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Med."],"abstract":"<jats:title>Abstract<\/jats:title><jats:p>Copy number (CN) polymorphisms of complement<jats:italic>C4<\/jats:italic>play distinct roles in many conditions, including immune-mediated diseases. We investigated the association of<jats:italic>C4<\/jats:italic>CN with systemic sclerosis (SSc) risk. Imputed total<jats:italic>C4, C4A<\/jats:italic>,<jats:italic>C4B<\/jats:italic>, and HERV-K CN were analyzed in 26,633 individuals and validated in an independent cohort. Our results showed that higher<jats:italic>C4<\/jats:italic>CN confers protection to SSc, and deviations from CN parity of<jats:italic>C4A<\/jats:italic>and<jats:italic>C4B<\/jats:italic>augmented risk. The protection contributed per copy of<jats:italic>C4A<\/jats:italic>and<jats:italic>C4B<\/jats:italic>differed by sex. Stronger protection was afforded by<jats:italic>C4A<\/jats:italic>in men and by<jats:italic>C4B<\/jats:italic>in women.<jats:italic>C4<\/jats:italic>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<jats:italic>C4<\/jats:italic>genetics strongly contributes to the SSc association within the major histocompatibility complex locus and highlights classical alleles and amino acid variants of<jats:italic>HLA-DRB1<\/jats:italic>and<jats:italic>HLA-DPB1<\/jats:italic>as<jats:italic>C4<\/jats:italic>-independent signals.<\/jats:p>","DOI":"10.1038\/s41525-022-00327-8","type":"journal-article","created":{"date-parts":[[2022,10,5]],"date-time":"2022-10-05T05:02:39Z","timestamp":1664946159000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":12,"title":["Complement component C4 structural variation and quantitative traits contribute to sex-biased vulnerability in systemic sclerosis"],"prefix":"10.1038","volume":"7","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-6298-4514","authenticated-orcid":false,"given":"Martin","family":"Kerick","sequence":"first","affiliation":[]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9868-6535","authenticated-orcid":false,"given":"Marialbert","family":"Acosta-Herrera","sequence":"additional","affiliation":[]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3390-9029","authenticated-orcid":false,"given":"Carmen Pilar","family":"Sime\u00f3n-Aznar","sequence":"additional","affiliation":[]},{"given":"Jos\u00e9 Luis","family":"Callejas","sequence":"additional","affiliation":[]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8059-9978","authenticated-orcid":false,"given":"Shervin","family":"Assassi","sequence":"additional","affiliation":[]},{"name":"International SSc Group","sequence":"additional","affiliation":[]},{"given":"P.","family":"Carreira","sequence":"additional","affiliation":[]},{"given":"I.","family":"Castellvi","sequence":"additional","affiliation":[]},{"given":"R.","family":"R\u00edos","sequence":"additional","affiliation":[]},{"given":"R. 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