Analysis of Complement C3 Gene Reveals Susceptibility to Severe Preeclampsia

Lokki, A. Inkeri; Kaartokallio, Tea; Holmberg, Ville; Onkamo, Päivi; Koskinen, Lotta; Saavalainen, Päivi; Heinonen, Seppo; Kajantie, Eero; Kere, Juha; Kivinen, Katja; Pouta, Anneli; Villa, Pia; Hiltunen, Leena; Laivuori, Hannele; Meri, Seppo

doi:10.3389/fimmu.2017.00589

Cited by 40 publications

(34 citation statements)

References 57 publications

(64 reference statements)

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“…Lokki et al performed a genetic case-control study, and discovered three SNPs within the C3 gene that were associated with severe preeclampsia [39]. These SNPs characterized a 16 nucleotide haplotype signature, in the highly conserved middle region of the maternal C3 gene, that could influence susceptibility to the disease.…”

Section: The Complement System In Stage 1 Of Placental Preeclampsiamentioning

confidence: 99%

The Complement System and Preeclampsia

2017

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Purpose of review Preeclampsia affects 3–4% of pregnancies with few treatment options to reduce maternal and fetal harm. Recent evidence that targeting the complement system may be an effective therapeutic strategy in prevention or treatment of preeclampsia will be reviewed. Recent findings Studies in humans confirm the safety and efficacy of C5 blockade in complement-mediated disorders of pregnancy, including preeclampsia. Animal models mimic the placental abnormalities, and/or the maternal symptoms, which characterize preeclampsia. These models in mouse and rat have defined a role for complement and its regulators in placental dysfunction, hypertension, proteinuria, endothelial dysfunction, fetal growth restriction and angiogenic imbalance, thus informing future human studies. Summary Targeting excessive complement activation, particularly the terminal complement complex (C5b-9) and C5a may be an effective strategy to prolong pregnancy in women with preeclampsia. Continued research is needed to identify the initiator(s) of activation, the pathways involved and the key component(s) in the pathophysiology to allow development of safe and effective therapeutics to target complement without compromising its role in homeostasis and host defense.

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Section: The Complement System In Stage 1 Of Placental Preeclampsiamentioning

confidence: 99%

The Complement System and Preeclampsia

2017

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“…It was speculated that these two SNPs may represent different tagging SNPs for an unknown causal SNP 30 . Interestingly, in a recent study the rs223005 was shown to be associated with severe PE 18 .…”

Section: Scientific Reports |mentioning

confidence: 93%

“…The exons including flanking intronic regions were sequenced using standard Sanger sequencing. We used primers for C3 as previously reported 18 . The primers used for factor H and CD46 are listed in Supplemental Tables 1 and 2.…”

Section: Study Populationmentioning

confidence: 99%

“…In PROMISSE study A304V mutation in CD46 was found to be associated with PE 16 whereas no such association was found in a Finnish cohort 17 . Recently, several synonymous and intronic common SNPs in maternal C3 gene have been shown to be associated with PE 18 . In silico analysis of these synonymous and intronic variations indicated a possible role in mRNA splicing or folding suggesting that those SNPS may have functional relevance.…”

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confidence: 99%

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Common variants of fetal and maternal complement genes in preeclampsia: pregnancy specific complotype

Banadakoppa

Balakrishnan

Yallampalli

2020

Sci Rep

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Preeclampsia (PE) is a pregnancy specific hypertensive disorder. If untreated PE leads to life threatening condition, eclampsia. Systemic complement activation levels are increased during pregnancy compared to non-pregnant women of childbearing age. In PE, systemic complement levels are further increased, and higher complement deposition has been observed on placentas. We hypothesize that combinations of common SNPs in maternal and fetal complement genes constitute pregnancy specific complotypes and predispose women to PE. In this study, we sequenced two maternal (factor H and C3) and one fetal (CD46) complement genes and identified a total of 9 common SNPs. Minor allele frequencies of two fetal CD46 SNPs were significantly higher in PE. Further, complotypes consisting of fetal CD46 variants and maternal CFH/C3 variants were highly prevalent in PE patients compared to normotensive pregnancies. Placental complement deposition and maternal alternative pathway 50 (AP50) values were higher in PE pregnancies. Irrespective of disease status, two CD46 variants were associated with reduced placental CD46 expression and one CFH variant was associated with increased maternal AP50 values.

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“…In vitro data also suggest that mutations in FOXD1, a transcription factor that directly seems to target C3, leading to both decreased and increased C3 expression, were deleterious (17). Genetic variants in the C3 gene have also been reported to be associated with severe preeclampsia (18). Thus, C3 appears to have an important physiological role in the early phase of pregnancy and in placental development and a subtle fine-tuning of the C3 level is necessary for optimal function.…”

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confidence: 99%

Analysis of C3 gene variants in patients with idiopathic, recurrent, spontaneous pregnancy loss

Mohlin

Mercier

Gris

et al. 2017

Molecular Immunology

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Miscarriage is the most common complication of pregnancy. Approximately 1% of couples trying to conceive will experience recurrent miscarriages, defined as three or more consecutive pregnancy losses and many of these cases remain idiopathic. Complement is implicated both in the physiology and pathology of pregnancy. Therefore, we hypothesized that alterations in the C3 gene could potentially predispose to this disorder. We performed full Sanger sequencing of all exons of C3, in 192 childless women, with at least two miscarriages and without any known risk factors. All exons carrying nonsynonymous alterations found in the patients were then sequenced in a control group of 192 women. None of the identified alterations were significantly associated with the disorder. Thirteen identified non-synonymous alterations (R102G, K155Q, L302P, P314L, Y325H, V326A, S327P, V330I, K633R, R735W, R1591G, G1606D, and S1619R) were expressed recombinantly, upon which C3 expression and secretion were determined. The L302P and S327P were not secreted from the cells, likely due to misfolding and intracellular degradation. Y325H, V326A, V3301I, R1591G, and G1606D yielded approximately half C3 concentration in the cell media compared with wild type (WT). We analyzed the hemolytic activity of the secreted C3 variants by reconstituting C3-depleted serum. In this assay, R1591G had impaired hemolytic activity while majority of remaining mutants instead had increased activity. R1591G also yielded more factor B activation in solution compared with WT. R1591G and G1606D showed impaired degradation by factor I, irrespectively if factor H, CD46, or C4b-binding protein were used as cofactors. These two C3 mutants showed impaired binding of the cofactors and/or factor I. Taken together, several alterations in C3 were identified and some of these affected the secretion and/or the function of the protein, which might contribute to the disorder but the degree of association must be evaluated in larger cohorts.

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Analysis of Complement C3 Gene Reveals Susceptibility to Severe Preeclampsia

Cited by 40 publications

References 57 publications

The Complement System and Preeclampsia

The Complement System and Preeclampsia

Common variants of fetal and maternal complement genes in preeclampsia: pregnancy specific complotype

Analysis of C3 gene variants in patients with idiopathic, recurrent, spontaneous pregnancy loss

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