Comparative analysis of gene expression in maternal peripheral blood and monocytes during spontaneous preterm labor

被引:45
作者
Paquette, Alison G. [1 ]
Shynlova, Oksana [2 ,3 ]
Kibschull, Mark [2 ]
Price, Nathan D. [1 ]
Lye, Stephen J. [2 ,3 ]
机构
[1] Inst Syst Biol, Seattle, WA USA
[2] Sinai Hlth Syst, Lunenfeld Tanenbaum Res Inst, Program Dev & Fetal Hlth, Toronto, ON, Canada
[3] Univ Toronto, Dept Obstet & Gynecol, Toronto, ON, Canada
关键词
monocytes; preterm birth; transcriptomics; CERVICAL LENGTH; TRANSCRIPTOMIC BIOMARKERS; FETAL FIBRONECTIN; MAST-CELLS; RISK; TERM; INFLAMMATION; LEUKOCYTES; BIRTH; PARTURITION;
D O I
10.1016/j.ajog.2017.12.234
中图分类号
R71 [妇产科学];
学科分类号
100211 ;
摘要
BACKGROUND: Preterm birth is the leading cause of newborn death worldwide, and is associated with significant cognitive and physiological challenges in later life. There is a pressing need to define the mechanisms that initiate spontaneous preterm labor, and for development of novel clinical biomarkers to identify high-risk pregnancies. Most preterm birth studies utilize fetal tissues, and there is limited understanding of the transcriptional changes that occur in mothers undergoing spontaneous preterm labor. Earlier work revealed that a specific population of maternal peripheral leukocytes (macrophages/monocytes) play an active role in the initiation of labor. Thus, we hypothesized that there are dynamic gene expression changes in maternal blood leukocytes during preterm labor. OBJECTIVE: Using next-generation sequencing we aim to characterize the transcriptome in whole blood leukocytes and peripheral monocytes of women undergoing spontaneous preterm labor compared to healthy pregnant women who subsequently delivered at full term. STUDY DESIGN: RNA sequencing was performed in both whole blood and peripheral monocytes from women who underwent preterm labor (24-34 weeks of gestation, N = 20) matched for gestational age to healthy pregnant controls (N = 30). All participants were a part of the Ontario Birth Study cohort (Toronto, Ontario, Canada). RESULTS: We identified significant differences in expression of 262 genes in peripheral monocytes and 184 genes in whole blood of women who were in active spontaneous preterm labor compared to pregnant women of the same gestational age not undergoing labor, with 43 of these genes differentially expressed in both whole blood and peripheral monocytes. ADAMTS2 expression was significantly increased in women actively undergoing spontaneous preterm labor, which we validated through digital droplet reverse transcriptase polymerase chain reaction. Intriguingly, we have also identified a number of gene sets including signaling by stem cell factor-KIT, nucleotide metabolism, and trans-Golgi network vesicle budding, which exhibited changes in relative gene expression that was predictive of preterm labor status in both maternal whole blood and peripheral monocytes. CONCLUSION: This study is the first to investigate changes in both whole blood leukocytes and peripheral monocytes of women actively undergoing spontaneous preterm labor through robust transcript measurements from RNA sequencing. Our unique study design overcame confounding based on gestational age by collecting blood samples from women matched by gestational age, allowing us to study transcriptomic changes directly related to the active preterm parturition. We performed RNA profiling using whole genome sequencing, which is highly sensitive and allowed us to identify subtle changes in specific genes. ADAMTS2 expression emerged as a marker of prematurity within peripheral blood leukocytes, an accessible tissue that plays a functional role in signaling during the onset of labor. We identified changes in relative gene expression in a number of gene sets related to signaling in monocytes and whole blood of women undergoing spontaneous preterm labor compared to controls. These genes and pathways may help identify potential targets for the development of novel drugs for preterm birth prevention.
引用
收藏
页码:345.e1 / 345.e30
页数:30
相关论文
共 53 条
  • [11] Phenotypic and metabolic characteristics of maternal monocytes and granulocytes in preterm labor with intact membranes
    Gervasi, MT
    Chaiworapongsa, T
    Naccasha, N
    Blackwell, S
    Yoon, BH
    Maymon, E
    Romero, R
    [J]. AMERICAN JOURNAL OF OBSTETRICS AND GYNECOLOGY, 2001, 185 (05) : 1124 - 1129
  • [12] Preterm birth 1 - Epidemiology and causes of preterm birth
    Goldenberg, Robert L.
    Culhane, Jennifer F.
    Iams, Jay D.
    Romero, Roberto
    [J]. LANCET, 2008, 371 (9606) : 75 - 84
  • [13] Maternal circulating leukocytes display early chemotactic responsiveness during late gestation
    Gomez-Lopez, Nardhy
    Tanaka, Satomi
    Zaeem, Zoya
    Metz, Gerlinde A.
    Olson, David M.
    [J]. BMC PREGNANCY AND CHILDBIRTH, 2013, 13
  • [14] The transcriptome of the uterine cervix before and after spontaneous term parturition
    Hassan, Sonia S.
    Romero, Roberto
    Haddad, Ramsi
    Hendler, Israel
    Khalek, Nahla
    Tromp, Gerard
    Diamond, Michael P.
    Sorokin, Yoram
    Malone, John, Jr.
    [J]. AMERICAN JOURNAL OF OBSTETRICS AND GYNECOLOGY, 2006, 195 (03) : 778 - 786
  • [15] Transcriptomic biomarkers for individual risk assessment in new-onset heart failure
    Heidecker, Bettina
    Kasper, Edward K.
    Wittstein, Ilan S.
    Champion, Hunter C.
    Breton, Elayne
    Russell, Stuart D.
    Kittleson, Michelle M.
    Baughman, Kenneth L.
    Hare, Joshua M.
    [J]. CIRCULATION, 2008, 118 (03) : 238 - 246
  • [16] Maternal Whole Blood Gene Expression at 18 and 28 Weeks of Gestation Associated with Spontaneous Preterm Birth in Asymptomatic Women
    Heng, Yujing J.
    Pennell, Craig E.
    McDonald, Sheila W.
    Vinturache, Angela E.
    Xu, Jingxiong
    Lee, Mary W. F.
    Briollais, Laurent
    Lyon, Andrew W.
    Slater, Donna M.
    Bocking, Alan D.
    de Koning, Lawrence
    Olson, David M.
    Dolan, Siobhan M.
    Tough, Suzanne C.
    Lye, Stephen J.
    [J]. PLOS ONE, 2016, 11 (06):
  • [17] Whole Blood Gene Expression Profile Associated with Spontaneous Preterm Birth in Women with Threatened Preterm Labor
    Heng, Yujing Jan
    Pennell, Craig Edward
    Chua, Hon Nian
    Perkins, Jonathan Edward
    Lye, Stephen James
    [J]. PLOS ONE, 2014, 9 (05):
  • [18] Prediction of preterm birth in symptomatic women using decision tree modeling for biomarkers
    Hill, Jacquelyn L.
    Campbell, Karen
    Zou, Guang Yong
    Challis, John R. G.
    Reid, Gregor
    Chisaka, Hiroshi
    Bocking, Alan D.
    [J]. AMERICAN JOURNAL OF OBSTETRICS AND GYNECOLOGY, 2008, 198 (04) : 468.e1 - 468.e9
  • [19] High-Throughput Droplet Digital PCR System for Absolute Quantitation of DNA Copy Number
    Hindson, Benjamin J.
    Ness, Kevin D.
    Masquelier, Donald A.
    Belgrader, Phillip
    Heredia, Nicholas J.
    Makarewicz, Anthony J.
    Bright, Isaac J.
    Lucero, Michael Y.
    Hiddessen, Amy L.
    Legler, Tina C.
    Kitano, Tyler K.
    Hodel, Michael R.
    Petersen, Jonathan F.
    Wyatt, Paul W.
    Steenblock, Erin R.
    Shah, Pallavi H.
    Bousse, Luc J.
    Troup, Camille B.
    Mellen, Jeffrey C.
    Wittmann, Dean K.
    Erndt, Nicholas G.
    Cauley, Thomas H.
    Koehler, Ryan T.
    So, Austin P.
    Dube, Simant
    Rose, Klint A.
    Montesclaros, Luz
    Wang, Shenglong
    Stumbo, David P.
    Hodges, Shawn P.
    Romine, Steven
    Milanovich, Fred P.
    White, Helen E.
    Regan, John F.
    Karlin-Neumann, George A.
    Hindson, Christopher M.
    Saxonov, Serge
    Colston, Bill W.
    [J]. ANALYTICAL CHEMISTRY, 2011, 83 (22) : 8604 - 8610
  • [20] Accuracy of cervical transvaginal sonography in predicting preterm birth: a systematic review
    Honest, H
    Bachmann, LM
    Coomarasamy, A
    Gupta, JK
    Kleijnen, J
    Khan, KS
    [J]. ULTRASOUND IN OBSTETRICS & GYNECOLOGY, 2003, 22 (03) : 305 - 322