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

Abstract

ObjectiveThe objective of the study was to investigate the role of genetic variants in complement proteins in pre‐eclampsia.DesignIn 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.SettingPre‐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.PopulationWe genotyped 609 pre‐eclampsia cases and 2092 controls from FINNPEC and the national FINRISK cohorts.MethodsComplement‐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 measuresSecretion, expression and ability to regulate complement activation were assessed for factor H proteins harbouring the mutations.ResultsWe 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.ConclusionsThese results suggest that complement dysregulation due to mutations in complement factor H is among the pathophysiological mechanisms underlying severe pre‐eclampsia.

Type I interferon alters invasive extravillous trophoblast function

“…We found heightened expression of several genes associated with increased PE risk including TNFSF13B, TFPI2, TIMP3, RBM25, IGF2R and CSF1 21,[23][24][25][26] in IFN-EVTs compared with control EVTs (Figure 3e). We also observed increased expression of complement activation components that have specifically been implicated in PE pathogenesis (CFH, CFB, C1R, C1S) in IFN-exposed EVTs 27,28 . Given these associations, we next compared our list of differentially expressed genes in IFN-exposed EVTs with a list of dysregulated genes in EVTs from single-cell transcriptomes of EVTs in PE patients recently published by Admati et al 29 .…”

“…We found IFN stimulation induced expression of known PE risk factors, such as complement activation. Aberrant activation of the complement system during first trimester is associated with onset of PE later in gestation and thereby considered a stage 1 risk factor 27,28 . Furthermore, we identified noteworthy overlap with PE dysregulated genes that are known to be increased in stage 2 of PE, such as SAT1.…”

Systematic review of the complement components as potential biomarkers of pre-eclampsia: pitfalls and opportunities

“…Interestingly, a recent study by Lokki et al. identified FH variants that predispose to PE onset, confirming the multifactorial nature of the pathophysiological mechanisms underlying PE ( 82 ).…”

“…A pivotal role in the dysregulation of C activation seems to be carried out by the reduction in FH levels, which could be caused by deficiency or consumption of FH. Interestingly, a recent study by Lokki et al identified FH variants that predispose to PE onset, confirming the multifactorial nature of the pathophysiological mechanisms underlying PE (82).…”

Pregnancy as a susceptible state for thrombotic microangiopathies

“…Mutations and/or variants have been reported in the context of PE or HELLP syndrome, related to genes involved in angiogenesis, blood pressure regulation, coagulation, or complement activation ( 40 , 202 , 204 , 205 ), underscoring the close pathophysiological connections with TMA. For instance, mutations or variations in Factor H, C3, or CD46 have been identified in cohorts of women with PE ( 206 , 207 ). These findings indicate that a multifaceted interplay of susceptibility factors is likely, potentially resulting in distinct patterns of preeclampsia.…”