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

Martin Kerick1, Marialbert Acosta-Herrera2,3, Carmen Pilar Simeón-Aznar4

  • 1Department of Cell Biology and Immunology, Institute of Parasitology and Biomedicine López-Neyra, CSIC, Granada, Spain. mkerick@ipb.csic.es.

NPJ Genomic Medicine
|October 5, 2022
PubMed

Insights

Higher complement C4 (C4) copy number (CN) protects against systemic sclerosis (SSc). Deviations in C4A and C4B copy number increase SSc risk, with sex-specific protective effects observed for C4A and C4B.

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.

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