Complement Component C4 Structural Variation and Quantitative Traits Contribute to Sex-Biased Vulnerability in Systemic Sclerosis

Authors

Martin Kerick
Marialbert Acosta-Herrera
Carmen Pilar Simeón-Aznar
José Luis Callejas
Shervin Assassi
Susanna M Proudman
Mandana Nikpour
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

Publication Date

10-5-2022

Journal

NPJ Genomic Medicine

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.

Keywords

Structural variation, Genetic association study, Quantitative trait, Systemic sclerosis

Comments

Supplementary Materials

PMID: 36198672