Copy number variation at the complement C4 locus is associated with risk for multiple sclerosis

Area of Science:

• Immunogenetics
• Neuroimmunology
• Genetics of Autoimmune Diseases

Background:

• The complement system is implicated in multiple sclerosis (MS) pathogenesis.
• Complement activation products are detected in MS lesions, suggesting a role.

Purpose of the Study:

• To investigate the association between complement component 4 (C4) gene variation and MS risk.
• To determine if C4 copy number variation influences susceptibility to MS.

Main Methods:

• Employed next-generation sequencing for C4 gene analysis.
• Utilized a novel bioinformatics tool, C4Investigator, to assess C4 copy number variation.
• Studied a cohort of MS patients and controls with European ancestry.

Main Results:

• Significantly higher C4 copy numbers were observed in controls compared to MS patients (p < 10^-16).
• An odds ratio (OR) of 0.43 (95% CI: 0.37-0.49) indicated a protective effect of higher C4 copies against MS.
• Lower C4 copy number was associated with increased MS risk in the studied population.

Conclusions:

• Reduced C4 gene copy number is a risk factor for developing MS.
• The findings align with observations in other autoimmune disorders, highlighting C4's role.
• C4 copy number variation represents a potential genetic marker for MS susceptibility.