Distinct Effects of Complement C4A and C4B Copy Numbers in Systemic Sclerosis Serological and Clinical Subtypes
Arthritis & Rheumatology, vol. 78, pp. 904–913
Abstract
Objective Complement component 4 (C4), encoded by C4A and C4B within the major histocompatibility complex (MHC) on chromosome 6, regulates the immune response and clears immune complexes. The variable copy number (CN) of C4 genes and retroviral human endogenous retrovirus K (HERV‐K) element influence its function. Given the relationship of C4 CN with systemic sclerosis (SSc) risk, we assessed associations with SSc clinical and serologic subtypes. Methods We compared imputed C4 CNs across SSc subgroups (4,049 anticentromere positive [ACA + ]; 2,200 anti–topoisomerase I [ATA + ]; 577 anti‐RNA polymerase [ARA + ]; 1,078 triple‐negative [TN] patients; 6,295 limited cutaneous SSc [lcSSc]; and 2,946 diffuse cutaneous SSc [dcSSc]) and 17,991 controls. We evaluated associations with SSc subtypes, identifying C4 ‐independent HLA alleles. Results Lower C4 CN and higher HERV‐K CN were associated with increased risk in all SSc subgroups. ATA + patients showed the strongest association, particularly with C4A (odds ratio = 1.88), and differences in C4A CN association were more pronounced between autoantibody subgroups (ATA + vs ACA + , P = 4 × 10 −11 ) than between clinical subgroups (dcSSc vs lcSSc, P = 1 × 10 −4 ). In ACA + patients, only low C4B CN showed a significant association to SSc risk ( P = 1.23 × 10 −5 ). We also observed sex‐biased associations: dcSSc, ATA + , and ARA + male patients showed stronger effects for C4A and ACA + and lcSSc female patients for C4B . Finally, our results suggest that the HLA alleles associated with SSc subgroups are independent of C4 CN. Conclusion This study highlights distinct genetic contributions of C4A and C4B in SSc subtypes susceptibility. Our findings suggest that lower C4 CNs, particularly C4A , increase the risk of the severe dcSSc subtype, potentially through a mechanism involving immune complex clearance. image
Authors 21
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Javier Martínez‐López corresponding
Consejo Superior de Investigaciones Científicas · Instituto de Investigación Biosanitaria de Granada · Instituto de Parasitología y Biomedicina "López - Neyra"
Affiliation as printed
Institute of Parasitology and Biomedicine López‐Neyra, Consejo Superior de Investigaciones Cientificas Granada Spain
Systemic Autoimmune Disease Unit, Hospital Universitario Clínico San Cecilio, Instituto de Investigación Biosanitaria Granada Spain
Institute of Parasitology and Biomedicine López‐Neyra CSIC 18016 Granada Spain
Systemic Autoimmune Disease Unit, Hospital Clínico San Cecilio, Instituto de Investigación Biosanitaria Ibs. GRANADA Granada Spain
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Consejo Superior de Investigaciones Científicas · Instituto de Parasitología y Biomedicina "López - Neyra"
Affiliation as printed
Institute of Parasitology and Biomedicine López‐Neyra, Consejo Superior de Investigaciones Cientificas Granada Spain
Institute of Parasitology and Biomedicine López‐Neyra CSIC 18016 Granada Spain
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Consejo Superior de Investigaciones Científicas · Instituto de Parasitología y Biomedicina "López - Neyra"
Affiliation as printed
Institute of Parasitology and Biomedicine López‐Neyra, Consejo Superior de Investigaciones Cientificas Granada Spain
Institute of Parasitology and Biomedicine López‐Neyra CSIC 18016 Granada Spain
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Vall d'Hebron Hospital Universitari
Affiliation as printed
Unit of Systemic Autoimmune Diseases, Department of Internal Medicine, Hospital Universitari Vall d'Hebron Barcelona Spain
Unit of Systemic Autoimmune Diseases, Department of Internal Medicine, Hospital Universitari Vall d'Hebron, Barcelona, Spain
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Vall d'Hebron Hospital Universitari
Affiliation as printed
Unit of Systemic Autoimmune Diseases, Department of Internal Medicine, Hospital Universitari Vall d'Hebron Barcelona Spain
Unit of Systemic Autoimmune Diseases, Department of Internal Medicine, Hospital Universitari Vall d'Hebron, Barcelona, Spain
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Instituto de Investigación Biosanitaria de Granada
Affiliation as printed
Systemic Autoimmune Disease Unit, Hospital Universitario Clínico San Cecilio, Instituto de Investigación Biosanitaria Granada Spain
Systemic Autoimmune Disease Unit, Hospital Clínico San Cecilio, Instituto de Investigación Biosanitaria Ibs. GRANADA Granada Spain
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The University of Sydney · Royal Adelaide Hospital · The University of Melbourne · The University of Adelaide
Affiliation as printed
Royal Adelaide Hospital and the University of Adelaide Adelaide South Australia Australia
Department of Medicine, University of Melbourne, Fitzroy, Victoria, Australia
The University of Sydney School of Public Health, Sydney, New South Wales, Australia
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The University of Sydney · The University of Melbourne · University of Cologne
Affiliation as printed
Department of Medicine University of Melbourne Fitzroy Victoria Australia
The University of Sydney School of Public Health, Sydney New South Wales Australia
Department of Dermatology, University of Cologne, Cologne, Germany
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University of Cologne · Leiden University Medical Center
Affiliation as printed
Department of Dermatology University of Cologne Cologne Germany
The Department of Rheumatology, Leiden University Medical Center, Leiden, the Netherlands
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Marche Polytechnic University · Manchester Academic Health Science Centre · University of Manchester · Azienda Ospedaliero-Universitaria delle Marche · Northern Care Alliance NHS Foundation Trust
Affiliation as printed
Department of Clinical and Molecular Science Marche Polytechnic University Ancona Italy
Department of Internal Medicine Marche University Hospital Ancona Italy
The University of Manchester, Northern Care Alliance NHS Foundation Trust, Manchester Academic Health Science Centre, Manchester, United Kingdom
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Jeska Kirsten De Vries-Bouwstra Aachen Department of Rheumatology Leiden University Medical Center Leiden The Netherlands
Université Paris Cité · Leiden University Medical Center
Affiliation as printed
The Department of Rheumatology Leiden University Medical Center Leiden the Netherlands
Department of Rheumatology Université Paris Cité UFR de Médecine Paris France
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Universidad de Granada · Manchester Academic Health Science Centre · University of Manchester · Pfizer-University of Granada-Junta de Andalucía Centre for Genomics and Oncological Research · Northern Care Alliance NHS Foundation Trust
Affiliation as printed
The University of Manchester, Northern Care Alliance NHS Foundation Trust, Manchester Academic Health Science Centre Manchester United Kingdom
Centre for Genomics and Oncological Research, Pfizer, University of Granada/Andalusian Regional Government, Granada, Spain
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Université Paris Cité · Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico
Affiliation as printed
Department of Rheumatology Université Paris Cité UFR de Médecine Paris France
Scleroderma Unit, Referral Center for Systemic Autoimmune Diseases, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico di Milano, Milan, Italy
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Universidad de Granada · Pfizer-University of Granada-Junta de Andalucía Centre for Genomics and Oncological Research · The University of Texas Health Science Center at Houston
Affiliation as printed
Centre for Genomics and Oncological Research, Pfizer, University of Granada/Andalusian Regional Government Granada Spain
Department of Internal Medicine, Division of Rheumatology, The University of Texas Health Science Center at Houston, Houston, TX, USA
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The Royal Free Hospital · Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico · University College London
Affiliation as printed
Scleroderma Unit, Referral Center for Systemic Autoimmune Diseases, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico di Milano Milan Italy
Centre for Rheumatology, Royal Free Hospital, UCL, London, UK
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The University of Texas Health Science Center at Houston
Affiliation as printed
Department of Internal Medicine, Division of Rheumatology The University of Texas Health Science Center at Houston
Department of Internal Medicine, Division of Rheumatology, The University of Texas Health Science Center at Houston, Houston, TX, USA
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Consejo Superior de Investigaciones Científicas · The Royal Free Hospital · Instituto de Parasitología y Biomedicina "López - Neyra" · University College London
Affiliation as printed
Centre for Rheumatology, Royal Free Hospital University College London London United Kingdom
Institute of Parasitology and Biomedicine López‐Neyra CSIC 18016 Granada Spain
These authors share senior authorship
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Consejo Superior de Investigaciones Científicas · Instituto de Parasitología y Biomedicina "López - Neyra" · The University of Texas Health Science Center at Houston
Affiliation as printed
Department of Internal Medicine, Division of Rheumatology The University of Texas Health Science Center at Houston
Institute of Parasitology and Biomedicine López‐Neyra CSIC 18016 Granada Spain
These authors share senior authorship
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Consejo Superior de Investigaciones Científicas · Instituto de Parasitología y Biomedicina "López - Neyra"
Affiliation as printed
Institute of Parasitology and Biomedicine López‐Neyra, Consejo Superior de Investigaciones Cientificas Granada Spain
Institute of Parasitology and Biomedicine López‐Neyra CSIC 18016 Granada Spain
These authors share senior authorship
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Consejo Superior de Investigaciones Científicas · Instituto de Parasitología y Biomedicina "López - Neyra"
Affiliation as printed
Institute of Parasitology and Biomedicine López‐Neyra, Consejo Superior de Investigaciones Cientificas Granada Spain
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Consejo Superior de Investigaciones Científicas · Instituto de Parasitología y Biomedicina "López - Neyra"
Affiliation as printed
Institute of Parasitology and Biomedicine López‐Neyra, Consejo Superior de Investigaciones Cientificas Granada Spain
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