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 Luís Callejas-Rubio, Shervin Assassi, International SSc Group, Patrícia Carreira, I. Castellví, Raimon Rios, R. García Portales, Antonio Fernández‐Nebro, Francisco José García Hernández, M. Á. Aguirre, Benjamín Fernández‐Gutiérrez, Luis Rodríguez‐Rodríguez, Paloma García de la Peña, Esther Vicente, José Luís Andreu, M. Fernández Castro, Francisco Javier López-Longo, V. Fonollosa, Alberto Guillén, Gerard Espinosa, Carlos Tolosa, A. Pros, E. Beltrán, Mónica Rodríguez‐Carballeira, Javier Narváez, Manuel Rubio Rivas, V. Ortiz-Santamaría, Ana Belén Madroñero, Miguel Á. González‐Gay, Bianca J. Diaz, Luis Trapiella, M. V. Egurbide, P. Fanlo-Mateo, Luís Sáez-Comet, Fidel Díez Díaz, José Andrés Román-Ivorra, Juan José Alegre Sancho, M. Freire, Fabián García, N. Oreiro, T Witte, Alexander Kreuter, G. Riemekasten, Paolo Airó, C. Magro, Alexandre E. Voskuyl, M. C. Vonk, Roger Hesselstrand, Annika Nordin, Claudio Lunardi, A. Gabrielli, Anna‐Maria Hoffmann‐Vold, Jörg H. W. Distler, Leonid Padyukov, Bobby P. C. Koeleman, Susanna Proudman, Mandana Nikpour, Australian Scleroderma Interest Group (ASIG), Wendy Stevens, Jane Zochling, J. Sahhar, Janet Roddy, Peter Nash, Kathleen Tymms, Maureen Rischmueller, Sue Lester, Barbara Vigone, Jacques‐Olivier Pers, Alain Saraux, Valérie Devauchelle‐Pensec, Divi Cornec, Sandrine Jousse‐Joulin, Bernard Lauwerys, Julie Ducreux, Anne‐Lise Maudoux, Carlos Vasconcelos, Ana Tavares, Esmeralda Neves, Raquel Faria, Mariana Brandão, Ana Campar, António Marinho, Fátima Farinha, Isabel Almeida, Miguel Á. González‐Gay, Ricardo Blanco, Alfonso Corrales Martínez, Ricard Cervera, Ignasi Rodríguez‐Pintó, Gerard Espinosa, Rik Lories, Ellen De Langhe, Doreen Belz, Torsten Witte, Niklas Baerlecken, Georg Stummvoll, Michael Zauner
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.