NPJ genomic medicine · 2022
Complement component C4 structural variation and quantitative traits contribute to sex-biased vulnerability in systemic sclerosis.
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Kerick Martin, Acosta-Herrera Marialbert, Simeón-Aznar Carmen Pilar, Callejas José Luis, Assassi Shervin, International SSc Group, Proudman Susanna M, Nikpour Mandana, Australian Scleroderma Interest Group (ASIG), PRECISESADS Clinical Consortium, Hunzelmann Nicolas, Moroncini Gianluca, de Vries-Bouwstra Jeska K, Orozco Gisela, Barton Anne, Herrick Ariane L, Terao Chikashi, Allanore Yannick, Fonseca Carmen, Alarcón-Riquelme Marta Eugenia, Radstake Timothy R D J, Beretta Lorenzo, Denton Christopher P, Mayes Maureen D, Martin Javier
Аннотация
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.