npj Genomic Medicine (Oct 2022)

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

  • Martin Kerick,
  • Marialbert Acosta-Herrera,
  • Carmen Pilar Simeón-Aznar,
  • José Luis Callejas,
  • Shervin Assassi,
  • International SSc Group,
  • Susanna M. Proudman,
  • Mandana Nikpour,
  • Australian Scleroderma Interest Group (ASIG),
  • PRECISESADS Clinical Consortium,
  • Nicolas Hunzelmann,
  • Gianluca Moroncini,
  • Jeska K. de Vries-Bouwstra,
  • Gisela Orozco,
  • Anne Barton,
  • Ariane L. Herrick,
  • Chikashi Terao,
  • Yannick Allanore,
  • Carmen Fonseca,
  • Marta Eugenia Alarcón-Riquelme,
  • Timothy R. D. J. Radstake,
  • Lorenzo Beretta,
  • Christopher P. Denton,
  • Maureen D. Mayes,
  • Javier Martin

DOI
https://doi.org/10.1038/s41525-022-00327-8
Journal volume & issue
Vol. 7, no. 1
pp. 1 – 12

Abstract

Read online

Abstract Copy number (CN) polymorphisms of complement C4 play distinct roles in many conditions, including immune-mediated diseases. We investigated the association of C4 CN with systemic sclerosis (SSc) risk. Imputed total C4, C4A, C4B, and HERV-K CN were analyzed in 26,633 individuals and validated in an independent cohort. Our results showed that higher C4 CN confers protection to SSc, and deviations from CN parity of C4A and C4B augmented risk. The protection contributed per copy of C4A and C4B differed by sex. Stronger protection was afforded by C4A in men and by C4B in women. C4 CN correlated well with its gene expression and serum protein levels, and less C4 was detected for both in SSc patients. Conditioned analysis suggests that C4 genetics strongly contributes to the SSc association within the major histocompatibility complex locus and highlights classical alleles and amino acid variants of HLA-DRB1 and HLA-DPB1 as C4-independent signals.