Tina Roostaei1, Shokufeh Sadaghiani2, Rahil Mashhadi3, Masih Falahatian4, Esmaeil Mohamadi5, Nina Javadian5, Aria Nazeri6, Rozita Doosti5, Abdorreza Naser Moghadasi7, Mahsa Owji5, Amir Pejman Hashemi Taheri8, Ali Shakouri Rad8, Amirreza Azimi7, Aristotle N Voineskos9, Arash Nazeri10, Mohammad Ali Sahraian7. 1. Multiple Sclerosis Research Center, Neuroscience Institute, Tehran University of Medical Sciences and Sina Hospital, Tehran, Iran/Interdisciplinary Neuroscience Research Program, Tehran University of Medical Sciences, Tehran, Iran/Kimel Family Translational Imaging-Genetics Laboratory, Research Imaging Centre, Campbell Family Mental Health Research Institute, Centre for Addiction and Mental Health, Toronto, ON, Canada/Department of Psychiatry, University of Toronto, Toronto, ON, Canada/Center for Translational and Computational Neuroimmunology, Department of Neurology, Columbia University Medical Center, New York, NY, USA. 2. Multiple Sclerosis Research Center, Neuroscience Institute, Tehran University of Medical Sciences and Sina Hospital, Tehran, Iran/Interdisciplinary Neuroscience Research Program, Tehran University of Medical Sciences, Tehran, Iran. 3. Urology Research Center, Tehran University of Medical Sciences, Tehran, Iran. 4. Multiple Sclerosis Research Center, Neuroscience Institute, Tehran University of Medical Sciences and Sina Hospital, Tehran, Iran/School of Medicine, Isfahan University of Medical Sciences, Isfahan, Iran. 5. Multiple Sclerosis Research Center, Neuroscience Institute, Tehran University of Medical Sciences and Sina Hospital, Tehran, Iran. 6. Multiple Sclerosis Research Center, Neuroscience Institute, Tehran University of Medical Sciences and Sina Hospital, Tehran, Iran/Mallinckrodt Institute of Radiology, Washington University School of Medicine, St. Louis, MO, USA. 7. Multiple Sclerosis Research Center, Neuroscience Institute, Tehran University of Medical Sciences and Sina Hospital, Tehran, Iran/Iranian Center of Neurological Research, Neuroscience Institute, Tehran University of Medical Sciences, Tehran, Iran. 8. Department of Radiology, Tehran University of Medical Sciences, Tehran, Iran. 9. Kimel Family Translational Imaging-Genetics Laboratory, Research Imaging Centre, Campbell Family Mental Health Research Institute, Centre for Addiction and Mental Health, Toronto, ON, Canada/Department of Psychiatry, University of Toronto, Toronto, ON, Canada. 10. Multiple Sclerosis Research Center, Neuroscience Institute, Tehran University of Medical Sciences and Sina Hospital, Tehran, Iran/Interdisciplinary Neuroscience Research Program, Tehran University of Medical Sciences, Tehran, Iran/Kimel Family Translational Imaging-Genetics Laboratory, Research Imaging Centre, Campbell Family Mental Health Research Institute, Centre for Addiction and Mental Health, Toronto, ON, Canada; Department of Psychiatry, University of Toronto, Toronto, ON, Canada; Mallinckrodt Institute of Radiology, Washington University School of Medicine, St. Louis, MO, USA.
Abstract
BACKGROUND: Complement system activation products are present in areas of neuroinflammation, demyelination, and neurodegeneration in brains of patients with multiple sclerosis (MS). C3 is a central element in the activation of complement cascades. A common coding variant in the C3 gene (rs2230199, C3R102G) affects C3 activity. OBJECTIVES: To assess the effects of rs2230199 on MS severity using clinical, cognitive, and imaging measures. METHODS: In total, 161 relapse-onset MS patients (Expanded Disability Status Scale (EDSS) ≤ 6) underwent physical assessments, cognitive tests (Paced Auditory Serial Addition Test (PASAT), Symbol Digit Modalities Test (SDMT), and California Verbal Learning Test (CVLT)), and magnetic resonance imaging (MRI). Lesion volumes were quantified semi-automatically. Voxel-wise analyses were performed to assess the effects of rs2230199 genotype on gray matter (GM) atrophy ( n = 155), white matter (WM) fractional anisotropy (FA; n = 105), and WM magnetization transfer ratio (MTR; n = 90). RESULTS: While rs2230199 minor-allele dosage (C3-102G) showed no significant effect on EDSS and Multiple Sclerosis Functional Composite (MSFC), it was associated with worse cognitive performance ( p = 0.02), lower brain parenchymal fraction ( p = 0.003), and higher lesion burden ( p = 0.02). Moreover, voxel-wise analyses showed lower GM volume in subcortical structures and insula, and lower FA and MTR in several WM areas with higher copies of rs2230199 minor allele. CONCLUSION: C3-rs2230199 affects white and GM damage as well as cognitive impairment in MS patients. Our findings support a causal role for complement system activity in the pathophysiology of MS.
BACKGROUND: Complement system activation products are present in areas of neuroinflammation, demyelination, and neurodegeneration in brains of patients with multiple sclerosis (MS). C3 is a central element in the activation of complement cascades. A common coding variant in the C3 gene (rs2230199, C3R102G) affects C3 activity. OBJECTIVES: To assess the effects of rs2230199 on MS severity using clinical, cognitive, and imaging measures. METHODS: In total, 161 relapse-onset MS patients (Expanded Disability Status Scale (EDSS) ≤ 6) underwent physical assessments, cognitive tests (Paced Auditory Serial Addition Test (PASAT), Symbol Digit Modalities Test (SDMT), and California Verbal Learning Test (CVLT)), and magnetic resonance imaging (MRI). Lesion volumes were quantified semi-automatically. Voxel-wise analyses were performed to assess the effects of rs2230199 genotype on gray matter (GM) atrophy ( n = 155), white matter (WM) fractional anisotropy (FA; n = 105), and WM magnetization transfer ratio (MTR; n = 90). RESULTS: While rs2230199 minor-allele dosage (C3-102G) showed no significant effect on EDSS and Multiple Sclerosis Functional Composite (MSFC), it was associated with worse cognitive performance ( p = 0.02), lower brain parenchymal fraction ( p = 0.003), and higher lesion burden ( p = 0.02). Moreover, voxel-wise analyses showed lower GM volume in subcortical structures and insula, and lower FA and MTR in several WM areas with higher copies of rs2230199 minor allele. CONCLUSION: C3-rs2230199 affects white and GM damage as well as cognitive impairment in MS patients. Our findings support a causal role for complement system activity in the pathophysiology of MS.
Authors: Kathryn C Fitzgerald; Kicheol Kim; Matthew D Smith; Sean A Aston; Nicholas Fioravante; Alissa M Rothman; Stephen Krieger; Stacey S Cofield; Dorlan J Kimbrough; Pavan Bhargava; Shiv Saidha; Katharine A Whartenby; Ari J Green; Ellen M Mowry; Gary R Cutter; Fred D Lublin; Sergio E Baranzini; Philip L De Jager; Peter A Calabresi Journal: Brain Date: 2019-09-01 Impact factor: 13.501
Authors: Evans Raballah; Samuel B Anyona; Qiuying Cheng; Elly O Munde; Ivy-Foo Hurwitz; Clinton Onyango; Caroline Ndege; Nicolas W Hengartner; Maria Andreína Pacheco; Ananias A Escalante; Christophe G Lambert; Collins Ouma; Henri C Jr T Obama; Kristan A Schneider; Philip D Seidenberg; Benjamin H McMahon; Douglas J Perkins Journal: Exp Biol Med (Maywood) Date: 2021-11-29
Authors: Carles Vilariño-Güell; Alexander Zimprich; Filippo Martinelli-Boneschi; Bruno Herculano; Zhe Wang; Fuencisla Matesanz; Elena Urcelay; Koen Vandenbroeck; Laura Leyva; Denis Gris; Charbel Massaad; Jacqueline A Quandt; Anthony L Traboulsee; Mary Encarnacion; Cecily Q Bernales; Jordan Follett; Irene M Yee; Maria G Criscuoli; Angela Deutschländer; Eva M Reinthaler; Tobias Zrzavy; Elisabetta Mascia; Andrea Zauli; Federica Esposito; Antonio Alcina; Guillermo Izquierdo; Laura Espino-Paisán; Jorge Mena; Alfredo Antigüedad; Patricia Urbaneja-Romero; Jesús Ortega-Pinazo; Weihong Song; A Dessa Sadovnick Journal: PLoS Genet Date: 2019-06-06 Impact factor: 5.917
Authors: Pablo L Cardozo; Izabella B Q de Lima; Esther M A Maciel; Nathália C Silva; Tomas Dobransky; Fabíola M Ribeiro Journal: Curr Neuropharmacol Date: 2019 Impact factor: 7.363