Transcriptomics Reveals Preterm Birth Risk: Identification and Validation of Key Genes in Monocytes

Overview

Journal BMC Pregnancy Childbirth

Publisher Biomed Central

Specialty Gynecology & Obstetrics

Date 2025 Feb 18

PMID 39962466

Authors

Tianqi Wang

Lu Sun

Meng Li

Yaozhong Zhang

Lu Huang

Affiliations

Soon will be listed here.

Abstract

Background: Preterm birth (PTB) is a leading cause of neonatal mortality and long-term disability worldwide. However, the molecular mechanisms underlying PTB remain incompletely understood, and the etiology of many PTB cases is still largely unexplained. Due to their close association with PTB, monocytes serve as an ideal matrix for identifying peripheral biomarkers predictive of preterm birth risk.

Objective: This study aims to identify and validate biomarkers that could predict PTB, improving clinical diagnostic accuracy and enhancing preventive measures against PTB.

Methods: This study conducted a comprehensive transcriptomic analysis of monocytes obtained from PTB patients (gestational age = 28-36 weeks) and age-matched healthy controls (HC, gestational age = 37-41 weeks). Blood samples were collected within 30 min of hospital admission and prior to labor initiation to ensure consistency. We further validated the findings after screening for potential biomarkers using quantitative real-time PCR (qPCR). While the sample size was relatively small, this study provides foundational evidence supporting the role of CXCL3 and IL-6 as biomarkers for PTB, laying a framework for future prospective research.

Results: We identified 295 significantly differentially expressed genes compared to the control group, and Weighted Gene Co-expression Network Analysis (WGCNA) further revealed genes significantly associated with PTB. These genes are involved in immune pathways such as rheumatoid arthritis, influenza A, and the MAPK signaling pathway. Machine learning analysis and qPCR validation identified two essential genes-CXCL3 and IL-6. Based on these two genes, the diagnostic model achieved an AUC value of 1 in the discovery cohort, distinguishing PTB patients from healthy controls.

Conclusion: The immune responses observed in peripheral blood mononuclear cells (PBMCs) may be closely related to the mechanisms underlying PTB. Monocyte-derived genes CXCL3 and IL-6 are promising biomarkers for predicting PTB risk, offering new diagnostic tools for clinical practice. These findings have the potential to enhance PTB prevention and management strategies.

References

Mandrekar J . Receiver operating characteristic curve in diagnostic test assessment. J Thorac Oncol. 2010; 5(9):1315-6. DOI: 10.1097/JTO.0b013e3181ec173d. View

Gui S, Ni S, Jia J, Gong Y, Gao L, Zhang L . Inconformity of CXCL3 plasma level and placenta expression in preeclampsia and its effect on trophoblast viability and invasion. PLoS One. 2014; 9(12):e114408. PMC: 4259324. DOI: 10.1371/journal.pone.0114408. View

Prairie E, Cote F, Tsakpinoglou M, Mina M, Quiniou C, Leimert K . The determinant role of IL-6 in the establishment of inflammation leading to spontaneous preterm birth. Cytokine Growth Factor Rev. 2021; 59:118-130. DOI: 10.1016/j.cytogfr.2020.12.004. View

Peng L, Zhao W, Yin T, Xu C, Wang G, Du M . The unique expression pattern of human leukocyte antigen in trophoblasts potentially explains the key mechanism of maternal-fetal tolerance and successful pregnancy. J Reprod Immunol. 2023; 158:103980. DOI: 10.1016/j.jri.2023.103980. View

Paulsson L, Arvini S, Bergstrom N, Klingberg G, Lindh C . The impact of premature birth on dental maturation in the permanent dentition. Clin Oral Investig. 2018; 23(2):855-861. PMC: 7736023. DOI: 10.1007/s00784-018-2501-3. View

Ginhoux F, Jung S . Monocytes and macrophages: developmental pathways and tissue homeostasis. Nat Rev Immunol. 2014; 14(6):392-404. DOI: 10.1038/nri3671. View

Inversetti A, Zambella E, Guarano A, DellAvanzo M, Di Simone N . Endometrial Microbiota and Immune Tolerance in Pregnancy. Int J Mol Sci. 2023; 24(3). PMC: 9917440. DOI: 10.3390/ijms24032995. View

Holst R, Hagberg H, Wennerholm U, Skogstrand K, Thorsen P, Jacobsson B . Prediction of spontaneous preterm delivery in women with preterm labor: analysis of multiple proteins in amniotic and cervical fluids. Obstet Gynecol. 2009; 114(2 Pt 1):268-277. DOI: 10.1097/AOG.0b013e3181ae6a08. View

Wang L, Liu Z, Huang D, Ran Y, Zhang H, He J . IL-37 Exerts Anti-Inflammatory Effects in Fetal Membranes of Spontaneous Preterm Birth via the NF-B and IL-6/STAT3 Signaling Pathway. Mediators Inflamm. 2020; 2020:1069563. PMC: 7369678. DOI: 10.1155/2020/1069563. View

10.

Cheng Y, Yang X, Liang L, Xin H, Dong X, Li W . Elevated expression of CXCL3 in colon cancer promotes malignant behaviors of tumor cells in an ERK-dependent manner. BMC Cancer. 2023; 23(1):1162. PMC: 10685652. DOI: 10.1186/s12885-023-11655-y. View

11.

Chen D, Liu J, Zang L, Xiao T, Zhang X, Li Z . Integrated Machine Learning and Bioinformatic Analyses Constructed a Novel Stemness-Related Classifier to Predict Prognosis and Immunotherapy Responses for Hepatocellular Carcinoma Patients. Int J Biol Sci. 2022; 18(1):360-373. PMC: 8692161. DOI: 10.7150/ijbs.66913. View

12.

Liao L, Liu M, Gao Y, Wei X, Yin Y, Gao L . The long noncoding RNA TARID regulates the CXCL3/ERK/MAPK pathway in trophoblasts and is associated with preeclampsia. Reprod Biol Endocrinol. 2022; 20(1):159. PMC: 9675252. DOI: 10.1186/s12958-022-01036-8. View

13.

Goossens J, Morrens M, Coppens V . The Potential Use of Peripheral Blood Mononuclear Cells as Biomarkers for Treatment Response and Outcome Prediction in Psychiatry: A Systematic Review. Mol Diagn Ther. 2021; 25(3):283-299. DOI: 10.1007/s40291-021-00516-8. View

14.

Aziz A, Saleem S, Nolen T, Pradhan N, McClure E, Jessani S . Why are the Pakistani maternal, fetal and newborn outcomes so poor compared to other low and middle-income countries?. Reprod Health. 2020; 17(Suppl 3):190. PMC: 7745345. DOI: 10.1186/s12978-020-01023-5. View

15.

Uciechowski P, Dempke W . Interleukin-6: A Masterplayer in the Cytokine Network. Oncology. 2020; 98(3):131-137. DOI: 10.1159/000505099. View

16.

Mellado M, Rodriguez-Frade J, Manes S, Martinez-A C . Chemokine signaling and functional responses: the role of receptor dimerization and TK pathway activation. Annu Rev Immunol. 2001; 19:397-421. DOI: 10.1146/annurev.immunol.19.1.397. View

17.

Kubler R, Ormel P, Sommer I, Kahn R, de Witte L . Gene expression profiling of monocytes in recent-onset schizophrenia. Brain Behav Immun. 2023; 111:334-342. DOI: 10.1016/j.bbi.2023.04.019. View

18.

Chen L, Song Z, Cao X, Fan M, Zhou Y, Zhang G . Interleukin-33 regulates the endoplasmic reticulum stress of human myometrium via an influx of calcium during initiation of labor. Elife. 2022; 11. PMC: 9398448. DOI: 10.7554/eLife.75072. View

19.

Harrison M, Goldenberg R . Global burden of prematurity. Semin Fetal Neonatal Med. 2016; 21(2):74-9. DOI: 10.1016/j.siny.2015.12.007. View

20.

Ohuma E, Moller A, Bradley E, Chakwera S, Hussain-Alkhateeb L, Lewin A . National, regional, and global estimates of preterm birth in 2020, with trends from 2010: a systematic analysis. Lancet. 2023; 402(10409):1261-1271. DOI: 10.1016/S0140-6736(23)00878-4. View