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.
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.
Mult Scler. 2019 Apr;25(4):532-540. doi: 10.1177/1352458518760715. Epub 2018 Feb 27.
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.
To assess the effects of rs2230199 on MS severity using clinical, cognitive, and imaging measures.
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).
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.
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.
补体系统激活产物存在于多发性硬化症（MS）患者大脑的神经炎症、脱髓鞘和神经退行性变区域。C3 是补体级联激活的核心要素。C3 基因中的一个常见编码变异（rs2230199，C3R102G）会影响 C3 活性。
使用临床、认知和影像学指标评估 rs2230199 对 MS 严重程度的影响。
共纳入 161 例复发缓解型 MS 患者（扩展残疾状况量表（EDSS）≤6）进行体格检查、认知测试（Paced Auditory Serial Addition Test（PASAT）、Symbol Digit Modalities Test（SDMT）和 California Verbal Learning Test（CVLT））和磁共振成像（MRI）。半自动量化病变体积。进行体素分析以评估 rs2230199 基因型对灰质（GM）萎缩（n=155）、白质（WM）各向异性分数（FA；n=105）和 WM 磁化传递率（MTR；n=90）的影响。
虽然 rs2230199 次要等位基因剂量（C3-102G）对 EDSS 和多发性硬化功能复合评分（MSFC）没有显著影响，但与认知表现更差（p=0.02）、脑实质分数更低（p=0.003）和病变负荷更高（p=0.02）相关。此外，体素分析显示，随着 rs2230199 次要等位基因拷贝数的增加，下皮质结构和脑岛的 GM 体积降低，多个 WM 区域的 FA 和 MTR 降低。
C3-rs2230199 影响 MS 患者的 WM 和 GM 损伤以及认知障碍。我们的研究结果支持补体系统活性在 MS 病理生理学中的因果作用。
