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01.12.2012 | Research | Ausgabe 1/2012 Open Access

Reproductive Biology and Endocrinology 1/2012

Quantitative ELISAs for serum soluble LHCGR and hCG-LHCGR complex: potential diagnostics in first trimester pregnancy screening for stillbirth, Down’s syndrome, preterm delivery and preeclampsia

Zeitschrift:
Reproductive Biology and Endocrinology > Ausgabe 1/2012
Autoren:
Anne E Chambers, Christopher Griffin, Samantha A Naif, Ian Mills, Walter E Mills, Argyro Syngelaki, Kypros H Nicolaides, Subhasis Banerjee
Wichtige Hinweise

Electronic supplementary material

The online version of this article (doi:10.​1186/​1477-7827-10-113) contains supplementary material, which is available to authorized users.

Competing interests

The use of sLHCGR-based immunodiagnostic tests has been patented.

Authors’ contributions

AEC developed and validated the ELISA system, performed most of the ELISAs, analyzed the data, contributed to the interpretation of results, creation of manuscript figures and first draft of the manuscript. CG collected whole blood, liased with consenting patients and provided clinical diagnoses based on ultrasound, biochemical (PAPP-A and hCGbeta) and molecular analyses. WEM performed statistical analysis on the data, contributed to the creation of manuscript figures and to the interpretation of the results. IM and SAN prepared and stored sera from whole blood, performed biochemical analyses (PAPP-A and hCGbeta) and collected clinical data. AS and KHN collected, prepared and stored sera, performed clinical diagnoses and provided clinical data. SB conceived and initiated the study, performed some ELISAs, including those for validation, did all western blotting, designed the standards and monoclonal antibodies used in the ELISAs, presided over the statistical analyses, interpretation of results, creation of manuscript figures and the first draft of the manuscript. All authors read and approved the final manuscript.

Abstract

Background

Soluble LH/hCG receptor (sLHCGR) released from placental explants and transfected cells can be detected in sera from pregnant women. To determine whether sLHCGR has diagnostic potential, quantitative ELISAs were developed and tested to examine the correlation between pregnancy outcome and levels of serum sLHCGR and hCG-sLHCGR complex.

Methods

Anti-LHCGR poly- and monoclonal antibodies recognizing defined LHCGR epitopes, commerical anti-hCGbeta antibody, together with recombinant LHCGR and yoked hCGbeta-LHCGR standard calibrators were used to develop two ELISAs. These assays were employed to quantify serum sLHCGR and hCG-sLHCGR at first trimester human pregnancy.

Results

Two ELISAs were developed and validated. Unlike any known biomarker, sLHCGR and hCG-sLHCGR are unique because Down’s syndrome (DS), preeclampsia and preterm delivery are linked to both low (less than or equal to 5 pmol/mL), and high (equal to or greater than 170 pmol/mL) concentrations. At these cut-off values, serum hCG-sLHCGR together with PAPP-A detected additional DS pregnancies (21%) which were negative by free hCGbeta plus PAPP-A screening procedure. Therefore, sLHCGR/hCG-sLHCGR has an additive effect on the current primary biochemical screening of aneuploid pregnancies. More than 88% of pregnancies destined to end in fetal demise (stillbirth) exhibited very low serum hCG-sLHCGR(less than or equal to 5 pmol/mL) compared to controls (median 16.15 pmol/mL, n = 390). The frequency of high hCG-sLHCGR concentrations (equal to or greater than 170 pmol/mL) in pathological pregnancies was at least 3-6-fold higher than that of the control, suggesting possible modulation of the thyrotropic effect of hCG by sLHCGR.

Conclusions

Serum sLHCGR/hCG-sLHCGR together with PAPP-A, have significant potential as first trimester screening markers for predicting pathological outcomes in pregnancy.
Zusatzmaterial
Authors’ original file for figure 1
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Authors’ original file for figure 2
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Authors’ original file for figure 3
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Authors’ original file for figure 4
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Authors’ original file for figure 5
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Authors’ original file for figure 6
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Literatur
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