{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,20]],"date-time":"2026-08-20T00:58:11Z","timestamp":1787187491074,"version":"build-2736575974"},"reference-count":37,"publisher":"Wiley","issue":"4","license":[{"start":{"date-parts":[[2026,2,18]],"date-time":"2026-02-18T00:00:00Z","timestamp":1771372800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"},{"start":{"date-parts":[[2026,2,18]],"date-time":"2026-02-18T00:00:00Z","timestamp":1771372800000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"funder":[{"DOI":"10.13039\/501100004587","name":"Instituto de Salud Carlos III","doi-asserted-by":"publisher","award":["FI23\/00231"],"award-info":[{"award-number":["FI23\/00231"]}],"id":[{"id":"10.13039\/501100004587","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100004587","name":"Instituto de Salud Carlos III","doi-asserted-by":"publisher","award":["PI22\/00092"],"award-info":[{"award-number":["PI22\/00092"]}],"id":[{"id":"10.13039\/501100004587","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100004587","name":"Instituto de Salud Carlos III","doi-asserted-by":"publisher","award":["RD21\/0002\/0039"],"award-info":[{"award-number":["RD21\/0002\/0039"]}],"id":[{"id":"10.13039\/501100004587","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100004587","name":"Instituto de Salud Carlos III","doi-asserted-by":"publisher","award":["RD24\/0007\/0016"],"award-info":[{"award-number":["RD24\/0007\/0016"]}],"id":[{"id":"10.13039\/501100004587","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["acrjournals.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Arthritis & Rheumatology"],"published-print":{"date-parts":[[2026,4]]},"abstract":"\n Objective<\/jats:title>\n \n Complement component 4 (C4), encoded by\n C4A<\/jats:italic>\n and\n C4B<\/jats:italic>\n 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\u2010K) element influence its function. Given the relationship of C4 CN with systemic sclerosis (SSc) risk, we assessed associations with SSc clinical and serologic subtypes.\n <\/jats:p>\n <\/jats:sec>\n \n Methods<\/jats:title>\n \n We compared imputed\n C4<\/jats:italic>\n CNs across SSc subgroups (4,049 anticentromere positive [ACA\n +<\/jats:sup>\n ]; 2,200 anti\u2013topoisomerase I [ATA\n +<\/jats:sup>\n ]; 577 anti\u2010RNA polymerase [ARA\n +<\/jats:sup>\n ]; 1,078 triple\u2010negative [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\n C4<\/jats:italic>\n \u2010independent HLA alleles.\n <\/jats:p>\n <\/jats:sec>\n \n Results<\/jats:title>\n \n Lower\n C4<\/jats:italic>\n CN and higher HERV\u2010K CN were associated with increased risk in all SSc subgroups. ATA\n +<\/jats:sup>\n patients showed the strongest association, particularly with\n C4A<\/jats:italic>\n (odds ratio = 1.88), and differences in\n C4A CN<\/jats:italic>\n association were more pronounced between autoantibody subgroups (ATA\n +<\/jats:sup>\n vs ACA\n +<\/jats:sup>\n ,\n P<\/jats:italic>\n = 4 \u00d7 10\n \u221211<\/jats:sup>\n ) than between clinical subgroups (dcSSc vs lcSSc,\n P<\/jats:italic>\n = 1 \u00d7 10\n \u22124<\/jats:sup>\n ). In ACA\n +<\/jats:sup>\n patients, only low\n C4B<\/jats:italic>\n CN showed a significant association to SSc risk (\n P<\/jats:italic>\n = 1.23 \u00d7 10\n \u22125<\/jats:sup>\n ). We also observed sex\u2010biased associations: dcSSc, ATA\n +<\/jats:sup>\n , and ARA\n +<\/jats:sup>\n male patients showed stronger effects for\n C4A<\/jats:italic>\n and ACA\n +<\/jats:sup>\n and lcSSc female patients for\n C4B<\/jats:italic>\n . Finally, our results suggest that the HLA alleles associated with SSc subgroups are independent of C4 CN.\n <\/jats:p>\n <\/jats:sec>\n \n Conclusion<\/jats:title>\n \n This study highlights distinct genetic contributions of\n C4A<\/jats:italic>\n and\n C4B<\/jats:italic>\n in SSc subtypes susceptibility. Our findings suggest that lower\n C4<\/jats:italic>\n CNs, particularly\n C4A<\/jats:italic>\n , increase the risk of the severe dcSSc subtype, potentially through a mechanism involving immune complex clearance.\n <\/jats:p>\n \n \n \n image<\/jats:alt-text>\n <\/jats:graphic>\n <\/jats:boxed-text>\n <\/jats:p>\n <\/jats:sec>","DOI":"10.1002\/art.43433","type":"journal-article","created":{"date-parts":[[2025,11,14]],"date-time":"2025-11-14T16:59:11Z","timestamp":1763139551000},"page":"904-913","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["Distinct Effects of Complement\n \n C4A<\/i>\n <\/scp>\n and\n \n C4B<\/i>\n <\/scp>\n Copy Numbers in Systemic Sclerosis Serological and Clinical Subtypes"],"prefix":"10.1002","volume":"78","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-0184-9543","authenticated-orcid":false,"given":"Javier","family":"Mart\u00ednez\u2010L\u00f3pez","sequence":"first","affiliation":[{"name":"Institute of Parasitology and Biomedicine L\u00f3pez\u2010Neyra, Consejo Superior de Investigaciones Cientificas Granada Spain"},{"name":"Systemic Autoimmune Disease Unit, Hospital Universitario Cl\u00ednico San Cecilio, Instituto de Investigaci\u00f3n Biosanitaria Granada Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7697-1696","authenticated-orcid":false,"given":"Carlos","family":"Rangel\u2010Pel\u00e1ez","sequence":"additional","affiliation":[{"name":"Institute of Parasitology and Biomedicine L\u00f3pez\u2010Neyra, Consejo Superior de Investigaciones Cientificas Granada Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Inmaculada","family":"Rodriguez\u2010Martin","sequence":"additional","affiliation":[{"name":"Institute of Parasitology and Biomedicine L\u00f3pez\u2010Neyra, Consejo Superior de Investigaciones Cientificas Granada Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alfredo","family":"Guillen\u2010Del\u2010Castillo","sequence":"additional","affiliation":[{"name":"Unit of Systemic Autoimmune Diseases, Department of Internal Medicine, Hospital Universitari Vall d'Hebron Barcelona Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Carmen P","family":"Sime\u00f3n\u2010Aznar","sequence":"additional","affiliation":[{"name":"Unit of Systemic Autoimmune Diseases, Department of Internal Medicine, Hospital Universitari Vall d'Hebron Barcelona Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jos\u00e9 L","family":"Callejas","sequence":"additional","affiliation":[{"name":"Systemic Autoimmune Disease Unit, Hospital Universitario Cl\u00ednico San Cecilio, Instituto de Investigaci\u00f3n Biosanitaria Granada Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0546-8310","authenticated-orcid":false,"given":"Oliver","family":"Distler","sequence":"additional","affiliation":[{"name":"Department of Rheumatology University Hospital Zurich, University of Zurich Zurich Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"name":"International SSc Group","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"name":"PRECISESADs Clinical Consortium","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3046-9884","authenticated-orcid":false,"given":"Susanna M","family":"Proudman","sequence":"additional","affiliation":[{"name":"Royal Adelaide Hospital and the University of Adelaide Adelaide South Australia Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mandana","family":"Nikpour","sequence":"additional","affiliation":[{"name":"Department of Medicine University of Melbourne Fitzroy Victoria Australia"},{"name":"The University of Sydney School of Public Health, Sydney New South Wales Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"name":"Australian Scleroderma Interest Group (ASIG)","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nicolas","family":"Hunzelmann","sequence":"additional","affiliation":[{"name":"Department of Dermatology University of Cologne Cologne Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gianluca","family":"Moroncini","sequence":"additional","affiliation":[{"name":"Department of Clinical and Molecular Science Marche Polytechnic University Ancona Italy"},{"name":"Department of Internal Medicine Marche University Hospital Ancona Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jeska K","family":"de Vries\u2010Bouwstra","sequence":"additional","affiliation":[{"name":"The Department of Rheumatology Leiden University Medical Center Leiden the Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4941-7926","authenticated-orcid":false,"given":"Ariane L","family":"Herrick","sequence":"additional","affiliation":[{"name":"The University of Manchester, Northern Care Alliance NHS Foundation Trust, Manchester Academic Health Science Centre Manchester United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yannick","family":"Allanore","sequence":"additional","affiliation":[{"name":"Department of Rheumatology Universit\u00e9 Paris Cit\u00e9 UFR de M\u00e9decine Paris 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