Convergent effects of a functional C3 variant on brain atrophy, demyelination, and cognitive impairment in multiple sclerosis

• Published in: Multiple sclerosis Vol. 25; no. 4; pp. 532 - 540
• Main Authors: Roostaei, Tina, Sadaghiani, Shokufeh, Mashhadi, Rahil, Falahatian, Masih, Mohamadi, Esmaeil, Javadian, Nina, Nazeri, Aria, Doosti, Rozita, Naser Moghadasi, Abdorreza, Owji, Mahsa, Hashemi Taheri, Amir Pejman, Shakouri Rad, Ali, Azimi, Amirreza, Voineskos, Aristotle N, Nazeri, Arash, Sahraian, Mohammad Ali
• Format: Journal Article
• Language: English
• Published: London, England SAGE Publications 01-04-2019; Sage Publications Ltd
• Subjects: Adult; Alleles; Anisotropy; Atrophy; Atrophy - pathology; C3 gene; Coding; Cognitive ability; Cognitive Dysfunction - etiology; Cognitive Dysfunction - physiopathology; Complement activation; Complement C3 - genetics; Complement component C3; Demyelination; Diffusion Tensor Imaging; Female; Genotypes; Gray Matter - diagnostic imaging; Gray Matter - pathology; Humans; Inflammation; Magnetic Resonance Imaging; Male; Multiple sclerosis; Multiple Sclerosis - complications; Multiple Sclerosis - genetics; Multiple Sclerosis - pathology; Multiple Sclerosis - physiopathology; Neurodegeneration; Neuroimaging; NMR; Nuclear magnetic resonance; Substantia alba; Substantia grisea; White Matter - diagnostic imaging; White Matter - pathology; diffusion tensor imaging; magnetization transfer contrast imaging; complement component 3; imaging genetics; Native immunity; diffusion-weighted MRI
• ISSN: 1352-4585; 1477-0970
• DOI: 10.1177/1352458518760715

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.