RT Journal Article T1 Complement component C4 structural variation and quantitative traits contribute to sex-biased vulnerability in systemic sclerosis. A1 Kerick, Martin A1 Acosta-Herrera, Marialbert A1 Simeón-Aznar, Carmen Pilar A1 Callejas, José Luis A1 Assassi, Shervin A1 International SSc Group, A1 Proudman, Susanna M A1 Nikpour, Mandana A1 Australian Scleroderma Interest Group (ASIG), A1 PRECISESADS Clinical Consortium, A1 Hunzelmann, Nicolas A1 Moroncini, Gianluca A1 de Vries-Bouwstra, Jeska K A1 Orozco, Gisela A1 Barton, Anne A1 Herrick, Ariane L A1 Terao, Chikashi A1 Allanore, Yannick A1 Fonseca, Carmen A1 Alarcón-Riquelme, Marta Eugenia A1 Radstake, Timothy R D J A1 Beretta, Lorenzo A1 Denton, Christopher P A1 Mayes, Maureen D A1 Martin, Javier AB 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. YR 2022 FD 2022-10-05 LK http://hdl.handle.net/10668/19554 UL http://hdl.handle.net/10668/19554 LA en DS RISalud RD Apr 19, 2025