Complement component C4 structural variation and quantitative traits contribute to sex-biased vulnerability in...

Area of Science:

• Immunogenetics
• Rheumatology
• Human Genetics

Background:

• Complement C4 (C4) copy number (CN) polymorphisms are implicated in various immune-mediated conditions.
• Understanding the role of C4 CN in systemic sclerosis (SSc) is crucial for disease etiology research.

Purpose of the Study:

• To investigate the association between C4 CN and the risk of developing systemic sclerosis (SSc).
• To explore sex-specific differences in the protective effects of C4A and C4B CN.
• To examine the relationship between C4 CN, gene expression, and protein levels in SSc patients.

Main Methods:

• Analysis of imputed total C4, C4A, C4B, and HERV-K CN in a large cohort (26,633 individuals).
• Validation of findings in an independent cohort.
• Correlation analysis of C4 CN with C4 gene expression and serum protein levels.
• Conditioned analysis to identify C4-independent signals within the MHC locus.

Main Results:

• Higher C4 CN was associated with a protective effect against SSc.
• Deviations from C4A and C4B copy number parity augmented SSc risk.
• C4A provided stronger protection in men, while C4B offered greater protection in women.
• Lower C4 gene expression and serum protein levels were observed in SSc patients.
• C4 genetics significantly contributes to SSc risk within the MHC locus, with independent signals from HLA-DRB1 and HLA-DPB1.

Conclusions:

• C4 CN is a significant genetic factor influencing SSc susceptibility.
• The interplay between C4 CN, sex, and SSc risk is complex and warrants further investigation.
• C4 CN variations provide insights into the pathogenesis of SSc and highlight potential therapeutic targets.