Approche De Modélisation De Biologie Des Systèmes Sur La Spondylarthrite Emmanuel Chaplais

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Une Approche De Modélisation De Biologie Des Systèmes Sur La Spondylarthrite Emmanuel Chaplais Une approche de modélisation de biologie des systèmes sur la spondylarthrite Emmanuel Chaplais To cite this version: Emmanuel Chaplais. Une approche de modélisation de biologie des systèmes sur la spondylarthrite. Génétique des populations [q-bio.PE]. Université de Versailles-Saint Quentin en Yvelines, 2015. Français. NNT : 2015VERS035V. tel-01306276 HAL Id: tel-01306276 https://tel.archives-ouvertes.fr/tel-01306276 Submitted on 22 Apr 2016 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. UNIVERSITÉ DE VERSAILLES SAINT-QUENTIN-EN-YVELINES UFR DES SCIENCES DE LA SANTÉ – SIMONE VEIL ECOLE DOCTORALE GAO THÈSE pour obtenir le grade de DOCTEUR DE L'UNIVERSITÉ DE VERSAILLES SAINT-QUENTIN-EN-YVELINES Sciences de la vie et de la santé Spécialité : Génétique Humaine Présentée et soutenue publiquement par Emmanuel Chaplais Le 28 Septembre 2015 UNE APPROCHE DE MODÉLISATION DE BIOLOGIE DES SYSTÈMES SUR LA SPONDYLARTHRITE JURY Mme le Dr. Valentina BOEVA Rapporteur Mr le Pr. Philippe Broet Rapporteur Mr le Pr. Christophe AMBROISE Examinateur Mr le Pr. Henri-Jean GARCHON Directeur de thèse 1 Résumé La Spondyloarthrite (SpA) est un rhumatisme inflammatoire chronique fréquent, avec une prévalence de 0,43 % en France. Elle consiste en une atteinte prédominante du squelette axial, mais aussi des articulations périphériques, et peut conduire à une immobilité du rachis et des articulations sacro-iliaques. Des atteintes extra-articulaires sont fréquentes, telles qu'une uvéite, un psoriasis ou une maladie inflammatoire chronique de l'intestin. Les traitements actuels ne sont que symptomatiques, ciblant principalement les manifestations inflammatoires. L'étiologie de la SpA est multifactorielle avec une composante génétique dominée par l'association forte et bien connue avec l'allèle HLA-B27. Cependant, ce facteur génétique n'est clairement pas suffisant pour induire le développement de la maladie. L'objectif de ce projet de thèse était donc d'identifier d'autres facteurs génétiques à l'origine du développement de la SpA. Mon travail a porté sur l'analyse de deux jeux de données complémentaires, dans une perspective de biologie des systèmes. Dans une première partie, j'ai conduit une analyse de liaison dans 210 familles atteintes de la maladie représentant 1310 personnes génotypées avec des puces Affymetrix 250k. Une nouvelle région significativement liée à la SpA a été détectée en 13q13, avec un intervalle de 1,3 Mb défini par des haplotypes recombinants chez les patients. Cette région est en cours de séquençage pour identifier les variants causaux. Ensuite, une analyse transcriptomique des cellules dendritiques dérivées des monocytes de 23 patients HLA-B27+, 23 témoins sains HLA-B27+ et 21 témoins sains HLA-B27-, et stimulées ou non par du LPS, a tenté de distinguer les gènes dont l'expression est modifiée par la maladie de ceux influencés par l'allèle HLA-B27 seul. L'annotation fonctionnelle et une analyse par réseau de gènes ont mis en évidence l'inhibition chez les patients des étapes précoces de la biosynthèse du cholestérol. La validation expérimentale par qPCR et par analyse de profils lipidiques est en cours dans le laboratoire. Pour conduire ces analyses de réseaux, j'ai développé un package R, stringgaussnet, permettant de combiner simplement des réseaux de gènes sémantiques et gaussiens et de les visualiser dans Cytoscape. 2 Abstract Spondyloarthritis is a frequent chronic inflammatory rheumatism, with a prevalence of 0.43 % in France. This disease presents axial skeleton injuries, but also on peripheral joints, and can results in a total spinal and sacro-iliac motility loss. Extra-articular features including uveitis, psoriasis and inflammatory bowel disease are frequent. Current SpA treatments are only symptomatic, relieving inflammatory symptoms. SpA etiology is largely multifactorial with a genetic component dominated by the long-known strong association with the HLA-B27 allele. This allele, however, is not sufficient for the disease to occur. This thesis project objective was then to identify other genetic factors in the origin of SpA. My work was mainly divided in two complementary data analyses, in a way to get a systems biology approach. The first one consisted in proceed linking analyses on data from Affymetrix genotyping chips gathered from DNA of 1310 people grouped in 210 families. This study allowed notably to detect a new significantly linked region to SpA : 13q13, with an interval of 1.3 Mb. This part of genome is currently being sequenced to allow a better causal SNP identification. Secondly, an Affymetrix HumanGene 1.0 st transcriptomic chips analysis was performed on MD-DCs extracted from 68 people, stimulated or not by LPS during 6 or 24 hours. This cohort was grouped between 23 patients HLA-B27+, 23 healthy controls HLA-B27+ and 21 healthy controls HLA-B27-. I could notice that HLA-B27 allele is farly enough to considerably affect cell transcriptomic profiles, which encourages to include HLA-B27+ healthy controls. Otherwise, a gene network analysis allowed me to highlight on an inhibition of early steps of cholesterol biosyntthesis. Validations by qPCR and and lipid profiles are currently done in the laboratory. Finally, I published an R package, stringaussnetnn allowing to simply create semantic and gaussien gene networks, and then to import those into Cytoscape. 3 REMERCIEMENTS Je tiens à remercier les membres de mon jury de thèse, qui m'ont permis de valider et de valoriser mon travail effectué pendant trois ans dans ce laboratoire. Je remercie particulièrement le docteur Valentina Boeva et le professeur Philippe Broet pour avoir généreusement accepté de rapporter mon travail. Je suis également reconnaissant au professeur Christophe Ambroise pour avoir accepté d'être examinateur au sein de mon jury. J'adresse tous mes remerciements au professeur Henri-Jean Garchon pour m'avoir permis de rejoindre ce laboratoire en tant qu'Ingénieur d'Etudes pendant un an, puis d'avoir cru en moi pour me diriger dans un projet de thèse aussi ambitieux que passionnant. Tout en ayant une certaine liberté et autonomie sur mon projet, j'ai été guidé exactement quand il le fallait, comme il est attendu pour ce type de projet. Cette collaboration était également pour moi très enrichissante, et j'ai pu apprendre à avoir toujours un recul important sur les résultats obtenus, et à ne jamais trop être optimiste tant que tout n'a pas été validé. C'est pour moi l'esprit même d'un chercheur, et notamment dans les domaines de la bioinformatique et de la biologie des systèmes. Je remercie également le professeur Maxime Breban et le directeur Gilles Chiocchia, co- directeurs de l'équipe « Inflammatory Response and Immune System » (IRIS), pour m'avoir accueilli dans cette équipe. J'apporte mes remerciements à l'Ecole Doctorale des Génomes Aux Organismes de l'UVSQ, ainsi qu'à l'ANR, pour avoir financé mes quatre années à travailler dans ce laboratoire. Je souhaite de nouveau remercier Christophe Ambroise, statisticien au laboratoire LaMME à Evry, pour ses conseils avisés sur les approches de permutation et de bootstrap, sur l'utilisation du package SIMoNe pour l'inférence de nos réseaux gaussiens, ainsi que pour avoir participé à mon comité de thèse de mi-parcours. Je remercie Sébastien Gaumer et Mathieu Sourdeval, qui m'ont encadré pendant mon monitorat à l'UVSQ et m'ont permis de vivre cette grande expérience que d'encadrer des TPs d'analyses expérimentales avec des étudiants de niveau L3. Je remercie très humblement Félicie Costantino et Alice Talpin, qui m'ont permis de prendre la suite des analyses des puces de génotypage et transcriptomiques. Vous avez su m'apporter votre expertise acquise au cours de vos thèses, afin de mieux comprendre l'enjeu des analyses de ces données. Je remercie toutes les personnes qui étaient présentes à l'Institut Cochin dans le même bâtiment que notre laboratoire, et avec qui j'ai pu beaucoup échanger. Merci à Nathalie pour avoir partagé ce bureau et m'avoir apporté ta joie de vivre pendant la fin de ta thèse. Merci à Barbara, pour ces 4 moments d'amitié et de voyage à Amsterdam, sans compter tout le groupe d'amis que j'ai pu connaître grâce aux personnes que tu m'as présentées. Merci à Maeva et Aurélie pour avoir amené une énergie débordante dans la vie du laboratoire. Merci également à la plate-forme PIPA, et notamment à Didier Fradelizi, qui en outre d'apporter une humeur débordante de joie de vivre autour de lui, m'a permis de développer un projet aussi intéressant que le développement du site web de l'association APEMM. Je remercie toutes les personnes de l'équipe IRIS, qui ont contribué à la vie du laboratoire. Merci à Ingrid, qui a partagé mon bureau et dont le départ a créé un vide certain. Merci à Luiza, toujours fidèle à l'équipe et pour son humeur à la brésilienne. Merci à Isabelle pour avoir partagé mon bureau : je te souhaite bonne continuation dans tes projets. Merci aux doctorants, Quentin et Ketia, et également à Nadège, pour apporter un jeune dynamisme à ce laboratoire. Merci à Christophe et Clémence, ce duo de choc aussi efficace dans la vie du laboratoire que dans la mise au points des manips. Merci à Olivier pour gérer tout ce planning des réunions de laboratoire. Merci à Claudine, qui est encore plus fidèle au laboratoire ! Je remercie une partie des anciens de Sup'Biotech avec qui j'ai gardé contact et qui m'ont soutenu après l'obtention du diplôme : Yann, Maxime, Guillaume, Maximilien.
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