Objective To systematically review the literature on human gene expression data of placental tissue in pre-eclampsia and to characterize a meta-signature of differentially expressed genes in order to identify novel putative diagnostic markers. Data Sources Medline through 11 February 2011 using MeSH terms and keywords related to placenta, gene expression and gene expression arrays; GEO database using the term “placent*”; and reference lists of eligible primary studies, without constraints. Methods From 1068 studies retrieved from the search, we included original publications that had performed gene expression array analyses of placental tissue in the third trimester and that reported on differentially expressed genes in pre-eclampsia versus normotensive controls. Two reviewers independently identified eligible studies, extracted descriptive and gene expression data and assessed study quality. Using a vote-counting method based on a comparative meta-profiling algorithm, we determined a meta-signature that characterizes the significant intersection of differentially expressed genes from the collection of independent gene signatures. Results We identified 33 eligible gene expression array studies of placental tissue in the 3rd trimester comprising 30 datasets on mRNA expression and 4 datasets on microRNA expression. The pre-eclamptic placental meta-signature consisted of 40 annotated gene transcripts and 17 microRNAs. At least half of the mRNA transcripts encode a protein that is secreted from the cell and could potentially serve as a biomarker. Conclusions In addition to well-known and validated genes, we identified 14 transcripts not reported previously in relation to pre-eclampsia of which the majority is also expressed in the 1st trimester placenta, and three encode a secreted protein.
References
[1]
Steegers EA, von Dadelszen P, Duvekot JJ, Pijnenborg R (2010) Pre-eclampsia. Lancet 376: 631–644.
[2]
Roberts JM, Hubel CA (2009) The Two Stage Model of Preeclampsia: Variations on the Theme. Placenta 30: 32–37.
[3]
Huppertz B (2008) Placental origins of preeclampsia: challenging the current hypothesis. Hypertension 51: 970–975.
[4]
Maynard SE, Min JY, Merchan J, Lim KH, Li J, et al. (2003) Excess placental soluble fms-like tyrosine kinase 1 (sFlt1) may contribute to endothelial dysfunction, hypertension, and proteinuria in preeclampsia. J Clin Invest 111: 649–658.
[5]
Venkatesha S, Toporsian M, Lam C, Hanai J, Mammoto T, et al. (2006) Soluble endoglin contributes to the pathogenesis of preeclampsia. Nat Med 12: 642–649.
[6]
Ein-Dor L, Kela I, Getz G, Givol D, Domany E (2005) Outcome signature genes in breast cancer: is there a unique set? Bioinformatics 21: 171–178.
[7]
Liberati A, Altman DG, Tetzlaff J, Mulrow C, Gotzsche PC, et al. (2009) The PRISMA statement for reporting systematic reviews and meta-analyses of studies that evaluate healthcare interventions: explanation and elaboration. BMJ 339: b2700.
[8]
Stroup DF, Berlin JA, Morton SC, Olkin I, Williamson GD, et al. (2000) Meta-analysis of observational studies in epidemiology: a proposal for reporting. Meta-analysis Of Observational Studies in Epidemiology (MOOSE) group. JAMA 283: 2008–2012.
[9]
Brown MA, Lindheimer MD, de Swiet M, Van Assche A, Moutquin JM (2001) The classification and diagnosis of the hypertensive disorders of pregnancy: statement from the International Society for the Study of Hypertension in Pregnancy (ISSHP). Hypertens Pregnancy 20: IX–XIV.
[10]
Pang ZJ, Xing FQ (2004) DNA microarrays detect the expression of apoptosis-related genes in preeclamptic placentas. J Perinat Med 32: 25–30.
[11]
Pang ZJ, Xing FQ (2003) Comparative study on the expression of cytokine–receptor genes in normal and preeclamptic human placentas using DNA microarrays. J Perinat Med 31: 153–162.
[12]
Pang ZJ, Xing FQ (2004) Comparative profiling of metabolism-related gene expression in pre-eclamptic and normal pregnancies. Arch Gynecol Obstet 269: 91–95.
[13]
Pang ZJ, Xing FQ (2003) Expression profile of trophoblast invasion-associated genes in the pre-eclamptic placenta. Br J Biomed Sci 60: 97–101.
[14]
Jarvenpaa J, Vuoristo JT, Santaniemi M, Ukkola O, Savolainen ER, et al. (2009) Adiponectin induced placental cell apoptosis could be mediated via the ADIPOR1-receptor in pre-eclampsia with IUGR. J Perinat Med 37: 257–262.
[15]
Jarvenpaa J, Vuoristo JT, Savolainen ER, Ukkola O, Vaskivuo T, et al. (2007) Altered expression of angiogenesis-related placental genes in pre-eclampsia associated with intrauterine growth restriction. Gynecol Endocrinol 23: 351–355.
[16]
Rhodes DR, Yu J, Shanker K, Deshpande N, Varambally R, et al. (2004) Large-scale meta-analysis of cancer microarray data identifies common transcriptional profiles of neoplastic transformation and progression. Proc Natl Acad Sci U S A 101: 9309–9314.
[17]
Szklarczyk D, Franceschini A, Kuhn M, Simonovic M, Roth A, et al. (2011) The STRING database in 2011: functional interaction networks of proteins, globally integrated and scored. Nucleic Acids Res 39: D561–D568.
[18]
Ahr A, Holtrich U, Karn T, Reitter A, Rody A, et al. (2006) [Identification of preeclampsia by cDNA-gene expression profiling in human placentas and serum – a pilot study]. Zentralbl Gynakol 128: 138–142.
[19]
Centlow M, Wingren C, Borrebaeck C, Brownstein MJ, Hansson SR (2011) Differential gene expression analysis of placentas with increased vascular resistance and pre-eclampsia using whole-genome microarrays. J Pregnancy 2011: 472354.
[20]
Enquobahrie DA, Meller M, Rice K, Psaty BM, Siscovick DS, et al. (2008) Differential placental gene expression in preeclampsia. Am J Obstet Gynecol 199: 566.e1–11.
[21]
Gack S, Marme A, Marme F, Wrobel G, Vonderstrass B, et al. (2005) Preeclampsia: increased expression of soluble ADAM 12. J Mol Med (Berl) 83: 887–896.
[22]
Han JY, Kim YS, Cho GJ, Roh GS, Kim HJ, et al. (2006) Altered gene expression of caspase-10, death receptor-3 and IGFBP-3 in preeclamptic placentas. Mol Cells 22: 168–174.
[23]
Hansson SR, Chen Y, Brodszki J, Chen M, Hernandez-Andrade E, et al. (2006) Gene expression profiling of human placentas from preeclamptic and normotensive pregnancies. Mol Hum Reprod 12: 169–179.
[24]
Heikkila A, Tuomisto T, Hakkinen SK, Keski-Nisula L, Heinonen S, et al. (2005) Tumor suppressor and growth regulatory genes are overexpressed in severe early-onset preeclampsia–an array study on case-specific human preeclamptic placental tissue. Acta Obstet Gynecol Scand 84: 679–689.
[25]
Herse F, Dechend R, Harsem NK, Wallukat G, Janke J, et al. (2007) Dysregulation of the circulating and tissue-based renin-angiotensin system in preeclampsia. Hypertension 49: 604–611.
[26]
Hoegh AM, Borup R, Nielsen FC, Sorensen S, Hviid TV (2010) Gene expression profiling of placentas affected by pre-eclampsia. J Biomed Biotechnol 2010: 787545.
[27]
Kang JH, Song H, Yoon JA, Park DY, Kim SH, et al. (2011) Preeclampsia leads to dysregulation of various signaling pathways in placenta. J Hypertens 29: 928–936.
[28]
Lee GS, Joe YS, Kim SJ, Shin JC (2010) Cytokine-related genes and oxidation-related genes detected in preeclamptic placentas. Arch Gynecol Obstet 282: 363–369.
[29]
Liu Y, Li N, You L, Liu X, Li H, et al. (2008) HSP70 is associated with endothelial activation in placental vascular diseases. Mol Med 14: 561–566.
[30]
Mayor-Lynn K, Toloubeydokhti T, Cruz AC, Chegini N (2011) Expression profile of microRNAs and mRNAs in human placentas from pregnancies complicated by preeclampsia and preterm labor. Reprod Sci 18: 46–56.
[31]
Nishizawa H, Ota S, Suzuki M, Kato T, Sekiya T, et al. (2011) Comparative gene expression profiling of placentas from patients with severe pre-eclampsia and unexplained fetal growth restriction. Reprod Biol Endocrinol 9: 107.
[32]
Nishizawa H, Pryor-Koishi K, Kato T, Kowa H, Kurahashi H, et al. (2007) Microarray analysis of differentially expressed fetal genes in placental tissue derived from early and late onset severe pre-eclampsia. Placenta 28: 487–497.
[33]
Reimer T, Koczan D, Gerber B, Richter D, Thiesen HJ, et al. (2002) Microarray analysis of differentially expressed genes in placental tissue of pre-eclampsia: up-regulation of obesity-related genes. Mol Hum Reprod 8: 674–680.
[34]
Sitras V, Paulssen RH, Gronaas H, Leirvik J, Hanssen TA, et al. (2009) Differential placental gene expression in severe preeclampsia. Placenta 30: 424–433.
[35]
Soleymanlou N, Jurisica I, Nevo O, Ietta F, Zhang X, et al. (2005) Molecular evidence of placental hypoxia in preeclampsia. J Clin Endocrinol Metab 90: 4299–4308.
[36]
Tsai S, Hardison NE, James AH, Motsinger-Reif AA, Bischoff SR, et al. (2011) Transcriptional profiling of human placentas from pregnancies complicated by preeclampsia reveals disregulation of sialic acid acetylesterase and immune signalling pathways. Placenta 32: 175–182.
[37]
Tsoi SC, Cale JM, Bird IM, Kay HH (2003) cDNA microarray analysis of gene expression profiles in human placenta: up-regulation of the transcript encoding muscle subunit of glycogen phosphorylase in preeclampsia. J Soc Gynecol Investig 10: 496–502.
[38]
Vaiman D, Mondon F, Garces-Duran A, Mignot TM, Robert B, et al. (2005) Hypoxia-activated genes from early placenta are elevated in preeclampsia, but not in Intra-Uterine Growth Retardation. BMC Genomics 6: 111.
[39]
Varkonyi T, Nagy B, Fule T, Tarca AL, Karaszi K, et al. (2011) Microarray profiling reveals that placental transcriptomes of early-onset HELLP syndrome and preeclampsia are similar. Placenta 32 Suppl: S21–S29
[40]
Winn VD, Gormley M, Paquet AC, Kjaer-Sorensen K, Kramer A, et al. (2009) Severe preeclampsia-related changes in gene expression at the maternal-fetal interface include sialic acid-binding immunoglobulin-like lectin-6 and pappalysin-2. Endocrinology 150: 452–462.
[41]
Zhou R, Zhu Q, Wang Y, Ren Y, Zhang L, et al. (2006) Genomewide oligonucleotide microarray analysis on placentae of pre-eclamptic pregnancies. Gynecol Obstet Invest 62: 108–114.
[42]
Enquobahrie DA, Abetew DF, Sorensen TK, Willoughby D, Chidambaram K, et al. (2011) Placental microRNA expression in pregnancies complicated by preeclampsia. Am J Obstet Gynecol 204: 178.e12–21.
[43]
Hu Y, Li P, Hao S, Liu L, Zhao J, et al. (2009) Differential expression of microRNAs in the placentae of Chinese patients with severe pre-eclampsia. Clin Chem Lab Med 47: 923–929.
[44]
Zhu XM, Han T, Sargent IL, Yin GW, Yao YQ (2009) Differential expression profile of microRNAs in human placentas from preeclamptic pregnancies vs normal pregnancies. Am J Obstet Gynecol 200: 661–667.
[45]
Huang da W, Sherman BT, Lempicki RA (2009) Systematic and integrative analysis of large gene lists using DAVID bioinformatics resources. Nat Protoc 4: 44–57.
[46]
Maynard SE, Karumanchi SA (2011) Angiogenic factors and preeclampsia. Semin Nephrol 31: 33–46.
[47]
Foidart JM, Schaaps JP, Chantraine F, Munaut C, Lorquet S (2009) Dysregulation of anti-angiogenic agents (sFlt-1, PLGF, and sEndoglin) in preeclampsia–a step forward but not the definitive answer. J Reprod Immunol 82: 106–111.
[48]
Verlohren S, Stepan H, Dechend R (2012) Angiogenic growth factors in the diagnosis and prediction of pre-eclampsia. Clin Sci (Lond) 122: 43–52.
[49]
El-Gharib MN, Morad M (2011) Maternal serum inhibin-A for predicting preeclampsia. J Matern Fetal Neonatal Med 24: 595–599.
[50]
Fitzgerald B, Levytska K, Kingdom J, Walker M, Baczyk D, et al. (2011) Villous trophoblast abnormalities in extremely preterm deliveries with elevated second trimester maternal serum hCG or inhibin-A. Placenta 32: 339–345.
[51]
Guo J, Tian T, Lu D, Xia G, Wang H, et al. (2012) Alterations of maternal serum and placental follistatin-like 3 and myostatin in pre-eclampsia. J Obstet Gynaecol Res 38: 988–996.
[52]
Morris RK, Cnossen JS, Langejans M, Robson SC, Kleijnen J, et al. (2008) Serum screening with Down’s syndrome markers to predict pre-eclampsia and small for gestational age: systematic review and meta-analysis. BMC Pregnancy Childbirth 8: 33.
[53]
Olsen RN, Woelkers D, Dunsmoor-Su R, Lacoursiere DY (2012) Abnormal second-trimester serum analytes are more predictive of preterm preeclampsia. Am J Obstet Gynecol 207: 228–7.
[54]
Perkins AV, Linton EA, Eben F, Simpson J, Wolfe CD, et al. (1995) Corticotrophin-releasing hormone and corticotrophin-releasing hormone binding protein in normal and pre-eclamptic human pregnancies. Br J Obstet Gynaecol 102: 118–122.
[55]
Shen Z, Cai LY, Suprapto IS, Shenoy P, Zhou X (2011) Placental and maternal serum inhibin A in patients with preeclampsia and small-for-gestational-age. J Obstet Gynaecol Res 37: 1290–1296.
[56]
Rumer KK, Uyenishi J, Hoffman MC, Fisher BM, Winn VD (2013) Siglec-6 expression is increased in placentas from pregnancies complicated by preterm preeclampsia. Reprod Sci 20: 646–653.
[57]
Askelund KJ, Chamley LW (2011) Trophoblast deportation part I: review of the evidence demonstrating trophoblast shedding and deportation during human pregnancy. Placenta 32: 716–723.
[58]
Rajakumar A, Cerdeira AS, Rana S, Zsengeller Z, Edmunds L, et al. (2012) Transcriptionally active syncytial aggregates in the maternal circulation may contribute to circulating soluble fms-like tyrosine kinase 1 in preeclampsia. Hypertension 59: 256–264.
[59]
Founds SA, Conley YP, Lyons-Weiler JF, Jeyabalan A, Hogge WA, et al. (2009) Altered global gene expression in first trimester placentas of women destined to develop preeclampsia. Placenta 30: 15–24.
[60]
Farina A, Morano D, Arcelli D, De Sanctis P, Sekizawa A, et al. (2009) Gene expression in chorionic villous samples at 11 weeks of gestation in women who develop preeclampsia later in pregnancy: implications for screening. Prenat Diagn 29: 1038–1044.
[61]
Mikheev AM, Nabekura T, Kaddoumi A, Bammler TK, Govindarajan R, et al. (2008) Profiling gene expression in human placentae of different gestational ages: an OPRU Network and UW SCOR Study. Reprod Sci 15: 866–877.
[62]
Huntzinger E, Izaurralde E (2011) Gene silencing by microRNAs: contributions of translational repression and mRNA decay. Nat Rev Genet 12: 99–110.
