Investigating the Role of Fetal Gene Expression in Preterm Birth.
Second-trimester amniotic fluid supernatant (AFS) contains cell-free fetal RNA (cffRNA) transcripts that can provide information about fetal gene expression. In a retrospective case-control study, we measured second-trimester fetal gene expression using cffRNA extracted from AFS in women who had spontaneous preterm birth (sPTB) <34 weeks and in women who delivered >37 weeks. We extracted cffRNA from AFS of women with singletons who had second-trimester genetic amniocenteses. Twenty-one gravidas who had sPTB and 21 term controls were matched 1:1 for maternal age, fetal sex, race, gestational age (GA) at the time of amniocentesis, and medication exposure. Cell-free fetal RNA was extracted and hybridized to a customized 65-gene NanoString panel containing genes related to oxidative stress, inflammation, and hypothalamic-pituitary-adrenal (HPA) axis and included 15 housekeeping genes. Two models were run, 1 examining sPTB in relation to case/control status and 1 examining sPTB in relation to GA as a continuous variable. Among cases, the gene expression of nitric oxide synthase 1 ( NOS1), d-aspartate oxidase ( DDO), and Beta-2-microglobulin ( B2M) was higher than controls ( P value < .05; false discovery rate-corrected Q value of ≤0.10). Nitric oxide synthase 1 and DDO are genes associated with oxidative stress; B2M is a marker of the fetal inflammatory response. Fetal HPA gene expression is not associated with GA at delivery or sPTB in second-trimester AFS. Alterations of fetal gene expression related to inflammation and oxidative stress antedate clinical symptoms and may be useful for early identification of patients at risk of having an sPTB.
1 Division of Maternal-Fetal Medicine, Department of Obstetrics & Gynecology, University of North Carolina School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
Neeta L
NL
Vora
2 Department of Environmental Sciences and Engineering, UNC Gillings School of Global Public Health, Chapel Hill, NC, USA.
Lisa
L
Smeester
1 Division of Maternal-Fetal Medicine, Department of Obstetrics & Gynecology, University of North Carolina School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
Kim
K
Boggess
2 Department of Environmental Sciences and Engineering, UNC Gillings School of Global Public Health, Chapel Hill, NC, USA.
Rebecca C
RC
Fry
D000328:Adult; D000653:Amniotic Fluid / Q000378:metabolism*; D016022:Case-Control Studies; D000073888:Cell-Free Nucleic Acids; D005260:Female; D015870:Gene Expression; D005865:Gestational Age; D006801:Humans; D007249:Inflammation / Q000235:genetics / Q000378:metabolism; D018384:Oxidative Stress / Q000235:genetics; D011247:Pregnancy; D011262:Pregnancy Trimester, Second; D047928:Premature Birth / Q000235:genetics* / Q000378:metabolism; D012189:Retrospective Studies
D000073888:Cell-Free Nucleic Acids
cell-free fetal RNA; inflammation; oxidative stress; preterm birth
Nat Biotechnol. 2008 Mar;26(3):317-25
18278033
Science. 2014 Aug 15;345(6198):760-5
25124429
Clin Chem. 2007 Apr;53(4):796-8
17405949
Proc Natl Acad Sci U S A. 2014 May 20;111(20):7361-6
24799715
Curr Protoc Mol Biol. 2011 Apr;Chapter 25:Unit25B.10
21472696
Am J Physiol. 1997 Jun;272(6 Pt 1):E1008-15
9227445
Genomics. 2013 Mar;101(3):163-70
23298525
Biochem Biophys Res Commun. 1993 Jul 15;194(1):1-8
7687424
Hum Reprod. 2004 Mar;19(3):723-4
14998976
Am J Obstet Gynecol. 1993 Nov;169(5):1285-91
7694467
Genome Biol. 2007;8(7):R133
17612401
Obstet Gynecol. 2001 Dec;98(6):1080-8
11755557
Nature. 1987 Oct 8-14;329(6139):506-12
3309677
Clin Perinatol. 2014 Dec;41(4):773-85
25459773
Am J Obstet Gynecol. 2015 Apr;212(4):533.e1-9
25687563
PLoS One. 2011 Feb 25;6(2):e17490
21364760
PLoS One. 2012;7(11):e47642
23144825
Prenat Diagn. 2016 Aug;36(8):738-43
27257136
J Clin Periodontol. 2005 Jan;32(1):45-52
15642058
Prenat Diagn. 2011 Jun;31(6):598-9
21480301