Global alteration in gene expression profiles of deciduas from women with idiopathic recurrent pregnancy loss

Abstract

Recurrent pregnancy loss (RPL) occurs in ∼5% of women. However, the etiology is still poorly understood. Defects in decidualization of the endometrium during early pregnancy contribute to several pregnancy complications, such as pre-eclampsia and intrauterine growth restriction (IUGR), and are believed to be important in the pathogenesis of idiopathic RPL. We performed microarray analysis to identify gene expression alterations in the deciduas of idiopathic RPL patients. Control patients had one antecedent term delivery, but were undergoing dilation and curettage for current aneuploid miscarriage. Gene expression differences were evaluated using both pathway and gene ontology (GO) analysis. Selected genes were validated using quantitative reverse transcription-polymerase chain reaction (qRT-PCR). A total of 155 genes were found to be significantly dysregulated in the deciduas of RPL patients (>2-fold change, P < 0.05), with 22 genes up-regulated and 133 genes down-regulated. GO analysis linked a large percentage of genes to discrete biological functions, including immune response (23%), cell signaling (18%) and cell invasion (17.1%), and pathway analysis revealed consistent changes in both the interleukin 1 (IL-1) and IL-8 pathways. All genes in the IL-8 pathway were up-regulated while genes in the IL-1 pathway were down-regulated. Although both pathways can promote inflammation, IL-1 pathway activity is important for normal implantation. Additionally, genes known to be critical for degradation of the extracellular matrix, including matrix metalloproteinase 26 and serine peptidase inhibitor Kazal-type 1, were also highly up-regulated. In this first microarray approach to decidual gene expression in RPL patients, our data suggest that dysregulation of genes associated with cell invasion and immunity may contribute significantly to idiopathic recurrent miscarriage.

Sphingolipid Pathway Regulates Innate Immune Responses at the Fetomaternal Interface during Pregnancy

“…Similar results were observed in human first-trimester DSCs in which the Sphk deficiency dramatically increased the secretion of CXCL1, IL-8, and IL-6. Recent microarray analysis demonstrated for the first time that genes in the IL-8 pathway were up-regulated in deciduas from patients with idiopathic RPL compared with those from control miscarriage patients with aneuploid embryonic demises who had experienced at least one term delivery and no previous miscarriages (50). Taken together, these results indicate that Sphk-deficient mice may be a useful animal model for gaining a comprehensive understanding of the mechanisms underlying pregnancy loss and assist in the development of treatment for human idiopathic RPL.…”

Functional single nucleotide polymorphisms of matrix metalloproteinase 7 and 12 genes in idiopathic recurrent spontaneous abortion

“…The MMP12 is a key mediator of elastolysis and contributes to the remodeling of spiral arteries. Expression of the MMP12 gene was found to be upregulated in deciduas of women with IRSA compared to controls [12]. The A allele of the MMP12 -82 A/G SNP enhances the binding of the transcription factor activator protein 1, increasing promoter activity [45].…”

“…During the secretory phase, including the implantation window and decidual transformation, the expression profiles of endometrial genes are changed considerably compared to proliferative phase [5][6][7][8]. It has been suggested that abnormalities in gene expression during the secretory phase may lead to inappropriate endometrial development and, consequently, various reproductive disorders, including recurrent spontaneous abortion [9][10][11][12].…”

“…Earlier studies have reported alterations in the expression of several MMP genes in women with IRSA and their spontaneously aborted conceptuses compared to women with normal pregnancies, which can lead to an altered ECM turnover [10,12,[17][18][19][20][21][22][23][24]. In addition, we previously evaluated the potential association of MMP1, 2, 3, and 9 functional single nucleotide polymorphisms (SNP) with IRSA and found a statistically significant increased frequency of the MMP2 -735 CT and MMP9 -1562 CC genotypes in IRSA women compared to controls, suggesting that these might be risk genotypes for IRSA [25].…”

Immunogenetic contributions to recurrent pregnancy loss

“…It has not been studied greatly, however in patients with euploid miscarriages, upregulation of the proinflammatory IL-8 in the decidua has been seen [123].…”