Identification of complement factor H variants that predispose to pre‐eclampsia: A genetic and functional study

• Published in: BJOG : an international journal of obstetrics and gynaecology Vol. 130; no. 12; pp. 1473 - 1482
• Main Authors: Lokki, A. Inkeri, Ren, Zhen, Triebwasser, Michael, Daly, Emma, Perola, Markus, Auro, Kirsi, Burwick, Richard, Salmon, Jane E., Daly, Mark, Laivuori, Hannele, Atkinson, John P., Java, Anuja, Meri, Seppo, Heinonen, Seppo, Kajantie, Eero, Kere, Juha, Kivinen, Katja, Pouta, Anneli
• Format: Journal Article
• Language: English
• Published: England Wiley Subscription Services, Inc 01.11.2023
• Subjects: Case-Control Studies; Complement activation; Complement component C3b; Complement factor H; Complement Factor H - genetics; Complement Factor H - metabolism; complement system; Eclampsia; factor H; Female; Fetuses; Genetic diversity; genetics; Genotype; Humans; Immunological tolerance; Medicin och hälsovetenskap; Morbidity; Mutation; Placenta - metabolism; Pre-Eclampsia - genetics; Pregnancy; pre‐eclampsia: basic science; Structure-function relationships; pre-eclampsia: basic science; genetics; factor H; complement system
• ISSN: 1470-0328; 1471-0528; 1471-0528
• DOI: 10.1111/1471-0528.17529

Objective The objective of the study was to investigate the role of genetic variants in complement proteins in pre‐eclampsia. Design In a case–control study involving 609 cases and 2092 controls, five rare variants in complement factor H (CFH) were identified in women with severe and complicated pre‐eclampsia. No variants were identified in controls. Setting Pre‐eclampsia is a leading cause of maternal and fetal morbidity and mortality. Immune maladaptation, in particular, complement activation that disrupts maternal‐fetal tolerance leading to placental dysfunction and endothelial injury, has been proposed as a pathogenetic mechanism, but this remains unproven. Population We genotyped 609 pre‐eclampsia cases and 2092 controls from FINNPEC and the national FINRISK cohorts. Methods Complement‐based functional and structural assays were conducted in vitro to define the significance of these five missense variants and each compared with wild type. Main outcome measures Secretion, expression and ability to regulate complement activation were assessed for factor H proteins harbouring the mutations. Results We identified five heterozygous rare variants in complement factor H (L3V, R127H, R166Q, C1077S and N1176K) in seven women with severe pre‐eclampsia. 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. Conclusions These results suggest that complement dysregulation due to mutations in complement factor H is among the pathophysiological mechanisms underlying severe pre‐eclampsia.