Complement component C4 structural variation and quantitative traits contribute to sex-biased vulnerability in systemic sclerosis
npj Genomic Medicine, vol. 7, pp. 57
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.
Authors 87
-
Martin Kerick corresponding
Instituto de Parasitología y Biomedicina "López - Neyra"
Affiliation as printed
Department of Cell Biology and Immunology, Institute of Parasitology and Biomedicine López-Neyra, CSIC, Granada, Spain. mkerick@ipb.csic.es
Department of Cell Biology and Immunology, Institute of Parasitology and Biomedicine López-Neyra, CSIC, Granada, Spain
-
Marialbert Acosta‐Herrera corresponding
Instituto de Investigación Biosanitaria de Granada · Instituto de Parasitología y Biomedicina "López - Neyra"
Affiliation as printed
Department of Cell Biology and Immunology, Institute of Parasitology and Biomedicine López-Neyra, CSIC, Granada, Spain. m.acostaherrera@ipb.csic.es
Systemic Autoimmune Disease Unit, Hospital Clínico San Cecilio, Instituto de Investigación Biosanitaria Ibs. GRANADA, Granada, Spain. m.acostaherrera@ipb.csic.es
Department of Cell Biology and Immunology, Institute of Parasitology and Biomedicine López-Neyra, CSIC, Granada, Spain
-
Vall d'Hebron Hospital Universitari
Affiliation as printed
Department of Internal Medicine, Valle de Hebrón Hospital, Barcelona, Spain
-
Affiliation as printed
Department of Internal Medicine, Hospital San Cecilio, Granada, Spain
-
The University of Texas Health Science Center at Houston
Affiliation as printed
Department of Rheumatology, The University of Texas Health Science Center at Houston, Houston, TX, USA
-
Hospital de Sant Pau · Research Institute Hospital 12 de Octubre · Hospital Universitario 12 De Octubre
Affiliation as printed
Department of Rheumatology, 12 de Octubre University Hospital, Madrid, Spain
Department of Rheumatology, Santa Creu i Sant Pau University Hospital, Barcelona, Spain
-
Affiliation as printed
Department of Rheumatology, Santa Creu i Sant Pau University Hospital, Barcelona, Spain
Department of Internal Medicine, Hospital San Cecilio, Granada, Spain
-
Hospital Clínico Universitario Virgen de la Victoria
Affiliation as printed
Department of Rheumatology, Virgen de la Victoria Hospital, Málaga, Spain
Department of Rheumatology, Carlos Haya Hospital, Málaga, Spain
-
Hospital Universitario Virgen del Rocío
Affiliation as printed
Department of Rheumatology, Carlos Haya Hospital, Málaga, Spain
Department of Internal Medicine, Virgen del Rocío Hospital, Sevilla, Spain
-
Instituto Maimónides de Investigación Biomédica de Córdoba · Hospital Universitario Virgen del Rocío
Affiliation as printed
Department of Internal Medicine, Virgen del Rocío Hospital, Sevilla, Spain
Department of Rheumatology, Reina Sofía/IMIBIC Hospital, Córdoba, Spain
-
Hospital Clínico San Carlos · Instituto Maimónides de Investigación Biomédica de Córdoba
Affiliation as printed
Department of Rheumatology, Reina Sofía/IMIBIC Hospital, Córdoba, Spain
Department of Rheumatology, San Carlos Clinic Hospital, Madrid, Spain
-
Affiliation as printed
Department of Rheumatology, San Carlos Clinic Hospital, Madrid, Spain
-
Hospital Clínico San Carlos · Hospital Universitario HM Sanchinarro
Affiliation as printed
Department of Rheumatology, San Carlos Clinic Hospital, Madrid, Spain
Department of Rheumatology, Madrid Norte Sanchinarro Hospital, Madrid, Spain
-
Hospital Universitario de La Princesa · Hospital Universitario HM Sanchinarro
Affiliation as printed
Department of Rheumatology, Madrid Norte Sanchinarro Hospital, Madrid, Spain
Department of Rheumatology, La Princesa Hospital, Madrid, Spain
-
Hospital Universitario Puerta de Hierro Majadahonda · Hospital Universitario de La Princesa
Affiliation as printed
Department of Rheumatology, La Princesa Hospital, Madrid, Spain
Department of Rheumatology, Puerta de Hierro Hospital-Majadahonda, Madrid, Spain
-
Hospital Universitario Puerta de Hierro Majadahonda
Affiliation as printed
Department of Rheumatology, Puerta de Hierro Hospital-Majadahonda, Madrid, Spain
-
Hospital General Universitario Gregorio Marañón · Hospital Universitario Puerta de Hierro Majadahonda
Affiliation as printed
Department of Rheumatology, Puerta de Hierro Hospital-Majadahonda, Madrid, Spain
Department of Rheumatology, Gregorio Marañón University Hospital, Madrid, Spain
-
Hospital General Universitario Gregorio Marañón · Vall d'Hebron Hospital Universitari
Affiliation as printed
Department of Rheumatology, Gregorio Marañón University Hospital, Madrid, Spain
Department of Internal Medicine, Valle de Hebrón Hospital, Barcelona, Spain
-
Hospital Clínic de Barcelona · Corporació Sanitària Parc Taulí
Affiliation as printed
Department of Internal Medicine, Clinic Hospital, Barcelona, Spain
Department of Internal Medicine, Parc Tauli Hospital, Sabadell, Spain
-
Corporació Sanitària Parc Taulí · Hospital Del Mar
Affiliation as printed
Department of Internal Medicine, Parc Tauli Hospital, Sabadell, Spain
Department of Rheumatology, Hospital Del Mar, Barcelona, Spain
-
Affiliation as printed
Department of Rheumatology, Hospital Del Mar, Barcelona, Spain
-
University Hospital Mútua de Terrassa · Hospital Del Mar
Affiliation as printed
Department of Rheumatology, Hospital Del Mar, Barcelona, Spain
Department of Internal Medicine, Hospital Universitari Mútua Terrasa, Barcelona, Spain
-
Bellvitge University Hospital · University Hospital Mútua de Terrassa
Affiliation as printed
Department of Internal Medicine, Hospital Universitari Mútua Terrasa, Barcelona, Spain
Department of Rheumatology, Bellvitge University Hospital, Barcelona, Spain
-
Affiliation as printed
Department of Rheumatology, Bellvitge University Hospital, Barcelona, Spain
-
Bellvitge University Hospital · Hospital General de Granollers
Affiliation as printed
Department of Rheumatology, Bellvitge University Hospital, Barcelona, Spain
Department of Rheumatology, Granollers Hospital, Granollers, Spain
-
Hospital General de Granollers · Hospital General San Jorge
Affiliation as printed
Department of Rheumatology, Granollers Hospital, Granollers, Spain
Department of Internal Medicine, Hospital General San Jorge, Huesca, Spain
-
Universidad de Cantabria · Instituto de Investigación Marqués de Valdecilla · Hospital General San Jorge
Affiliation as printed
Department of Internal Medicine, Hospital General San Jorge, Huesca, Spain
Epidemiology, Genetics and Atherosclerosis Research Group on Systemic Inflammatory Diseases, DIVAL, University of Cantabria, Santander, Spain
-
Universidad de Cantabria · Instituto de Investigación Marqués de Valdecilla · Hospital Universitario Central de Asturias
Affiliation as printed
Epidemiology, Genetics and Atherosclerosis Research Group on Systemic Inflammatory Diseases, DIVAL, University of Cantabria, Santander, Spain
Department of Internal Medicine, Hospital Central de Asturias, Oviedo, Spain
-
Hospital Universitario Central de Asturias · Hospital de Cruces
Affiliation as printed
Department of Internal Medicine, Hospital Central de Asturias, Oviedo, Spain
Department of Internal Medicine, Hospital Universitario Cruces, Barakaldo, Spain
-
Hospital de Cruces · Hospital Virgen del Camino
Affiliation as printed
Department of Internal Medicine, Hospital Universitario Cruces, Barakaldo, Spain
Department of Internal Medicine, Hospital Virgen del Camino, Pamplona, Spain
-
Hospital Universitario Miguel Servet · Hospital Virgen del Camino
Affiliation as printed
Department of Internal Medicine, Hospital Virgen del Camino, Pamplona, Spain
Department of Internal Medicine, Hospital Universitario Miguel Servet, Zaragoza, Spain
-
Hospital Universitario de Canarias · Hospital Universitario Miguel Servet
Affiliation as printed
Department of Internal Medicine, Hospital Universitario Miguel Servet, Zaragoza, Spain
Department of Rheumatology, Hospital Universitario de Canarias, Tenerife, Spain
-
Hospital Universitari i Politècnic La Fe · Hospital Universitario Doctor Peset
Affiliation as printed
Department of Rheumatology, Hospital Universitari i Politecnic La Fe, Valencia, Spain
Department of Rheumatology, Hospital Universitari Doctor Peset, Valencia, Spain
-
University Hospital Complex Of Vigo · Hospital Universitario Doctor Peset
Affiliation as printed
Department of Rheumatology, Hospital Universitari Doctor Peset, Valencia, Spain
Department of Internal Medicine, Thrombosis and Vasculitis Unit, Complexo Hospitalario Universitario de Vigo, Vigo, Spain
-
University Hospital Complex Of Vigo · Instituto de Investigación Biomédica de A Coruña
Affiliation as printed
Department of Internal Medicine, Thrombosis and Vasculitis Unit, Complexo Hospitalario Universitario de Vigo, Vigo, Spain
Department of Rheumatology, INIBIC-Hospital Universitario A Coruña, La Coruña, Spain
-
Medizinische Hochschule Hannover · Instituto de Investigación Biomédica de A Coruña
Affiliation as printed
Department of Rheumatology, INIBIC-Hospital Universitario A Coruña, La Coruña, Spain
Department of Clinical Immunology, Hannover Medical School, Hannover, Germany
-
Medizinische Hochschule Hannover · St. Josef-Hospital · Ruhr University Bochum
Affiliation as printed
Department of Clinical Immunology, Hannover Medical School, Hannover, Germany
Department of Dermatology, Josefs-Hospital, Ruhr University Bochum, Bochum, Germany
-
St. Josef-Hospital · Ruhr University Bochum · University of Lübeck
Affiliation as printed
Department of Dermatology, Josefs-Hospital, Ruhr University Bochum, Bochum, Germany
Clinic of Rheumatology, University of Lübeck, Lübeck, Germany
-
Azienda Socio Sanitaria Territoriale degli Spedali Civili di Brescia · University of Lübeck
Affiliation as printed
Clinic of Rheumatology, University of Lübeck, Lübeck, Germany
Service of Rheumatology and Clinic Immunology Spedali Civili, Brescia, Italy
-
Leiden University Medical Center · Azienda Socio Sanitaria Territoriale degli Spedali Civili di Brescia
Affiliation as printed
Service of Rheumatology and Clinic Immunology Spedali Civili, Brescia, Italy
Department of Rheumatology, Leiden University Medical Center, Leiden, The Netherlands
-
Radboud University Nijmegen · Radboud University Medical Center · Amsterdam UMC Location Vrije Universiteit Amsterdam
Affiliation as printed
Department of Rheumatology, VU University Medical Center, Amsterdam, The Netherlands
Department of Rheumatology, Radboud University Nijmegen Medical Center, Nijmegen, Netherlands
-
Karolinska University Hospital · Lund University · Karolinska Institutet
Affiliation as printed
Department of Rheumatology, Lund University, Lund, Sweden
Division of Rheumatology, Department of Medicine, Karolinska University Hospital, Karolinska Institute, Stockholm, Sweden
-
University of Verona · Karolinska University Hospital · Karolinska Institutet
Affiliation as printed
Division of Rheumatology, Department of Medicine, Karolinska University Hospital, Karolinska Institute, Stockholm, Sweden
Department of Medicine, Università degli Studi di Verona, Verona, Italy
-
University of Verona · Marche Polytechnic University
Affiliation as printed
Department of Medicine, Università degli Studi di Verona, Verona, Italy
Istituto di Clinica Medica Generale, Ematologia ed Immunologia Clinica, Università Politecnica delle Marche, Ancona, Italy
-
Oslo University Hospital · Friedrich-Alexander-Universität Erlangen-Nürnberg · Universitätsklinikum Erlangen
Affiliation as printed
Department of Rheumatology, Oslo University Hospital, Oslo, Norway
Department of Internal Medicine 3, Institute for Clinical Immunology, University of Erlangen-Nuremberg, Erlangen, Germany
-
Karolinska University Hospital · Friedrich-Alexander-Universität Erlangen-Nürnberg · Karolinska Institutet · Universitätsklinikum Erlangen
Affiliation as printed
Department of Internal Medicine 3, Institute for Clinical Immunology, University of Erlangen-Nuremberg, Erlangen, Germany
Division of Rheumatology, Department of Medicine, Karolinska University Hospital, Karolinska Institute, Stockholm, Sweden
-
Karolinska University Hospital · Karolinska Institutet · University Medical Center Utrecht
Affiliation as printed
Division of Rheumatology, Department of Medicine, Karolinska University Hospital, Karolinska Institute, Stockholm, Sweden
Department of Genetics, University Medical Center Utrecht, Utrecht, The Netherlands
-
Royal Adelaide Hospital · University Medical Center Utrecht · The University of Adelaide
Affiliation as printed
Department of Genetics, University Medical Center Utrecht, Utrecht, The Netherlands
Rheumatology Unit, Royal Adelaide Hospital and University of Adelaide, Adelaide, SA, Australia
-
Royal Adelaide Hospital · The University of Melbourne · St Vincent's Hospital Melbourne · The University of Adelaide
Affiliation as printed
Rheumatology Unit, Royal Adelaide Hospital and University of Adelaide, Adelaide, SA, Australia
The University of Melbourne at St. Vincent's Hospital, Melbourne, VIC, Australia
-
The University of Melbourne · St Vincent's Hospital Melbourne
Affiliation as printed
The University of Melbourne at St. Vincent's Hospital, Melbourne, VIC, Australia
-
The University of Melbourne · Monash Medical Centre · St Vincent's Hospital Melbourne · Monash Health
Affiliation as printed
The University of Melbourne at St. Vincent’s Hospital, Melbourne, VIC, Australia
Department Rheumatology, Monash Medical Centre, Melbourne, VIC, Australia
-
University of Tasmania · Royal Perth Hospital
Affiliation as printed
Menzies Research Institute Tasmania, University of Tasmania, Hobart, TAS, Australia
Rheumatology, Royal Perth Hospital, Perth, WA, Australia
-
Monash Medical Centre · Monash Health
Affiliation as printed
Department Rheumatology, Monash Medical Centre, Melbourne, VIC, Australia
Research Unit, Sunshine Coast Rheumatology, Maroochydore, QLD, Australia
-
Affiliation as printed
Rheumatology, Royal Perth Hospital, Perth, WA, Australia
Canberra Rheumatology, Canberra, ACT, Australia
-
Affiliation as printed
Research Unit, Sunshine Coast Rheumatology, Maroochydore, QLD, Australia
Department Rheumatology, The Queen Elizabeth Hospital, Woodville, SA, Australia
-
Affiliation as printed
Canberra Rheumatology, Canberra, ACT, Australia
Department Rheumatology, The Queen Elizabeth Hospital, Woodville, SA, Australia
-
Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico · Queen Elizabeth Hospital
Affiliation as printed
Department Rheumatology, The Queen Elizabeth Hospital, Woodville, SA, Australia
Referral Center for Systemic Autoimmune Diseases, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico di Milano, Milan, Italy
-
Queen Elizabeth Hospital · Centre Hospitalier Régional Universitaire de Brest
Affiliation as printed
Department Rheumatology, The Queen Elizabeth Hospital, Woodville, SA, Australia
Centre Hospitalier Universitaire de Brest, Hospital de la Cavale Blanche, Brest, France
-
Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico · Centre Hospitalier Régional Universitaire de Brest
Affiliation as printed
Referral Center for Systemic Autoimmune Diseases, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico di Milano, Milan, Italy
Centre Hospitalier Universitaire de Brest, Hospital de la Cavale Blanche, Brest, France
-
Centre Hospitalier Régional Universitaire de Brest
Affiliation as printed
Centre Hospitalier Universitaire de Brest, Hospital de la Cavale Blanche, Brest, France
-
Centre Hospitalier Régional Universitaire de Brest
Affiliation as printed
Centre Hospitalier Universitaire de Brest, Hospital de la Cavale Blanche, Brest, France
-
Centre Hospitalier Régional Universitaire de Brest
Affiliation as printed
Centre Hospitalier Universitaire de Brest, Hospital de la Cavale Blanche, Brest, France
-
Centre Hospitalier Régional Universitaire de Brest · UCLouvain · KU Leuven
Affiliation as printed
Centre Hospitalier Universitaire de Brest, Hospital de la Cavale Blanche, Brest, France
Pôle de pathologies rhumatismales systémiques et inflammatoires, Institut de Recherche Expérimentale et Clinique, Université catholique de Louvain, Brussels, Belgium
-
Centre Hospitalier Régional Universitaire de Brest · UCLouvain · KU Leuven
Affiliation as printed
Centre Hospitalier Universitaire de Brest, Hospital de la Cavale Blanche, Brest, France
Pôle de pathologies rhumatismales systémiques et inflammatoires, Institut de Recherche Expérimentale et Clinique, Université catholique de Louvain, Brussels, Belgium
-
Affiliation as printed
Pôle de pathologies rhumatismales systémiques et inflammatoires, Institut de Recherche Expérimentale et Clinique, Université catholique de Louvain, Brussels, Belgium
-
Centro Hospitalar do Porto · UCLouvain · KU Leuven
Affiliation as printed
Pôle de pathologies rhumatismales systémiques et inflammatoires, Institut de Recherche Expérimentale et Clinique, Université catholique de Louvain, Brussels, Belgium
Centro Hospitalar do Porto, Porto, Portugal
-
Centro Hospitalar do Porto · UCLouvain · KU Leuven
Affiliation as printed
Pôle de pathologies rhumatismales systémiques et inflammatoires, Institut de Recherche Expérimentale et Clinique, Université catholique de Louvain, Brussels, Belgium
Centro Hospitalar do Porto, Porto, Portugal
-
Affiliation as printed
Centro Hospitalar do Porto, Porto, Portugal
-
Affiliation as printed
Centro Hospitalar do Porto, Porto, Portugal
-
Affiliation as printed
Centro Hospitalar do Porto, Porto, Portugal
-
Affiliation as printed
Centro Hospitalar do Porto, Porto, Portugal
-
Affiliation as printed
Centro Hospitalar do Porto, Porto, Portugal
-
Affiliation as printed
Centro Hospitalar do Porto, Porto, Portugal
-
Affiliation as printed
Centro Hospitalar do Porto, Porto, Portugal
-
Universidad de Cantabria · Instituto de Investigación Marqués de Valdecilla · Centro Hospitalar do Porto
Affiliation as printed
Centro Hospitalar do Porto, Porto, Portugal
Epidemiology, Genetics and Atherosclerosis Research Group on Systemic Inflammatory Diseases, DIVAL, University of Cantabria, Santander, Spain
-
Universidad de Cantabria · Instituto de Investigación Marqués de Valdecilla · Centro Hospitalar do Porto
Affiliation as printed
Centro Hospitalar do Porto, Porto, Portugal
Epidemiology, Genetics and Atherosclerosis Research Group on Systemic Inflammatory Diseases, DIVAL, University of Cantabria, Santander, Spain
-
Universidad de Cantabria · Instituto de Investigación Marqués de Valdecilla · Hospital Clínic de Barcelona
Affiliation as printed
Epidemiology, Genetics and Atherosclerosis Research Group on Systemic Inflammatory Diseases, DIVAL, University of Cantabria, Santander, Spain
Department of Internal Medicine, Clinic Hospital, Barcelona, Spain
-
Universidad de Cantabria · Instituto de Investigación Marqués de Valdecilla · Hospital Clínic de Barcelona
Affiliation as printed
Epidemiology, Genetics and Atherosclerosis Research Group on Systemic Inflammatory Diseases, DIVAL, University of Cantabria, Santander, Spain
Department of Internal Medicine, Clinic Hospital, Barcelona, Spain
-
Affiliation as printed
Department of Internal Medicine, Clinic Hospital, Barcelona, Spain
-
Hospital Clínic de Barcelona · KU Leuven
Affiliation as printed
Department of Internal Medicine, Clinic Hospital, Barcelona, Spain
Katholieke Universiteit Leuven, Leuven, Belgium
-
University of Cologne · KU Leuven
Affiliation as printed
Katholieke Universiteit Leuven, Leuven, Belgium
Department of Dermatology, University of Cologne, Cologne, Germany
-
Medizinische Hochschule Hannover · KU Leuven
Affiliation as printed
Katholieke Universiteit Leuven, Leuven, Belgium
Department of Clinical Immunology, Hannover Medical School, Hannover, Germany
-
University of Cologne · Medizinische Hochschule Hannover
Affiliation as printed
Department of Dermatology, University of Cologne, Cologne, Germany
Department of Clinical Immunology, Hannover Medical School, Hannover, Germany
-
Medizinische Hochschule Hannover · Medical University of Vienna
Affiliation as printed
Department of Clinical Immunology, Hannover Medical School, Hannover, Germany
Medical University Vienna, Vienna, Austria
-
Medizinische Hochschule Hannover · Medical University of Vienna
Affiliation as printed
Department of Clinical Immunology, Hannover Medical School, Hannover, Germany
Medical University Vienna, Vienna, Austria
-
Affiliation as printed
Medical University Vienna, Vienna, Austria
-
Andalusian Health Service · Hospital Universitario Reina Sofía · Medical University of Vienna
Affiliation as printed
Medical University Vienna, Vienna, Austria
Servicio Andaluz de Salud, Hospital Universitario Reina Sofía Córdoba, Córdoba, Spain
Cited by 18 stored of 18
18 results
No patents citing this paper on Lens.org (checked 2026-10-11).