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Here, we assessed whether CN variation within the\n C4<\/jats:italic>\n gene contributes to giant cell arteritis (GCA) and IgA vasculitis (IgAV), two complex vasculitides involving complement dysregulation.\n <\/jats:p>\n <\/jats:sec>\n \n Methods<\/jats:title>\n \n C4A<\/jats:italic>\n ,\n C4B<\/jats:italic>\n , and\n HERV\u2010K<\/jats:italic>\n CNs were imputed from genotypic data of 3,498 patients with GCA, 284 patients with IgAV, and 16,867 controls. We evaluated their associations with vasculitis risk overall and stratified by sex (inferred from genetic data), alongside classical HLA alleles.\n <\/jats:p>\n <\/jats:sec>\n \n Results<\/jats:title>\n \n Contrary to other IMIDs, we identified higher\n C4<\/jats:italic>\n CN to confer risk to GCA and IgAV. Specifically, in GCA, higher\n C4B<\/jats:italic>\n CN conferred risk in male patients (odds ratio (OR) 1.23, 95% confidence interval (CI) 1.07\u20131.42,\n P<\/jats:italic>\n \u00a0=\u00a04.52\u2009\u00d7\u200910\n \u22123<\/jats:sup>\n ,\n P<\/jats:italic>\n adjusted by false discovery rate (\n P<\/jats:italic>\n FDR<\/jats:sub>\n )\u00a0=\u00a01.40\u2009\u00d7\u200910\n \u22122<\/jats:sup>\n ). In IgAV, elevated\n C4A<\/jats:italic>\n CN was significantly associated with disease susceptibility in the overall cohort (OR 1.68, 95% CI 1.22\u20132.30,\n P<\/jats:italic>\n \u00a0=\u00a01.49\u2009\u00d7\u200910\n \u22123<\/jats:sup>\n ,\n P<\/jats:italic>\n FDR<\/jats:sub>\n \u00a0=\u00a04.48\u2009\u00d7\u200910\n \u22123<\/jats:sup>\n ), whereas\n C4B<\/jats:italic>\n CN showed a male\u2010biased trend, as observed in GCA (OR 1.46, 95% CI 1.02\u20132.08,\n P<\/jats:italic>\n \u00a0=\u00a03.88\u2009\u00d7\u200910\n \u22122<\/jats:sup>\n ,\n P<\/jats:italic>\n FDR<\/jats:sub>\n \u00a0=\u00a05.80\u2009\u00d7\u200910\n \u22122<\/jats:sup>\n ). Conditional analyses confirmed that these associations were independent of classical HLA alleles.\n <\/jats:p>\n <\/jats:sec>\n \n Conclusion<\/jats:title>\n \n This study reveals sex\u2010dependent variation in\n C4<\/jats:italic>\n CN as a novel genetic risk factor for GCA and IgAV, suggesting shared biologic mechanisms involving complement dysregulation, sustained inflammation, and vascular damage.\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.70203","type":"journal-article","created":{"date-parts":[[2026,4,28]],"date-time":"2026-04-28T03:36:12Z","timestamp":1777347372000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Higher Complement\n \n C4<\/i>\n <\/scp>\n Gene Copy Number Constitutes a Shared Genetic Risk Factor for Giant Cell Arteritis and\n IgA<\/scp>\n Vasculitis"],"prefix":"10.1002","author":[{"ORCID":"https:\/\/orcid.org\/0009-0006-3291-5821","authenticated-orcid":false,"given":"Laura","family":"Mart\u00ednez\u2010Guti\u00e9rrez","sequence":"first","affiliation":[{"name":"Institute of Parasitology and Biomedicine L\u00f3pez\u2010Neyra Spanish National Research Council Granada Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1474-2884","authenticated-orcid":false,"given":"Gonzalo","family":"Borrego\u2010Yaniz","sequence":"additional","affiliation":[{"name":"Institute of Parasitology and Biomedicine L\u00f3pez\u2010Neyra Spanish National Research Council Granada Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jos\u00e9","family":"Hern\u00e1ndez\u2010Rodr\u00edguez","sequence":"additional","affiliation":[{"name":"Vasculitis Research Unit, Department of Autoimmune Diseases, Hospital Clinic of Barcelona University of Barcelona, and Institut d'Investigacions Biom\u00e8diques August Pi i Sunyer Barcelona Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3708-3148","authenticated-orcid":false,"given":"Carlo","family":"Salvarani","sequence":"additional","affiliation":[{"name":"Azienda USLIRCCS di Reggio Emilia and Universit\u00e0 di Modena e Reggio Emilia Reggio Emilia Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mar\u00eda Cinta","family":"Cid","sequence":"additional","affiliation":[{"name":"Vasculitis Research Unit, Department of Autoimmune Diseases, Hospital Clinic of Barcelona University of Barcelona, and Institut d'Investigacions Biom\u00e8diques August Pi i Sunyer Barcelona Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ann W.","family":"Morgan","sequence":"additional","affiliation":[{"name":"Leeds Institute of Cardiovascular and Metabolic Medicine University of Leeds Leeds United Kingdom"},{"name":"NIHR Leeds Biomedical Research Centre Leeds Teaching Hospitals NHS Trust Leeds United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"name":"International GCA Consortium","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"name":"UK GCA Consortium","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7924-7406","authenticated-orcid":false,"given":"Miguel \u00c1ngel","family":"Gonz\u00e1lez\u2010Gay","sequence":"additional","affiliation":[{"name":"Division of Rheumatology Instituto de Investigaci\u00f3n Sanitaria Fundaci\u00f3n Jim\u00e9nez D\u00edaz Madrid Spain"},{"name":"Department of Medicine University of Cantabria Santander Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Javier","family":"Mart\u00edn","sequence":"additional","affiliation":[{"name":"Institute of Parasitology and Biomedicine L\u00f3pez\u2010Neyra Spanish National Research Council Granada 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