C3F gene mutation is involved in the susceptibility to pre-eclampsia

Rhim, Mohamed Salah; Meddeb, S.; Kaabia, Ons; Jalloul, Mohamed; Sakouhi, Mohamed; Jrzad, Besma Bel Hadj; Felah, Raja

doi:10.1007/s00404-014-3515-y

Cited by 6 publications

(5 citation statements)

References 24 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…C3F has been described as predisposing to PE (55), but we did not find any association of C3F with severe PE. Our result concurs with an early study of C3 allotypes that did not find association of C3F with PE (56).…”

Section: Discussioncontrasting

confidence: 94%

Analysis of Complement C3 Gene Reveals Susceptibility to Severe Preeclampsia

et al. 2017

View full text Add to dashboard Cite

Preeclampsia (PE) is a common vascular disease of pregnancy with genetic predisposition. Dysregulation of the complement system has been implicated, but molecular mechanisms are incompletely understood. In this study, we determined the potential linkage of severe PE to the most central complement gene, C3. Three cohorts of Finnish patients and controls were recruited for a genetic case-control study. Participants were genotyped using Sequenom genotyping and Sanger sequencing. Initially, we studied 259 Finnish patients with severe PE and 426 controls from the Southern Finland PE and the Finnish population-based PE cohorts. We used a custom-made single nucleotide polymorphism (SNP) genotyping assay consisting of 98 SNPs in 18 genes that encode components of the complement system. Following the primary screening, C3 was selected as the candidate gene and consequently Sanger sequenced. Fourteen SNPs from C3 were also genotyped by a Sequenom panel in 960 patients with severe PE and 705 controls, including already sequenced individuals. Three of the 43 SNPs observed within C3 were associated with severe PE: rs2287845 (p = 0.038, OR = 1.158), rs366510 (p = 0.039, OR = 1.158), and rs2287848 (p = 0.041, OR = 1.155). We also discovered 16 SNP haplotypes with extreme linkage disequilibrium in the middle of the gene with a protective (p = 0.044, OR = 0.628) or a predisposing (p = 0.011, OR = 2.110) effect to severe PE depending on the allele combination. Genetic variants associated with PE are located in key domains of C3 and could thereby influence the function of C3. This is, as far as we are aware, the first candidate gene in the complement system with an association to a clinically relevant PE subphenotype, severe PE. The result highlights a potential role for the complement system in the pathogenesis of PE and may help in defining prognostic and therapeutic subgroups of preeclamptic women.

show abstract

Section: Discussioncontrasting

confidence: 94%

Analysis of Complement C3 Gene Reveals Susceptibility to Severe Preeclampsia

et al. 2017

View full text Add to dashboard Cite

show abstract

“…Pre-eclampsia is a heterogeneous disease with multiple genetic and environmental risk factors. Although complement activation has been implicated in PE, 33,36,37 the aetiology of an overactive system has not been clearly delineated.…”

Section: Discussionmentioning

confidence: 99%

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

Lokki,

Ren,

Triebwasser

et al. 2023

BJOG

View full text Add to dashboard Cite

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.

show abstract

“…Variant rs2230199 in C3 is known as the slow/fast mutation affecting the mobility of the protein during the electrophoresis process and was associated with the pathogenesis of PE [35]. On the other hand, other published studies found no correlation between this specific variant and preeclampsia [36,37]. Interestingly, according to Banadakoppa et al, the high-risk variant rs800292 in the CFH gene is associated with the activation of the alternative pathway in patients with preeclampsia, only in the coexistence of a variant in the CD46 gene [38].…”

Section: Discussionmentioning

confidence: 99%

“…The patients' group included 30 Caucasian preeclamptic pregnant women with a median age of 36 years [median age (IQR): 36(10,(29)(30)(31)(32)(33)(34)(35)(36)(37)(38)(39)] and a median gestational age of 32 weeks. The control group, on the other hand, comprised 15 healthy pregnant women with a median age of 30 years [median age (IQR): 30(11,(27)(28)(29)(30)(31)(32)(33)(34)(35)(36)(37)(38) years] and a median gestational age of 30 weeks. Both groups shared similar baseline characteristics, and the control group had otherwise uncomplicated pregnancies.…”

mentioning

confidence: 99%

Increased Complement Activation and Decreased ADAMTS13 Activity Are Associated with Genetic Susceptibility in Patients with Preeclampsia/HELLP Syndrome Compared to Healthy Pregnancies: An Observational Case-Controlled Study

Venou,

Vetsiou,

Varelas

et al. 2024

JPM

View full text Add to dashboard Cite

Preeclampsia is a progressive multi-systemic disorder characterized by proteinuria, critical organ damage, and new-onset hypertension. It can be further complicated by HELLP syndrome (hemolysis, elevated liver enzymes, low platelets), resulting in critical liver or renal damage, disseminated coagulation, and grand mal seizures. This study aimed to examine the involvement of ADAMTS13, von Willebrand, and the complement system in the pathogenesis of preeclampsia/HELLP syndrome. We studied 30 Caucasian preeclamptic pregnant women and a control group of 15 healthy pregnancies. Genetic sequencing of ADAMTS13 and complement regulatory genes (MiniSeq System, Illumina) was performed. The modified Ham test was used to check for complement activation, ADAMTS13 activity, von Willebrand antigen (vWFAg) levels, and soluble C5b-9 levels were measured. Patients with preeclampsia had a decreased ADAMTS13 activity and increased C5b-9 levels. The vWFAg was significantly correlated with ADAMTS13 activity (r = 0.497, p = 0.003). Risk-factor variants were found in the genes of ADAMTS13, C3, thrombomodulin, CFB, CFH, MBL2, and, finally, MASP2. A portion of pregnant women with preeclampsia showed a decline in ADAMTS13 activity, correlated with vWFAg levels. These patients also exhibited an elevated complement activation and high-risk genetic variants in regulatory genes. Further research is needed to determine if these factors can serve as reliable biomarkers.

show abstract

C3F gene mutation is involved in the susceptibility to pre-eclampsia

Abstract: The gene polymorphism of complement component C3 was significantly associated with the onset of pre-eclampsia. These results should be confirmed by other studies looking at larger scale to consider this gene as a new biomarker with predictive potential therapeutic consequences.

Cited by 6 publications

References 24 publications

Analysis of Complement C3 Gene Reveals Susceptibility to Severe Preeclampsia

Analysis of Complement C3 Gene Reveals Susceptibility to Severe Preeclampsia

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

Increased Complement Activation and Decreased ADAMTS13 Activity Are Associated with Genetic Susceptibility in Patients with Preeclampsia/HELLP Syndrome Compared to Healthy Pregnancies: An Observational Case-Controlled Study

Contact Info

Product

Resources

About