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.
|Journal||BJOG: An International Journal of Obstetrics and Gynaecology|
|State||Accepted/In press - 2023|
- complement system
- factor H
- pre-eclampsia: basic science