Complement component C4 structural variation and quantitative traits contribute to sex-biased vulnerability in systemic sclerosis
Authors: Kerick Martin , Acosta-Herrera Marialbert , Simeón-Aznar Carmen Pilar , Callejas José Luis , Assassi Shervin ,   International SSc Group, Carreira P. , Castellvi I. , Ríos R. , Portales R. García , Fernández-Nebro A. , García-Hernández F. J. , Aguirre M. A. , Fernández-Gutiérrez B. , Rodríguez-Rodríguez L. , de la Peña P. García , Vicente E. , Andreu J. L. , de Castro M. Fernández , López-Longo F. J. , Fonollosa V. , Guillén A. , Espinosa G. , Tolosa C. , Pros A. , Beltrán E. , Carballeira M. Rodríguez , Narváez F. J. , Rivas M. Rubio , Ortiz-Santamaría V. , Madroñero A. B. , González-Gay M. A. , Díaz B. , Trapiella L. , Egurbide M. V. , Fanlo-Mateo P. , Saez-Comet L. , Díaz F. , Roman-Ivorra J. A. , Sancho J. J. Alegre , Freire M. , Garcia F. J. Blanco , Oreiro N. , Witte T. , Kreuter A. , Riemekasten G. , Airò P. , Magro C. , Voskuyl A. E. , Vonk M. C. , Hesselstrand R. , Nordin A. , Lunardi C. , Gabrielli A. , Hoffmann-Vold A. , Distler J. H. W. , Padyukov L. , Koeleman B. P. C. , Proudman Susanna M. , Nikpour Mandana ,   Australian Scleroderma Interest Group (ASIG), Stevens W. , Zochling J. , Sahhar J. , Roddy J. , Nash P. , Tymms K. , Rischmueller M. , Lester S. ,   PRECISESADS Clinical Consortium, Vigone Barbara , Pers Jacques-Olivier , Saraux Alain , Devauchelle-Pensec Valérie , Cornec Divi , Jousse-Joulin Sandrine , Lauwerys Bernard , Ducreux Julie , Maudoux Anne-Lise , Vasconcelos Carlos , Tavares Ana , Neves Esmeralda , Faria Raquel , Brandão Mariana , Campar Ana , Marinho António , Farinha Fátima , Almeida Isabel , Mantecón Miguel Angel Gonzalez-Gay , Alonso Ricardo Blanco , Martínez Alfonso Corrales , Cervera Ricard , Rodríguez-Pintó Ignasi , Espinosa Gerard , Lories Rik , De Langhe Ellen , Belz Doreen , Witte Torsten , Baerlecken Niklas , Stummvoll Georg , Zauner Michael , Lehner Michaela , Collantes Eduardo , Ortega-Castro Rafaela , Aguirre-Zamorano Ma Angeles , Escudero-Contreras Alejandro , Castro-Villegas Ma Carmen , Roldán María Concepción Fernández , Ortego Norberto , Raya Enrique , Moleón Inmaculada Jiménez , de Ramon Enrique , Quintero Isabel Díaz , Meroni Pier Luigi , Gerosa Maria , Schioppo Tommaso , Artusi Carolina , Chizzolini Carlo , Zuber Aleksandra , Wynar Donatienne , Kovács Laszló , Balog Attila , Deák Magdolna , Bocskai Márta , Dulic Sonja , Kádár Gabriella , Hiepe Falk , Gerl Velia , Thiel Silvia , Maresca Manuel Rodriguez , López-Berrio Antonio , Aguilar-Quesada Rocío , Navarro-Linares Héctor , 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 
Published: October 2022

Copy number (CN) polymorphisms of complementC4play distinct roles in many conditions, including immune-mediated diseases. We investigated the association ofC4CN with systemic sclerosis (SSc) risk. Imputed totalC4, C4A,C4B, and HERV-K CN were analyzed in 26,633 individuals and validated in an independent cohort. Our results showed that higherC4CN confers protection to SSc, and deviations from CN parity ofC4AandC4Baugmented risk. The protection contributed per copy ofC4AandC4Bdiffered by sex. Stronger protection was afforded byC4Ain men and byC4Bin women.C4CN correlated well with its gene expression and serum protein levels, and less C4 was detected for both in SSc patients. Conditioned analysis suggests thatC4genetics strongly contributes to the SSc association within the major histocompatibility complex locus and highlights classical alleles and amino acid variants ofHLA-DRB1andHLA-DPB1asC4-independent signals.