TY - JOUR
T1 - Complement component C4 structural variation and quantitative traits contribute to sex-biased vulnerability in systemic sclerosis
AU - International SSc Group
AU - Australian Scleroderma Interest Group (ASIG)
AU - PRECISESADS Clinical Consortium
AU - Kerick, Martin
AU - Acosta-Herrera, Marialbert
AU - Simeón-Aznar, Carmen Pilar
AU - Callejas, José Luis
AU - Assassi, Shervin
AU - Carreira, P.
AU - Castellvi, I.
AU - Ríos, R.
AU - Portales, R. García
AU - Fernández-Nebro, A.
AU - García-Hernández, F. J.
AU - Aguirre, M. A.
AU - Fernández-Gutiérrez, B.
AU - Rodríguez-Rodríguez, L.
AU - de la Peña, P. García
AU - Vicente, E.
AU - Andreu, J. L.
AU - de Castro, M. Fernández
AU - López-Longo, F. J.
AU - Fonollosa, V.
AU - Guillén, A.
AU - Espinosa, G.
AU - Tolosa, C.
AU - Pros, A.
AU - Beltrán, E.
AU - Carballeira, M. Rodríguez
AU - Narváez, F. J.
AU - Rivas, M. Rubio
AU - Ortiz-Santamaría, V.
AU - Madroñero, A. B.
AU - González-Gay, M. A.
AU - Díaz, B.
AU - Trapiella, L.
AU - Egurbide, M. V.
AU - Fanlo-Mateo, P.
AU - Saez-Comet, L.
AU - Díaz, F.
AU - Roman-Ivorra, J. A.
AU - Sancho, J. J.Alegre
AU - Freire, M.
AU - Garcia, F. J.Blanco
AU - Oreiro, N.
AU - Witte, T.
AU - Kreuter, A.
AU - Riemekasten, G.
AU - Airò, P.
AU - Magro, C.
AU - Voskuyl, A. E.
AU - Vonk, M. C.
AU - Terao, Chikashi
N1 - Publisher Copyright:
© 2022, The Author(s).
PY - 2022/12
Y1 - 2022/12
N2 - 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.
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.
UR - https://www.scopus.com/pages/publications/85139419835
UR - https://www.scopus.com/pages/publications/85139419835#tab=citedBy
U2 - 10.1038/s41525-022-00327-8
DO - 10.1038/s41525-022-00327-8
M3 - Article
AN - SCOPUS:85139419835
SN - 2056-7944
VL - 7
JO - npj Genomic Medicine
JF - npj Genomic Medicine
IS - 1
M1 - 57
ER -