Long non-coding RNA maternally expressed gene 3 (MEG3) rs4081134 gene polymorphism and preeclampsia risk

Shaghayegh Saljoughi; Hasan Dana; Mahtab Norouzi; Hossein Shahraki Ghadimi; Marzieh Ghasemi; Mansooreh Zargar; Mohsen Saravani

doi:10.4274/tjod.galenos.2026.06626

Abstract

Objective

Preeclampsia (PE), a significant challenge for health systems, is a hypertensive disorder of pregnancy. Some studies have suggested that long non-coding ribonucleic acids play a major role in the pathogenesis of PE by regulating the biological behaviors of maternal vascular smooth muscle cells and trophoblasts. In this study, the impact of the maternally expressed gene 3 (MEG3) rs4081134 gene polymorphism on susceptibility to PE has been evaluated.

Materials and Methods

We conducted a case-control study comprising 130 PE patients and 140 normotensive pregnant women with normal gestational outcomes genotype analysis was performed using the polymerase chain reaction-restriction fragment length polymorphism method.

Results

A significant association was evident between the AA genotype and PE risk under the recessive model, indicating that these may serve as protective factors against the development of PE. No significant relationships were detected between other genotypes, genetic models, or allelic distributions and PE risk. Additionally, among pregnant women with PE, a notable correlation was observed between newborn birth weight and the rs4081134 polymorphism in the MEG3 gene.

Conclusion

We found a significant association between the AA genotype, as well as the recessive model of the MEG3 rs4081134 gene polymorphism, and PE deployment. Among women diagnosed with PE, MEG3 rs4081134 gene polymorphism was significantly associated with newborn’s birth weight.

Keywords:

Maternally expressed gene 3, preeclampsia, gene, polymorphism

PRECIS: Based on our results, AA genotype and recessive model may be act as a protective factor on preeclampsia development. Furthermore, the maternally expressed gene 3 rs4081134 gene polymorphism had a significant impact on newborns’ birth weight.

Introduction

Preeclampsia (PE), as a significant risk for mother and fetus, is specified by unprecedented hypertension (>140/90 mmHG) and proteinuria (>300 mg/24 hours) after 20 weeks of gestation, which occurs in about 3% of all pregnancies⁽¹⁾. PE is divided into two main categories based on the time of diagnosis: early-onset PE (occurring before 34 weeks) and late-onset PE (occurring after 34 weeks)⁽²⁾. The increased frequency of certain maternal and fetal adverse outcomes in early-onset PE suggests that this type represents a more severe manifestation of the condition compared to late-onset PE, thus requiring particular attention^{(3, 4)}. Impacts of PE on the fetus include intrauterine growth restriction, lower birth weight, stillbirth, preterm birth, and its associated complications⁽⁵⁾. Maternal complications vary among individuals because of variability in organ involvement during PE. Hypertension, liver failure, renal failure, cardiomyopathy, coronary artery disease, pulmonary edema, diabetes mellitus, and stroke are some maternal outcomes of PE. Despite the advancement of our knowledge in the field of PE, Considerable progress has still not been made in the clinical context to address our challenges in exposure to PE^{(6, 7)}.

Findings including the predisposition to PE in certain molar pregnancies (where no fetus is present), along with the resolution of PE-related symptoms after childbirth, indicate that the placenta has a central role in the PE pathogenesis⁽⁸⁾. In contrast to late-onset PE, the underlying pathophysiology of early-onset PE is more closely related to abnormalities during placental development⁽⁹⁾. In normal placentation, the remodeling of maternal myometrial and decidual spiral arteries plays a pivotal role in providing sufficient uteroplacental blood flow⁽¹⁰⁾. Interstitial and endovascular extravillous trophoblasts invasion and migration to decidua of the uterus, drive spiral artery remodeling by influencing vascular smooth muscle cells (VSMCs) and endothelial cells, respectively⁽¹¹⁾. Shallow invasion of the spiral arteries following defective placentation causes poor placental perfusion. In response to hypoxic conditions, an imbalance of angiogenic factors occurs, and proinflammatory cytokines and reactive oxygen species are released into the maternal bloodstream. These substances are key contributors to the pathogenesis of PE⁽¹²⁾.

Non-coding ribonucleic acids (ncRNAs) are functional RNA transcripts that lack protein-coding capacity. They are divided into two subgroups: structural and regulatory. Regulatory noncoding RNAs consisting of <200 nucleotide (nt) are considered small non-coding RNAs (sncRNAs), and those with more than 200 nt are called long ncRNAs (lncRNAs)⁽¹³⁾. LncRNAs influence numerous biological and pathological processes within cells by modulating gene expression at various levels, including transcription and chromatin remodeling. multiple studies have demonstrated the key role of lncRNAs in the development of PE by modifying trophoblast biological behaviors, including proliferation, migration, invasion, and apoptosis^{(14, 15)}. Furthermore, using microarray and RNA-seq approaches has revealed dysregulation of lncRNAs within placental and decidual tissues from preeclamptic individuals compared to healthy controls^{(16, 17)}.

Maternally expressed gene 3 (MEG3) is a tumor suppressor lncRNA from chromosome 14q32.2⁽¹⁸⁾. Yu et al.⁽¹⁹⁾ have demonstrated lower expression of MEG3 in placental tissue of PE compared to standard controls. In addition to, lower expression of MEG3 decreased the migratory and invasive properties of human trophoblasts in vitro by attenuating the epithelial-mesenchymal transition (EMT) process. Although MEG3 regulatory mechanism on EMT remains to be elucidated, a negative relationship between EMT and the transforming growth factor β (TGF-β)/Smad pathway has been documented upon MEG3 dysregulation. On the other hand, it has been suggested that downregulating MEG3 by inhibiting the Notch1 signaling pathway diminishes EMT process in trophoblasts and subsequently leads to PE as a possible mechanism of action⁽²⁰⁾. The effects of MEG3 in placentation are not limited to trophoblasts. On the maternal side, initiation of spiral artery remodeling requires proliferation arrest of VSMCs, induction of apoptosis, and enhanced migration of these cells. Upregulation of MEG3 induced by factors released from uterine natural killer cells facilitates these essential alterations of VSMCs in the maternal spiral arteries of the uterus^{(21, 22)}.

Regarding the significance of MEG3 in healthy placentation, this study aimed to evaluate the involvement of the MEG3 rs4081134 gene polymorphism in PE susceptibility.

Materials and Methods

Participants Data

We conducted a case-control study comprising 130 PE patients and 140 healthy pregnant women. All participants were recruited from among pregnant women seeking prenatal care at the obstetrics clinic of Ali-ebn Abitaleb Hospital, which is affiliated with Zahedan University of Medical Sciences in Iran. Patients in the case group were determined to have PE according to diagnostic criteria which was defined as unprecedented systolic blood pressure ≥140 mmHg or diastolic blood pressure ≥90 mmHg measured twice separately. Additionally, protein excretion in urine higher than 300 mg in a 24-hour urine specimen was present in all patients after 20 weeks of pregnancy. All participants with diabetes, gestational diabetes, chronic hypertension, chronic kidney disease, cardiovascular disease, hyperthyroidism, or who smoked were excluded from the study. All participants provided written informed consent, and the study protocol received approval from the Ethics Committee of Zahedan University of Medical Sciences (approval number: IR.ZAUMS.REC.1399.239, date: 09.08.2020).

Genotyping

After drawing blood samples from all participants, the samples were stored in K2-EDTA-containing tubes. Peripheral leukocyte deoxyribonucleic acid (DNA) was extracted from 500 µL of blood using the salting-out method and stored at -20 °C until further use. The forward primer (5›-TTTCTTGTAGCTGCCTCCTCC-3›) and the reverse primer (5›-CGTCTGTTGGCTGTGAGTGAATGA-3›) were used to amplify the desired gene fragment by polymerase chain reaction (PCR). The PCR mixture consisted of 7.5 µL master mix Red 2x, 0.82 forward primers, 0.82 reverse primer, 4.86 µL H₂O, and one µL of DNA. The PCR program was set for 40 cycles, with denaturation at 95 °C for 30 seconds, annealing at 65 °C for 40 seconds, and extension at 72 °C for 35 seconds. 2.7 µL H₂O, 0.3 µL Ndel enzyme, and one µL H₂O were added to 6 µL of PCR product for MEG3 rs4081134 genotypic determination⁽²³⁾. After overnight incubation at 37 °C, the microtube contents were separated by gel electrophoresis.

Statistical Analysis

Statistical analysis was performed using SPSS Statistics version 26.0 (SPSS Inc., Chicago, IL, USA). The independent-samples t-test was used to compare demographic and clinical characteristics between the two groups. For women with PE versus healthy controls, odds ratios with 95% confidence intervals were computed for various genotypes, genetic models, and alleles. furthermore, chi-square test and one-way analysis of variance were used to compare PE clinical characteristics in different genotypes of case group. Results with p-values were defined as statistically significant.

Results

Demographic and Clinical Characteristics of PE Patients and Controls

Table 1 demonstrates the demographic and clinical characteristics of the two groups. All precipitants were matched respect to the maternal age (26.7±5.6 and 27.75±6.65 in the control and PE groups, respectively, p=0.164). Significant differences were found between the two groups in birth weight, systolic blood pressure, and diastolic blood pressure. The frequencies of mild and severe PE were 52.3% and 47.7%, respectively. Moreover, 55.4% of participants had early-onset PE, while 44.6% had late-onset PE.

The Correlation Between MEG3 rs4081134 Gene Polymorphism and PE Susceptibility

As shown in Table 2, the genotype frequencies for GG, GA, and AA were 61.6%, 36.9%, and 1.5% in the PE group and 57.1%, 35.8%, and 7.1% in the control group. A significant association with PE risk was found for both the AA genotype and the recessive model, indicating that they may be protective against the development of PE. Other genotypes, genetic models, and allelic distributions were not significantly associated with PE risk.

Relationship of The Clinical and Demographic Characteristics of PE Patients with MEG3 rs4081134 Gene Polymorphism

The average maternal age [mean ± standard deviation (SD), years] for the GG, GA and AA genotypes was 28.53±6.78, 26.64±6.4 and 23±5.65, sequentially, which was not statistically significant (p=0.180). The average gestation age (mean ± SD, weeks) for GG, GA and AA genotypes was 36.10±3.61, 35.48±3.91 and 36±2.82, respectively, which was not statistically significant (p=0.66). A significant relationship was found between birth weight (mean ± SD, grams) and the MEG3 rs4081134 gene polymorphism (p=0.043). The average birth weight for GG, GA and AA genotypes was 2879.38±628.18, 2576.04±817.15 and 3225±318.19, respectively. Moreover, there was no significant correlation between the MEG3 rs4081134 polymorphism and other clinical characteristics in patients with PE (Table 3).

Discussion

Prior research has supported the involvement of lncRNAs such as MEG3 in the pathogenesis of PE. Through alternative splicing, various isoforms of MEG3 are generated. To date, 12 isoforms of MEG3 have been described. Among them, MEG3 has been well-reputed⁽²⁴⁾. Based on information extracted from GenBank, this isoform contains exons 1-4 and 8-10. The studies have not identified any functional open reading frame (ORF) in the MEG3 isoforms. The functional studies of ORFs revealed that one ORF does not mediate the functions of MEG3 . In other words, the whole-length sequence of MEG3 is needed for essential functions of this ncRNA⁽²⁵⁾. Gene expression profiling of MEG3-knockdown mice revealed increased expression of genes that contribute to angiogenesis, including vascular endothelial growth factor alpha and its receptor. Angiogenesis is a pivotal step in tumor growth. Therefore, it seems that MEG3 is involved in procedures that contribute to tumor suppression⁽²⁴⁾. MEG3 interacts with some targets, through which multiple genes involved in the TGF-β pathway are regulated⁽²⁶⁾. The decreased or lost level of MEG3 was associated with some cancers including pituitary adenomas and meningioma⁽²⁷^,²⁸⁾. The studies showed that MEG3 is likely to regulate the p53 protein in different ways. For example, the MEG3 could block MDM2 transcription, leading to inhibiting the degradation of p53⁽²⁹⁾. While many studies confirmed the tumor suppressor role of MEG3, primarily through activation and accumulation of p53, there is evidence of an association between knockdown MEG3 and activation of p53 and metastasis⁽³⁰⁾.

MEG3 is a key participant in several cancer-related signaling pathways, including Wnt, PI3k/Akt/mTOR, WT1, and TGF-β. Additionally, the serum level of MEG3, as well as several single-nucleotide polymorphisms in this ncRNA, serves as a biomarker for specific cancers⁽³¹^,³²⁾. MEG3 contributes to the response of cancer cells to chemotherapy agents. An expression study on non-small cell lung carcinoma demonstrated an association between reduced MEG3 levels and unfavorable responses to cisplatin treatment. In addition, MEG3 improved the sensitivity of chemotherapy drug response in correlation with miR-21-5p⁽³³⁾.

Bone morphogenetic protein (BMP) and its receptors, BMPR1 and BMPR2, form a tetrameric structure that triggers specific signal cascades. BMP signals through BMPRs induce several alterations that are assumed to result in cell proliferation, differentiation, and metastasis⁽³⁴⁾. The evidence shows that BMPR2 is involved in embryonic development and angiogenesis and appears to be correlated with hypertension. The study by Andruska et al.⁽³⁵⁾ showed a link between BMPR2 gene mutations and pulmonary hypertension. The expression profile of the placental tissue of PE women showed an increase in miR-21 expression⁽³⁶^,³⁷⁾. Overexpression of miR-21 inhibitors induced proliferation and invasion of trophoblast cells. These results are consistent with the findings from in silico analysis, which confirmed BMPR2 as a key direct target of miR-21. Furthermore, MEG3 has decreased in the placentas of PE participants. Based on bioinformatics results, MEG3 acts as a molecular sponge that regulates miR-21. Therefore, it is not surprising that the downregulation of MEG3 led to increased miR-21 expression in women with PE. Conclusively, MEG3 , acting as a sponge for miR-21, regulates the expression of BMPR2 and thereby improves trophoblast proliferation. Therefore, MEG3 is involved in a regulatory mechanism that prevents premature ejaculation (PE)⁽³⁸⁾. These do not bear on the MEG3 effects in the pathogenesis of PE. It is suggested that MEG3 is involved in metastasis by expression regulation of elements that contribute to the metastasis process, including nuclear factor kappa B, caspase, and Bax⁽³⁹⁾. The documents showed that MEG3 blocked cell proliferation by targeting Notch1 in endometrial carcinoma cells. In addition, Notch1 downregulation in PE promotes trophoblast cell apoptosis. Consistent with these findings, the evaluation of the expression of MEG3 and Notch1 showed decreased levels in PE subjects compared with their regular counterparts, promoting apoptotic processes. On the other hand, MEG3 enhancement showed the opposite effect and promotes cell proliferation and inhibits cell apoptosis⁽²⁰⁾.

In the present study, we evaluated the association between the MEG3 rs4081134 variant and PE risk in an Iranian population. according to the results, we did not observe a statistically significant correlation between the allelic frequency of rs4081134 and the risk of PE in our sample, likely due to the small sample size.

To our knowledge, this study is the first to investigate whether MEG3 rs4081134 is associated with the risk of PE. previous studies have evaluated the association of MEG3 rs4081134 and the risk of some tumors, including papillary thyroid carcinoma⁽⁴⁰⁾, neuroblastom⁽⁴¹⁾, and lung cancer⁽⁴²⁾.

Study Limitations

In the current study, we faced several challenges, including the small size of the study population and technical limitations. It is recommended that future work evaluate the expression levels of MEG3 and its downstream targets, such as miR-21 or FOXM1, as key participants in the proliferation of placental cells.

Conclusion

We found a significant relationship between the AA genotype of the MEG3 rs4081134 polymorphism and the risk of PE development. Furthermore, there MEG3 rs4081134 gene polymorphism showed a significant relationship with newborn’s birth weight in patients with PE.

Ethics

Ethics Committee Approval: The study protocol received approval from the Ethics Committee of Zahedan University of Medical Sciences (approval number: IR.ZAUMS.REC.1399.239, date: 09.08.2020).

Informed Consent: All participants provided written informed consent.

Authorship Contributions

Surgical and Medical Practices: S.S., H.D., M.N., H.S.G., M.G., M.Z., M.S., Concept: S.S., H.D., M.N., H.S.G., M.G., M.Z., M.S., Design: S.S., H.D., M.N., H.S.G., M.G., M.Z., M.S., Data Collection or Processing: S.S., H.D., M.N., H.S.G., M.G., M.Z., M.S., Analysis or Interpretation: Literature Search: S.S., H.D., M.N., H.S.G., M.G., M.Z., M.S., Writing: S.S., H.D., M.N., H.S.G., M.G., M.Z., M.S.

Conflict of Interest: No conflict of interest was declared by the authors.

Financial Disclosure: The authors declared that this study received no financial support.

References

Hutcheon JA, Lisonkova S, Joseph KS. Epidemiology of pre-eclampsia and the other hypertensive disorders of pregnancy. Best Pract Res Clin Obstet Gynaecol. 2011;25:391-403.

CrossRef PubMed Google Scholar

Yung HW, Atkinson D, Campion-Smith T, Olovsson M, Charnock-Jones DS, Burton GJ. Differential activation of placental unfolded protein response pathways implies heterogeneity in causation of early- and late-onset pre-eclampsia. J Pathol. 2014;234:262-76.

CrossRef PubMed Google Scholar

Wojtowicz A, Zembala-Szczerba M, Babczyk D, Kolodziejczyk-Pietruszka M, Lewaczynska O, Huras H. Early- and late-onset preeclampsia: a comprehensive cohort study of laboratory and clinical findings according to the new ISHHP criteria. Int J Hypertens. 2019;2019:4108271.

Tranquilli AL, Dekker G, Magee L, Roberts J, Sibai BM, Steyn W, et al. The classification, diagnosis and management of the hypertensive disorders of pregnancy: a revised statement from the ISSHP. Pregnancy Hypertens. 2014;4:97-104.

CrossRef

Bokslag A, van Weissenbruch M, Mol BW, de Groot CJ. Preeclampsia; short and long-term consequences for mother and neonate. Early Hum Dev. 2016;102:47-50.

CrossRef PubMed Google Scholar

Roberts JM, Rich-Edwards JW, McElrath TF, Garmire L, Myatt L, Global Pregnancy C. Subtypes of preeclampsia: recognition and determining clinical usefulness. Hypertension. 2021;77:1430-41.

CrossRef

Armaly Z, Jadaon JE, Jabbour A, Abassi ZA. Preeclampsia: novel mechanisms and potential therapeutic approaches. Front Physiol. 2018;9:973.

CrossRef PubMed Google Scholar

He X, He Y, Xi B, Zheng J, Zeng X, Cai Q, et al. LncRNAs expression in preeclampsia placenta reveals the potential role of LncRNAs contributing to preeclampsia pathogenesis. PLoS One. 2013;8:e81437.

Raymond D, Peterson E. A critical review of early-onset and late-onset preeclampsia. Obstet Gynecol Survey. 2011;66:497-506.

CrossRef

Whitley GS, Cartwright JE. Trophoblast-mediated spiral artery remodelling: a role for apoptosis. J Anat. 2009;215:21-6.

CrossRef PubMed Google Scholar

Sato Y, Fujiwara H, Konishi I. Mechanism of maternal vascular remodeling during human pregnancy. Reprod Med Biol. 2012;11:27-36.

CrossRef PubMed Google Scholar

Qu H, Khalil RA. Vascular mechanisms and molecular targets in hypertensive pregnancy and preeclampsia. Am J Physiol Heart Circ Physiol. 2020;319:H661-81.

CrossRef PubMed Google Scholar

Ahmad P, Bensaoud C, Mekki I, Rehman MU, Kotsyfakis M. Long non-coding RNAs and their potential roles in the vector-host-pathogen triad. Life (Basel). 2021;11.

PubMed

Zhao Y-H, Liu Y-L, Fei K-L, Li P. Long non-coding RNA HOTAIR modulates the progression of preeclampsia through inhibiting miR-106 in an EZH2-dependent manner. Life Sciences. 2020;253.

Pengjie Z, Xionghui C, Yueming Z, Ting X, Na L, Jianying T, et al. LncRNA uc003fir promotes CCL5 expression and negatively affects proliferation and migration of trophoblast cells in preeclampsia. Pregnancy Hypertension. 2018;14:90-6.

Tong J, Zhao W, Lv H, Li WP, Chen ZJ, Zhang C. Transcriptomic profiling in human decidua of severe preeclampsia detected by RNA sequencing. J Cell Biochem. 2018;119:607-15.

Long W, Rui C, Song X, Dai X, Xue X, Lu Y, et al. Distinct expression profiles of lncRNAs between early-onset preeclampsia and preterm controls. Clin Chim Acta. 2016;463:193-9.

CrossRef

Xie X, Tang B, Xiao Y-F, Xie R, Li B-S, Dong H, et al. Long non-coding RNAs in colorectal cancer. Oncotarget. 2016;7:5226.

Yu L, Kuang LY, He F, Du LL, Li QL, Sun W, et al. The role and molecular mechanism of long nocoding RNA-MEG3 in the pathogenesis of preeclampsia. Reprod Sci. 2018;25:1619-28.

Wang R, Zou L. Downregulation of LncRNA-MEG3 promotes HTR8/SVneo cells apoptosis and attenuates its migration by repressing Notch1 signal in preeclampsia. Reproduction. 2020;160:21-9.

CrossRef PubMed Google Scholar

Liu W, Luo M, Zou L, Liu X, Wang R, Tao H, et al. uNK cell-derived TGF-beta1 regulates the long noncoding RNA MEG3 to control vascular smooth muscle cell migration and apoptosis in spiral artery remodeling. J Cell Biochem. 2019;120:15997-6007.

Liu W, Liu X, Luo M, Liu X, Luo Q, Tao H, et al. dNK derived IFN-gamma mediates VSMC migration and apoptosis via the induction of LncRNA MEG3: a role in uterovascular transformation. Placenta. 2017;50:32-9.

Abdi Pastaki M, Salimi S, Heidari Z, Saravani M. An Association Between GAS5 rs145204276, NEAT1 rs512715, and MEG3 rs4081134 Gene Polymorphisms and Papillary Thyroid Carcinoma. Rep Biochem Mol Biol. 2023;12:487-94.

CrossRef PubMed Google Scholar

Zhou Y, Zhang X, Klibanski A. MEG3 noncoding RNA: a tumor suppressor. J Mol Endocrinol. 2012;48:R45-53.

Zhou Y, Zhong Y, Wang Y, Zhang X, Batista DL, Gejman R, et al. Activation of p53 by MEG3 non-coding RNA. J Biol Chem. 2007;282:24731-42.

Mondal T, Subhash S, Vaid R, Enroth S, Uday S, Reinius B, et al. MEG3 long noncoding RNA regulates the TGF-β pathway genes through formation of RNA–DNA triplex structures. Nat Commun. 2015;6:7743.

Zhang X, Gejman R, Mahta A, Zhong Y, Rice KA, Zhou Y, et al. Maternally expressed gene 3, an imprinted noncoding RNA gene, is associated with meningioma pathogenesis and progression. Cancer Res. 2010;70:2350-8.

CrossRef

Zhao J, Dahle D, Zhou Y, Zhang X, Klibanski A. Hypermethylation of the promoter region is associated with the loss of MEG3 gene expression in human pituitary tumors. J Clin Endocrinol Metab. 2005;90:2179-86.

Ghafouri-Fard S, Taheri M. Maternally expressed gene 3 (MEG3): a tumor suppressor long non coding RNA. Biomed Pharmacother. 2019;118:109129.

CrossRef PubMed Google Scholar

Shihabudeen Haider Ali MS, Cheng X, Moran M, Haemmig S, Naldrett MJ, Alvarez S, et al. LncRNA Meg3 protects endothelial function by regulating the DNA damage response. Nucleic Acids Res. 2019;47:1505-22.

CrossRef

Lyu Y, Lou J, Yang Y, Feng J, Hao Y, Huang S, et al. Dysfunction of the WT1-MEG3 signaling promotes AML leukemogenesis via p53-dependent and-independent pathways. Leukemia. 2017;31:2543-51.

Hou Y, Zhang B, Miao L, Ji Y, Yu Y, Zhu L, et al. Association of long non-coding RNA MEG3 polymorphisms with oral squamous cell carcinoma risk. Oral Dis. 2019;25:1318-24.

CrossRef

Wang P, Chen D, Ma H, Li Y. LncRNA MEG3 enhances cisplatin sensitivity in non-small cell lung cancer by regulating miR-21-5p/SOX7 axis. Onco Targets Ther. 2017:5137-49.

Sanchez-Duffhues G, Williams E, Goumans M-J, Heldin C-H, Ten Dijke P. Bone morphogenetic protein receptors: structure, function and targeting by selective small molecule kinase inhibitors. Bone. 2020;138:115472.

CrossRef PubMed Google Scholar

Andruska A, Spiekerkoetter E. Consequences of BMPR2 deficiency in the pulmonary vasculature and beyond: contributions to pulmonary arterial hypertension. Int J Mol Sci. 2018;19:2499.

CrossRef PubMed Google Scholar

Kolkova Z, Holubekova V, Grendar M, Nachajova M, Zubor P, Pribulova T, et al. Association of circulating miRNA expression with preeclampsia, its onset, and severity. Diagnostics (Basel). 2021;11:476.

CrossRef

Jairajpuri DS, Malalla ZH, Mahmood N, Almawi WY. Circulating microRNA expression as predictor of preeclampsia and its severity. Gene. 2017;627:543-8.

CrossRef PubMed Google Scholar

Liu H, Cai X, Liu J, Zhang F, He A, Li R. The lncRNA MEG3 promotes trophoblastic cell growth and invasiveness in preeclampsia by acting as a sponge for miR-21, which regulates BMPR2 levels. Eur J Histochem. 2021;65.

Zhang Y, Zou Y, Wang W, Zuo Q, Jiang Z, Sun M, et al. Down-regulated long non-coding RNA MEG3 and its effect on promoting apoptosis and suppressing migration of trophoblast cells. Journal of Cellular Biochemistry. 2015;116:542-50.

CrossRef

Pastaki MA, Salimi S, Heidari Z, Saravani M. An association between GAS5 rs145204276, NEAT1 rs512715, and MEG3 rs4081134 gene polymorphisms and papillary thyroid carcinoma. Rep Biochem Mol Biol. 2023;12:487.

Zhuo Z-J, Zhang R, Zhang J, Zhu J, Yang T, Zou Y, et al. Associations between lncRNA MEG3 polymorphisms and neuroblastoma risk in Chinese children. Aging (Albany NY). 2018;10:481-91.

CrossRef

Yang Z, Li H, Li J, Lv X, Gao M, Bi Y, et al. Association between long noncoding RNA MEG3 polymorphisms and lung cancer susceptibility in Chinese northeast population. DNA Cell Biol. 2018;37:812-20.