The complement system has been suspected to play a role in multiple sclerosis (MS) due to presence of complement activation products in MS lesions.
Objective:
We sought to understand whether variation in the complement component 4 (C4) gene is associated with MS.
Methods:
Here we used next-generation sequencing and our novel bioinformatics tool, C4Investigator, to interrogate C4 copy number variation in MS.
Results:
We found higher overall copy number of C4 in controls (p < 10−16, odds ratio (OR) = 0.43, 95% confidence interval (CI): 0.37–0.49) compared to MS patients with European ancestry.
Conclusion:
This finding suggests that lower C4 copies confer risk for MS, similar to associations seen in other autoimmune disorders.
PettigrewHDTeuberSSGershwinME. Clinical significance of complement deficiencies. Ann N Y Acad Sci2009; 1173: 108–123.
2.
CossSLZhouDChuaGT, et al. The complement system and human autoimmune diseases. J Autoimmun2023; 137: 102979.
3.
YangYChungEKZhouB, et al. Diversity in intrinsic strengths of the human complement system: Serum C4 protein concentrations correlate with C4 gene size and polygenic variations, hemolytic activities, and body mass index. J Immunol2003; 171: 2734–2745.
4.
YangYChungEKWuYL, et al. Gene copy-number variation and associated polymorphisms of complement component C4 in human systemic lupus erythematosus (SLE): Low copy number is a risk factor for and high copy number is a protective factor against SLE susceptibility in European Americans. Am J Hum Genet2007; 80(6): 1037–1054.
5.
EstradaKWhelanCWZhaoF, et al. A whole-genome sequence study identifies genetic risk factors for neuromyelitis optica. Nat Commun2018; 9: 1929.
6.
HollenbachJAOksenbergJR. The immunogenetics of multiple sclerosis: A comprehensive review. J Autoimmun2015; 64: 13–25.
IngramGHakobyanSRobertsonNP, et al. Complement in multiple sclerosis: Its role in disease and potential as a biomarker. Clin Exp Immunol2009; 155(2): 128–139.
9.
University of California San Francisco MS-EPIC Team, CreeBAGourraudPA, et al. Long-term evolution of multiple sclerosis disability in the treatment era. Ann Neurol2016; 80(4): 499–510.
10.
HollenbachJANormanPJCrearyLE, et al. A specific amino acid motif of HLA-DRB1 mediates risk and interacts with smoking history in Parkinson’s disease. Proc Natl Acad Sci USA2019; 116: 7419–7424.
11.
ThompsonAJBanwellBLBarkhofF, et al. Diagnosis of multiple sclerosis: 2017 revisions of the McDonald criteria. Lancet Neurol2018; 17: 162–173.
12.
International Multiple Sclerosis Genetics Consortium. Multiple sclerosis genomic map implicates peripheral immune cells and microglia in susceptibility. Science2019; 365: eaav7188.
13.
NormanPJNorbergSJGuethleinLA, et al. Sequences of 95 human MHC haplotypes reveal extreme coding variation in genes other than highly polymorphic HLA class I and II. Genome Res2017; 27(5): 813–823.
14.
MarinWMAugustoDGWadeKJ, et al. High-throughput complement component 4 genomic sequence analysis with C4Investigator. HLA2023; 103: e15273.
15.
IngramGLovelessSHowellOW, et al. Complement activation in multiple sclerosis plaques: An immunohistochemical analysis. Acta Neuropathol Commun2014; 2: 53.
16.
MisickaEHuangYLoomisS, et al. Adaptive and innate immunity are key drivers of age at onset of multiple sclerosis. Neurol Genet2024; 10(3): e200159.
