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.
Original language | English |
---|---|
Article number | 57 |
Number of pages | 12 |
Journal | npj Genomic Medicine |
Volume | 7 |
Issue number | 1 |
DOIs | |
Publication status | Published - Dec 2022 |
Externally published | Yes |
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In: npj Genomic Medicine, Vol. 7, No. 1, 57, 12.2022.
Research output: Contribution to journal › Article › Research › peer-review
TY - JOUR
T1 - Complement component C4 structural variation and quantitative traits contribute to sex-biased vulnerability in systemic sclerosis
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-Zamorano, Ma Angeles
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 - Hesselstrand, R.
AU - Nordin, A.
AU - Lunardi, C.
AU - Gabrielli, A.
AU - Hoffmann-Vold, A.
AU - Distler, J. H.W.
AU - Padyukov, L.
AU - Koeleman, B. P.C.
AU - Proudman, Susanna M.
AU - Nikpour, Mandana
AU - Stevens, W.
AU - Zochling, J.
AU - Sahhar, J.
AU - Roddy, J.
AU - Nash, P.
AU - Tymms, K.
AU - Rischmueller, M.
AU - Lester, S.
AU - Vigone, Barbara
AU - Pers, Jacques Olivier
AU - Saraux, Alain
AU - Devauchelle-Pensec, Valérie
AU - Cornec, Divi
AU - Jousse-Joulin, Sandrine
AU - Lauwerys, Bernard
AU - Ducreux, Julie
AU - Maudoux, Anne Lise
AU - Vasconcelos, Carlos
AU - Tavares, Ana
AU - Neves, Esmeralda
AU - Faria, Raquel
AU - Brandão, Mariana
AU - Campar, Ana
AU - Marinho, António
AU - Farinha, Fátima
AU - Almeida, Isabel
AU - Mantecón, Miguel Angel Gonzalez Gay
AU - Alonso, Ricardo Blanco
AU - Martínez, Alfonso Corrales
AU - Cervera, Ricard
AU - Rodríguez-Pintó, Ignasi
AU - Espinosa, Gerard
AU - Lories, Rik
AU - De Langhe, Ellen
AU - Belz, Doreen
AU - Witte, Torsten
AU - Baerlecken, Niklas
AU - Stummvoll, Georg
AU - Zauner, Michael
AU - Lehner, Michaela
AU - Collantes, Eduardo
AU - Ortega-Castro, Rafaela
AU - Aguirre-Zamorano, Ma Angeles
AU - Escudero-Contreras, Alejandro
AU - Castro-Villegas, Ma Carmen
AU - Roldán, María Concepción Fernández
AU - Ortego, Norberto
AU - Raya, Enrique
AU - Moleón, Inmaculada Jiménez
AU - de Ramon, Enrique
AU - Quintero, Isabel Díaz
AU - Meroni, Pier Luigi
AU - Gerosa, Maria
AU - Schioppo, Tommaso
AU - Artusi, Carolina
AU - Chizzolini, Carlo
AU - Zuber, Aleksandra
AU - Wynar, Donatienne
AU - Kovács, Laszló
AU - Balog, Attila
AU - Deák, Magdolna
AU - Bocskai, Márta
AU - Dulic, Sonja
AU - Kádár, Gabriella
AU - Hiepe, Falk
AU - Gerl, Velia
AU - Thiel, Silvia
AU - Maresca, Manuel Rodriguez
AU - López-Berrio, Antonio
AU - Aguilar-Quesada, Rocío
AU - Navarro-Linares, Héctor
AU - Hunzelmann, Nicolas
AU - Moroncini, Gianluca
AU - de Vries-Bouwstra, Jeska K.
AU - Orozco, Gisela
AU - Barton, Anne
AU - Herrick, Ariane L.
AU - Terao, Chikashi
AU - Allanore, Yannick
AU - Fonseca, Carmen
AU - Alarcón-Riquelme, Marta Eugenia
AU - Radstake, Timothy R.D.J.
AU - Beretta, Lorenzo
AU - Denton, Christopher P.
AU - Mayes, Maureen D.
AU - Martin, Javier
AU - International SSc Group
AU - the Australian Scleroderma Interest Group (ASIG)
AU - PRECISESADS Clinical Consortium
N1 - Funding Information: We would like to thank Guillermo Barturen Briñas and Elena Carnero-Montoro for fruitful discussions and Sofia Vargas and Gema Robledo for their excellent technical assistance. We would like to thank Elena López-Isac for organizing all SSc GWAS datasets and all members of the PRECISESADS consortium, especially Ralf Lesche, Sepideh Babaei, Anne Buttgereit, Suzana Makowska and Martina Runge for preparing the RNA Seq data and Johan Frostegård and Jacques-Olivier Pers for preparing and normalizing the serum C4 data. We greatly appreciate the patients and healthy donors for their essential participation in these studies. This work was supported by grant RTI2018101332-B-100 funded by MCIN/AEI/10.13039/501100011033 by “ERDF A way of making Europe”, Red de Investigación en Inflamación y Enfermedades Reumáticas (RIER) from Instituto de Salud Carlos III (RD16/0012/0013). This work has received funding from the Innovative Medicines Initiative 1 & 2 Joint Undertaking (JU) under grant agreements No 115565 (PRECISESADS) and No 831434 (3TR). The JU receives support from the European Union’s FP7 and Horizon 2020 research and innovation programs and EFPIA. MAH was supported by the Juan de la Cierva Incorporacion program, grant IJC2018-035131-I funded by MCIN/AEI/10.13039/501100011033. This work is dedicated to the memory of Annette Kerick (1945-2020). 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 - http://www.scopus.com/inward/record.url?scp=85139419835&partnerID=8YFLogxK
U2 - 10.1038/s41525-022-00327-8
DO - 10.1038/s41525-022-00327-8
M3 - Article
C2 - 36198672
AN - SCOPUS:85139419835
SN - 2056-7944
VL - 7
JO - npj Genomic Medicine
JF - npj Genomic Medicine
IS - 1
M1 - 57
ER -