{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,17]],"date-time":"2026-08-17T14:31:53Z","timestamp":1786977113526,"version":"build-2736575974"},"reference-count":40,"publisher":"Wiley","issue":"11","license":[{"start":{"date-parts":[[2022,10,7]],"date-time":"2022-10-07T00:00:00Z","timestamp":1665100800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100003426","name":"G\u00f6ran Gustafssons Stiftelse f\u00f6r Naturvetenskaplig och Medicinsk Forskning","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100003426","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100007857","name":"Stiftelsen Konung Gustaf V:s 80-\u00e5rsfond","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100007857","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100003793","name":"Hj\u00e4rt-Lungfonden","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100003793","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100007949","name":"Reumatikerf\u00f6rbundet","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100007949","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100003748","name":"Svenska S\u00e4llskapet f\u00f6r Medicinsk Forskning","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100003748","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100007687","name":"Svenska L\u00e4kares\u00e4llskapet","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100007687","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":[[2022,11]]},"abstract":"\n Objective<\/jats:title>\n \n Complete genetic deficiency of the complement component\n C2<\/jats:italic>\n is a strong risk factor for monogenic systemic lupus erythematosus (SLE), but whether heterozygous\n C2<\/jats:italic>\n deficiency adds to the risk of SLE or primary Sj\u00f6gren's syndrome (SS) has not been studied systematically. This study was undertaken to investigate potential associations of heterozygous\n C2<\/jats:italic>\n deficiency and\n C4<\/jats:italic>\n copy number variation with clinical manifestations in patients with SLE and patients with primary SS.\n <\/jats:p>\n <\/jats:sec>\n \n Methods<\/jats:title>\n \n The presence of the common 28\u2010bp\n C2<\/jats:italic>\n deletion rs9332736 and\n C4<\/jats:italic>\n copy number variation was examined in Scandinavian patients who had received a diagnosis of SLE (n\u00a0=\u00a0958) or primary SS (n\u00a0=\u00a0911) and in 2,262 healthy controls through the use of DNA sequencing. The concentration of complement proteins in plasma and classical complement function were analyzed in a subgroup of SLE patients.\n <\/jats:p>\n <\/jats:sec>\n \n Results<\/jats:title>\n \n Heterozygous\n C2<\/jats:italic>\n deficiency\n \u2014<\/jats:bold>\n when present in combination with a low\n C4A<\/jats:italic>\n copy number\n \u2014<\/jats:bold>\n substantially increased the risk of SLE (odds ratio [OR] 10.2 [95% confidence interval (95% CI) 3.5\u201337.0]) and the risk of primary SS (OR 13.0 [95% CI 4.5\u201348.4]) when compared to individuals with 2\n C4A<\/jats:italic>\n copies and normal\n C2<\/jats:italic>\n . For patients heterozygous for rs9332736 with 1\n C4A<\/jats:italic>\n copy, the median age at diagnosis was 7\u2009years earlier in patients with SLE and 12\u2009years earlier in patients with primary SS when compared to patients with normal\n C2<\/jats:italic>\n . Reduced C2 levels in plasma (\n P<\/jats:italic>\n \u00a0=\u00a02\u2009\u00d7\u200910\n \u22129<\/jats:sup>\n ) and impaired function of the classical complement pathway (\n P<\/jats:italic>\n \u00a0=\u00a00.03) were detected in SLE patients with heterozygous\n C2<\/jats:italic>\n deficiency. Finally, in a primary SS patient homozygous for\n C2<\/jats:italic>\n deficiency, we observed low levels of anti\u2013Scl\u201070, which suggests a risk of developing systemic sclerosis or potential overlap between primary SS and other systemic autoimmune diseases.\n <\/jats:p>\n <\/jats:sec>\n \n Conclusion<\/jats:title>\n \n We demonstrate that a genetic pattern involving partial deficiencies of\n C2<\/jats:italic>\n and\n C4A<\/jats:italic>\n in the classical complement pathway is a strong risk factor for SLE and for primary SS. Our results emphasize the central role of the complement system in the pathogenesis of both SLE and primary SS.\n <\/jats:p>\n <\/jats:sec>","DOI":"10.1002\/art.42270","type":"journal-article","created":{"date-parts":[[2022,6,21]],"date-time":"2022-06-21T23:59:21Z","timestamp":1655855961000},"page":"1842-1850","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":36,"title":["Strong Association of Combined Genetic Deficiencies in the Classical Complement Pathway With Risk of Systemic Lupus Erythematosus and Primary Sj\u00f6gren's Syndrome"],"prefix":"10.1002","volume":"74","author":[{"given":"Christian","family":"Lundtoft","sequence":"first","affiliation":[{"name":"Department of Medical Sciences, Rheumatology Uppsala University Uppsala Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christopher","family":"Sj\u00f6wall","sequence":"additional","affiliation":[{"name":"Division of Inflammation and Infection, 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