Shimrat Mamrut1, Nili Avidan1, Frédérique Truffault2, Elsebeth Staun-Ram1, Tarek Sharshar3, Bruno Eymard4, Mélinée Frenkian2, Jiri Pitha5, Marc de Baets6, Laurent Servais7, Sonia Berrih-Aknin2, Ariel Miller8. 1. Rappaport Faculty of Medicine, Technion-Israel Institute of Technology, Haifa, 31096, Israel. 2. INSERM - U974/CNRS UMR7215//UPMC UM76/AIM, Institute of Myology Pitie-Salpetriere, Paris, 73013, France. 3. General Intensive Care Medicine, Assistance Publique Hôpitaux de Paris, Raymond Poincaré Hospital, University of Versailles Saint-Quentin en Yvelines, 92380, Garches, France. 4. Department of Neuromuscular Disorders, CHU Salpêtrière, Paris, 75013, France. 5. Department of Neurology and Clinical Neuroscience Center, 1st Faculty of Medicine, Charles University and General Teaching Hospital, Prague, Czech Republic. 6. Neuroimmunology Group, Division of Neuroscience, School for Mental Health and Neuroscience, Maastricht University, Maastricht, The Netherlands. 7. Institute of Myology, Groupe hospitalier Pitié-Salpêtrière, AP-HP, Sorbonne Universités, UPMC Universités Paris 06, INSERM, Paris, 75013, France. 8. Rappaport Faculty of Medicine, Technion-Israel Institute of Technology, Haifa, 31096, Israel; Division of Neuroimmunology, Lady Davis Carmel Medical Center, Haifa, 34362, Israel. Electronic address: milleras@netvision.net.il.
Abstract
OBJECTIVE: To identify novel genetic and epigenetic factors associated with Myasthenia gravis (MG) using an identical twins experimental study design. METHODS: The transcriptome and methylome of peripheral monocytes were compared between monozygotic (MZ) twins discordant and concordant for MG, as well as with MG singletons and healthy controls, all females. Sets of differentially expressed genes and differentially methylated CpGs were validated using RT-PCR for expression and target bisulfite sequencing for methylation on additional samples. RESULTS: >100 differentially expressed genes and ∼1800 differentially methylated CpGs were detected in peripheral monocytes between MG patients and controls. Several transcripts associated with immune homeostasis and inflammation resolution were reduced in MG patients. Only a relatively few genes differed between the discordant healthy and MG co-twins, and both their expression and methylation profiles demonstrated very high similarity. INTERPRETATION: This is the first study to characterize the DNA methylation profile in MG, and the expression profile of immune cells in MZ twins with MG. Results suggest that numerous small changes in gene expression or methylation might together contribute to disease. Impaired monocyte function in MG and decreased expression of genes associated with inflammation resolution could contribute to the chronicity of the disease. Findings may serve as potential new predictive biomarkers for disease and disease activity, as well as potential future targets for therapy development. The high similarity between the healthy and the MG discordant twins, suggests that a molecular signature might precede a clinical phenotype, and that genetic predisposition may have a stronger contribution to disease than previously assumed.
OBJECTIVE: To identify novel genetic and epigenetic factors associated with Myasthenia gravis (MG) using an identical twins experimental study design. METHODS: The transcriptome and methylome of peripheral monocytes were compared between monozygotic (MZ) twins discordant and concordant for MG, as well as with MG singletons and healthy controls, all females. Sets of differentially expressed genes and differentially methylated CpGs were validated using RT-PCR for expression and target bisulfite sequencing for methylation on additional samples. RESULTS: >100 differentially expressed genes and ∼1800 differentially methylated CpGs were detected in peripheral monocytes between MG patients and controls. Several transcripts associated with immune homeostasis and inflammation resolution were reduced in MG patients. Only a relatively few genes differed between the discordant healthy and MG co-twins, and both their expression and methylation profiles demonstrated very high similarity. INTERPRETATION: This is the first study to characterize the DNA methylation profile in MG, and the expression profile of immune cells in MZ twins with MG. Results suggest that numerous small changes in gene expression or methylation might together contribute to disease. Impaired monocyte function in MG and decreased expression of genes associated with inflammation resolution could contribute to the chronicity of the disease. Findings may serve as potential new predictive biomarkers for disease and disease activity, as well as potential future targets for therapy development. The high similarity between the healthy and the MG discordant twins, suggests that a molecular signature might precede a clinical phenotype, and that genetic predisposition may have a stronger contribution to disease than previously assumed.