A proteomic approach identifies early pregnancy biomarkers for preeclampsia: Novel linkages between a predisposition to preeclampsia and cardiovascular disease

School of Biological Sciences, Faculty of Science, University of Auckland, Auckland, New Zealand.
Proteomics (Impact Factor: 3.81). 06/2009; 9(11):2929-45. DOI: 10.1002/pmic.200800625
Source: PubMed


Preeclampsia (PE) is a common, potentially life-threatening pregnancy syndrome triggered by placental factors released into the maternal circulation, resulting in maternal vascular dysfunction along with activated inflammation and coagulation. Currently there is no screening test for PE. We sought to identify differentially expressed plasma proteins in women who subsequently develop PE that may perform as predictive biomarkers. In seven DIGE experiments, we compared the plasma proteome at 20 wk gestation in women who later developed PE with an appropriate birth weight for gestational age baby (n=27) or a small for gestational age baby (n=12) to healthy controls with uncomplicated pregnancies (n=57). Of the 49 differentially expressed spots associated with PE-appropriate for gestational age, PE-small for gestational age or both (p<0.05, false discovery rate corrected), 39 were identified by LC-MS/MS. Two protein clusters that accurately (>90%) classified women at risk of developing PE were identified. Immunoblots confirmed the overexpression of fibrinogen gamma chain and alpha-1-antichymotrypsin in plasma prior to PE. The proteins identified are involved in lipid metabolism, coagulation, complement regulation, extracellular matrix remodeling, protease inhibitor activity and acute-phase responses, indicating novel synergism between pathways involved in the pathogenesis of PE. Our findings are remarkably similar to recently identified proteins complexed to high-density lipoprotein and linked to cardiovascular disease.

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    • "One example of this is provided by SERPINA3, which plays very important homeostatic functions (coagulation, healing, brain function. . .) but whose high expression level associated with a polymorphism within the promoter [42] is associated with pregnancy diseases caused by placentation defects [43] [44] [45] [46]. Recently, another example has been the gene ERAP2, involved in MHC-I presentation which has a signature of balancing selection between two haplotypes, equilibrating favorable and noxious effects [47]. "
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    ABSTRACT: Preeclampsia (PE) is a deadly gestational disease affecting up to 10% of women and specific of the human species. Preeclampsia is clearly multifactorial, but the existence of a genetic basis for this disease is now clearly established by the existence of familial cases, epidemiological studies and known predisposing gene polymorphisms. PE is very common despite the fact that Darwinian pressure should have rapidly eliminated or strongly minimized the frequency of predisposing alleles. Consecutive pregnancies with the same partner decrease the risk and severity of PE. Here, we show that, due to this peculiar feature, preeclampsia predisposing-alleles can be differentially maintained according to the familial structure. Thus, we suggest that an optimal frequency of PE-predisposing alleles in human populations can be achieved as a result of a trade-off between benefits of exogamy, importance for maintaining genetic diversity and increase of the fitness owing to a stable paternal investment.
    Full-text · Article · May 2013 · Medical Hypotheses
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    • "Therefore, we can speculate that reduced PSG expression may contribute to the maternal syndrome in preeclampsia by facilitating fibrinogen binding to activated platelets. Interestingly, in a LC-MS/MS proteomics screen of the SCOPE collection of preeclampsia maternal blood samples taken at 20 weeks, increased fibrinogen gamma chain expression provided one of two strong predictors of subsequent development of preeclampsia [47]. "
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    ABSTRACT: Pregnancy-specific glycoproteins (PSGs) are immunoglobulin superfamily members encoded by multigene families in rodents and primates. In human pregnancy, PSGs are secreted by the syncytiotrophoblast, a fetal tissue, and reach a concentration of up to 400 ug/ml in the maternal bloodstream at term. Human and mouse PSGs induce release of anti-inflammatory cytokines such as IL-10 and TGFβ1 from monocytes, macrophages, and other cell types, suggesting an immunoregulatory function. RGD tri-peptide motifs in the majority of human PSGs suggest that they may function like snake venom disintegrins, which bind integrins and inhibit interactions with ligands. We noted that human PSG1 has a KGD, rather than an RGD motif. The presence of a KGD in barbourin, a platelet integrin αIIbβ3 antagonist found in snake venom, suggested that PSG1 may be a selective αIIbβ3 ligand. Here we show that human PSG1 binds αIIbβ3 and inhibits the platelet - fibrinogen interaction. Unexpectedly, however, the KGD is not critical as multiple PSG1 domains independently bind and inhibit αIIbβ3 function. Human PSG9 and mouse Psg23 are also inhibitory suggesting conservation of this function across primate and rodent families. Our results suggest that in species with haemochorial placentation, in which maternal blood is in direct contact with fetal trophoblast, the high expression level of PSGs reflects a requirement to antagonise abundant (3 mg/ml) fibrinogen in the maternal circulation, which may be necessary to prevent platelet aggregation and thrombosis in the prothrombotic maternal environment of pregnancy.
    Full-text · Article · Feb 2013 · PLoS ONE
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    • "Since preeclampsia is associated with structural placental anomalies, the underlying alterations in protein expression should be reflected in plasma proteome. Consequently, this serves as a promising route for the detection of biomarkers indicative of abnormal placentation [11]. Consequently, a recent study carried out under this premise [12] has shown that alterations in protein expression are evident maternal serum or plasma of affected pregnancies . "
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    ABSTRACT: A current major obstacle is that no reliable screening markers exist to detect pregnancies at risk for preeclampsia. Quantitative proteomic analysis employing isobaric labelling (iTRAQ) has been suggested to be suitable for the detection of potential plasma biomarkers, a feature we recently verified in analysis of pregnancies with Down syndrome foetuses.We have now examined whether this approach could yield biomarkers to screen pregnancies at risk for preeclampsia. In our study, we used maternal plasma samples obtained at 12 weeks of gestation, six fromwomen who subsequently developed preeclampsia and six with uncomplicated deliveries. In our analysis, we observed elevations in 10 proteins out of 64 proteins in the preeclampsia study group when compared to the healthy control group. These proteins included clusterin, fibrinogen, fibronectin, and angiotensinogen, increased levels of which are known to be associated with preeclampsia. An elevation in the immune-modulatory molecule, galectin 3 binding protein, was also noted. Our pilot study, therefore, indicates that quantitative proteomic iTRAQ analysis could be a useful tool for the detection of new preeclampsia screening markers
    Full-text · Article · Apr 2012
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