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No variants were identified in controls.<\/jats:p><\/jats:sec><jats:sec><jats:title>Setting<\/jats:title><jats:p>Pre\u2010eclampsia is a leading cause of maternal and fetal morbidity and mortality. Immune maladaptation, in particular, complement activation that disrupts maternal\u2010fetal tolerance leading to placental dysfunction and endothelial injury, has been proposed as a pathogenetic mechanism, but this remains unproven.<\/jats:p><\/jats:sec><jats:sec><jats:title>Population<\/jats:title><jats:p>We genotyped 609 pre\u2010eclampsia cases and 2092 controls from FINNPEC and the national FINRISK cohorts.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>Complement\u2010based functional and structural assays were conducted in vitro to define the significance of these five missense variants and each compared with wild type.<\/jats:p><\/jats:sec><jats:sec><jats:title>Main outcome measures<\/jats:title><jats:p>Secretion, expression and ability to regulate complement activation were assessed for factor H proteins harbouring the mutations.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>We identified five heterozygous rare variants in complement factor H (L3V, R127H, R166Q, C1077S and N1176K) in seven women with severe pre\u2010eclampsia. These variants were not identified in controls. Variants C1077S and N1176K were novel. Antigenic, functional and structural analyses established that four (R127H, R166Q, C1077S and N1176K) were deleterious. Variants R127H and C1077S were synthesised, but not secreted. Variants R166Q and N1176K were secreted normally but showed reduced binding to C3b and consequently defective complement regulatory activity. No defect was identified for L3V.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions<\/jats:title><jats:p>These results suggest that complement dysregulation due to mutations in complement factor H is among the pathophysiological mechanisms underlying severe pre\u2010eclampsia.<\/jats:p><\/jats:sec>","DOI":"10.1111\/1471-0528.17529","type":"journal-article","created":{"date-parts":[[2023,5,9]],"date-time":"2023-05-09T02:53:43Z","timestamp":1683600823000},"page":"1473-1482","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":19,"title":["Identification of complement factor H variants that predispose to pre\u2010eclampsia: A genetic and functional study"],"prefix":"10.1111","volume":"130","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-4397-8415","authenticated-orcid":false,"given":"A. Inkeri","family":"Lokki","sequence":"first","affiliation":[{"name":"Immunobiology Research Program, Bacteriology and Immunology University of Helsinki and Helsinki University Hospital  Helsinki Finland"},{"name":"Heart and Lung Centre Helsinki University Hospital  Helsinki Finland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhen","family":"Ren","sequence":"additional","affiliation":[{"name":"Division of Clinical Immunology and Allergy, Department of Medicine Washington University School of Medicine  St. Louis Missouri USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael","family":"Triebwasser","sequence":"additional","affiliation":[{"name":"Division of Pediatric Hematology and Oncology, Department of Pediatrics University of Michigan  Ann Arbor Michigan USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Emma","family":"Daly","sequence":"additional","affiliation":[{"name":"Hospital and Harvard Medical School  Boston 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