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Serum lncRNAs in early pregnancy as potential biomarkers for the prediction of pregnancy-induced hypertension, including preeclampsia.

ABSTRACT: Long noncoding RNAs (lncRNAs) are key mediators of biological regulation with diagnostic value as disease biomarkers. We explored serum lncRNA levels in early pregnancy as potential biomarkers of pregnancy-induced hypertension (PIH), including gestational hypertension (GH) and preeclampsia (PE). We performed a two-phase nested case-control study in pregnant women before 20 weeks' gestation (before clinical diagnosis). The screening phase assessed lncRNA expression profiles with a human lncRNA microarray in 5 pairs of serum samples (5 PE patients and 5 matched controls). The second phase validated levels of 8 candidate lncRNAs selected via the random walk method by quantitative real-time polymerase chain reaction (qRT-PCR). Serum levels of the 8 lncRNAs were markedly increased in women with PIH compared with matched normotensive pregnant (NP) women (p < 0.001), consistent with the microarray results. In addition, 7 candidate lncRNAs were correlated with PIH severity. Logistic regression analysis revealed that serum levels of ENST00000527727 (odds ratio [OR], 1.113; 95% confidence interval [CI], 1.024-1.209; p = 0.0113) and ENST00000415029 (OR, 1.126; 95% CI, 1.000-1.267; p = 0.0496) were associated with adverse pregnancy outcomes, such as fetal growth restriction (FGR) and placenta accreta of PIH. Nine pathways associated with the candidate lncRNAs had confirmed associations with PIH.

SUBMITTER: Dai C

PROVIDER: S-EPMC8042241 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:BACKGROUND:Placental protein expression plays a crucial role during pregnancy. We hypothesized that: (1) circulating levels of pregnancy-associated, placenta-related proteins throughout gestation reflect the temporal progression of the uncomplicated, full-term pregnancy, and can effectively estimate gestational ages (GAs); and (2) preeclampsia (PE) is associated with disruptions in these protein levels early in gestation; and can identify impending PE. We also compared gestational profiles of proteins in the human and mouse, using pregnant heme oxygenase-1 (HO-1) heterozygote (Het) mice, a mouse model reflecting PE-like symptoms. METHODS:Serum levels of placenta-related proteins-leptin (LEP), chorionic somatomammotropin hormone like 1 (CSHL1), elabela (ELA), activin A, soluble fms-like tyrosine kinase 1 (sFlt-1), and placental growth factor (PlGF)-were quantified by ELISA in blood serially collected throughout human pregnancies (20 normal subjects with 66 samples, and 20 subjects who developed PE with 61 samples). Multivariate analysis was performed to estimate the GA in normal pregnancy. Mean-squared errors of GA estimations were used to identify impending PE. The human protein profiles were then compared with those in the pregnant HO-1 Het mice. RESULTS:An elastic net-based gestational dating model was developed (R2 = 0.76) and validated (R2 = 0.61) using serum levels of the 6 proteins measured at various GAs from women with normal uncomplicated pregnancies. In women who developed PE, the model was not (R2 = -0.17) associated with GA. Deviations from the model estimations were observed in women who developed PE (P = 0.01). The model developed with 5 proteins (ELA excluded) performed similarly from sera from normal human (R2 = 0.68) and WT mouse (R2 = 0.85) pregnancies. Disruptions of this model were observed in both human PE-associated (R2 = 0.27) and mouse HO-1 Het (R2 = 0.30) pregnancies. LEP outperformed sFlt-1 and PlGF in differentiating impending PE at early human and late mouse GAs. CONCLUSIONS:Serum placenta-related protein profiles are temporally regulated throughout normal pregnancies and significantly disrupted in women who develop PE. LEP changes earlier than the well-established biomarkers (sFlt-1 and PlGF). There may be evidence of a causative action of HO-1 deficiency in LEP upregulation in a PE-like murine model.

Project description:BackgroundLong non-coding RNAs (lncRNAs) are an important class of pervasive genes involved in a variety of biological functions. They are aberrantly expressed in many types of diseases. In this study, we aimed to investigate the lncRNA profiles in preeclampsia. Preeclampsia has been observed in patients with molar pregnancy where a fetus is absent, which demonstrate that the placenta is sufficient to cause this condition. Thus, we analyzed the lncRNA profiles in preeclampsia placentas.Methodology/principal findingsIn this study, we described the lncRNA profiles in six preeclampsia placentas (T) and five normal pregnancy placentas (N) using microarray. With abundant and varied probes accounting for 33,045 LncRNAs in our microarray, 28,443 lncRNAs that were expressed at a specific level were detected. From the data, we found 738 lncRNAs that were differentially expressed (≥ 1.5-fold-change) among preeclampsia placentas compared with controls. Coding-non-coding gene co-expression networks (CNC network) were constructed based on the correlation analysis between the differentially expressed lncRNAs and mRNAs. According to the CNC network and GO analysis of differentially expressed lncRNAs/mRNAs, we selected three lncRNAs to analyze the relationship between lncRNAs and preeclampsia. LOC391533, LOC284100, and CEACAMP8 were evaluated using qPCR in 40 preeclampsia placentas and 40 controls. These results revealed that three lncRNAs were aberrantly expressed in preeclampsia placentas compared with controls.Conclusions/significanceOur study is the first study to determine the genome-wide lncRNAs expression patterns in preeclampsia placenta using microarray. These results revealed that clusters of lncRNAs were aberrantly expressed in preeclampsia placenta compared with controls, which indicated that lncRNAs differentially expressed in preeclampsia placenta might play a partial or key role in preeclampsia development. Misregulation of LOC391533, LOC284100, and CEACAMP8 might contribute to the mechanism underlying preeclampsia. Taken together, this study may provide potential targets for the future treatment of preeclampsia and novel insights into preeclampsia biology.

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Serum lncRNAs in early pregnancy as potential biomarkers for the prediction of pregnancy-induced hypertension, including preeclampsia.

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