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Evaluation of polymorphisms in predicted target sites for micro RNAs differentially expressed in endometriosis.

ABSTRACT: Previous microarray analyses identified 22 microRNAs (miRNAs) differentially expressed in paired ectopic and eutopic endometrium of women with and without endometriosis. To investigate further the role of these miRNAs in women with endometriosis, we conducted an association study aiming to explore the relationship between endometriosis risk and single-nucleotide polymorphisms (SNPs) in miRNA target sites for these differentially expressed miRNAs. A panel of 102 SNPs in the predicted miRNA binding sites were evaluated for an endometriosis association study and an ingenuity pathway analysis was performed. Fourteen rare variants were identified in this study. We found SNP rs14647 in the Wolf-Hirschhorn syndrome candidate gene1 (WHSC1) 3'UTR (untranslated region) was associated with endometriosis-related infertility presenting an odds ratio of 12.2 (95% confidence interval = 2.4-60.7, P = 9.03 × 10(-5)). SNP haplotype AGG in the solute carrier family 22, member 23 (SLC22A23) 3'UTR was associated with endometriosis-related infertility and more severe disease. With the individual genotyping data, ingenuity pathways analysis identified the tumour necrosis factor and cyclin-dependant kinase inhibitor as major factors in the molecular pathways. Significant associations between WHSC1 alleles and endometriosis-related infertility and SLC22A23 haplotypes and the disease severe stage were identified. These findings may help focus future research on subphenotypes of this disease. Replication studies in independent large sample sets to confirm and characterize the involvement of the gene variation in the pathogenesis of endometriosis are needed.

SUBMITTER: Zhao ZZ

PROVIDER: S-EPMC3023296 | biostudies-literature | 2011 Feb

REPOSITORIES: biostudies-literature

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Evaluation of polymorphisms in predicted target sites for micro RNAs differentially expressed in endometriosis.

Zhao Zhen Zhen ZZ Croft Larry L Croft Larry L Nyholt Dale R DR Chapman Brett B Treloar Susan A SA Hull M Louise ML Montgomery Grant W GW

Molecular human reproduction 20101008 2

Previous microarray analyses identified 22 microRNAs (miRNAs) differentially expressed in paired ectopic and eutopic endometrium of women with and without endometriosis. To investigate further the role of these miRNAs in women with endometriosis, we conducted an association study aiming to explore the relationship between endometriosis risk and single-nucleotide polymorphisms (SNPs) in miRNA target sites for these differentially expressed miRNAs. A panel of 102 SNPs in the predicted miRNA bindin ...[more]

PMID: 20935158

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Project description:Background: Endometriosis is interpreted as the existence of endometrium outside the uterine cavity, such as ovaries, fallopian tubes and pelvic cavity. Dysmenorrhea, abnormal menstruation, infertility, and chronic pelvic pain are the primary symptoms of endometriosis. Although there are many theories about the origin of endometriosis, the exact factor of the disease has not been confirmed. Therefore, many other mechanisms are still worth exploring. Materials and Methods: The gene lists of the transcription factors (TFs) were selected from the intersections of three databases. The limma R package was used to analyze the differentially expressed genes (DEGs) of GSE6364 and GSE7305 and the DEGs intersected with the TFs to obtain the differentially expressed TFs (DETFs). Subsequently, one-way ANOVA and Student's t-test were used to analyze the expression of DETFs in different phases of the endometrium and the endometrium of the infertile and fertile females with endometriosis, respectively. Enrichment analysis and PPI network were performed to reveal the molecular mechanisms of endometriosis. Finally, the plotROC R package was used to evaluate the sensitivity and specificity of hub TFs for the diagnosis of endometriosis. Results: A total of 54 DETFs were screened out in endometriosis. The expression of up-regulated DETFs was gradually increased from the early secretory to the proliferative phase of the endometrium. Most up-regulated DETFs increased expression in the endometrium of infertile females. The pathways of DETFs were mainly enriched in stem cell differentiation, transcription activity, steroid hormone receptor activity and herpes simplex virus. Two hub TFs (RUNX2 and BATF) and two sub-networks were finally acquired from the PPI network. RUNX2 and BATF also had high diagnostic value in endometriosis. Conclusion: We discovered and analyzed 54 DETFs that were closely related to endometriosis, which would contribute to explore new mechanisms of endometriosis and search for new diagnostic markers and effective therapeutic targets.

Project description:AimEndometriosis is one of the most common reproductive system diseases, but the mechanisms of disease progression are still unclear. Due to its high recurrence rate, searching for potential therapeutic biomarkers involved in the pathogenesis of endometriosis is an urgent issue.MethodsDue to the similarities between endometriosis and ovarian cancer, four endometriosis datasets and one ovarian cancer dataset were downloaded from Gene Expression Omnibus (GEO) database. Differentially expressed genes (DEGs) were identified, followed by gene ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway and protein-protein interaction (PPI) analyses. Then, we validated gene expression and performed survival analysis with ovarian serous cystadenocarcinoma (OV) datasets in TCGA/GTEx database, and searched for potential drugs in the Drug-Gene Interaction Database. Finally, we explored the miRNAs of key genes to find biomarkers associated with the recurrence of endometriosis.ResultsIn total, 104 DEGs were identified in the endometriosis datasets, and the main enriched GO functions included cell adhesion, extracellular exosome and actin binding. Fifty DEGs were identified between endometriosis and ovarian cancer datasets including 11 consistently regulated genes, and nine DEGs with significant expression in TCGA/GTEx. Only IGHM had both significant expression and an association with survival, three module DEGs and two significantly expressed DEGs had drug associations, and 10 DEGs had druggability.ConclusionsITGA7, ITGBL1 and SORBS1 may help us understand the invasive nature of endometriosis, and IGHM might be related to recurrence; moreover, these genes all may be potential therapeutic targets.KEY MESSAGEThis manuscript used a bioinformatics approach to find target genes for the treatment of endometriosis.This manuscript used a new approach to find target genes by drawing on common characteristics between ovarian cancer and endometriosis.We screened relevant therapeutic agents for target genes in the drug database, and performed histological validation of target genes with both expression and survival analysis difference in cancer databases.

Project description:Allergic asthma is one of the most common allergic diseases; however, the mechanisms underlying its development have yet to be fully elucidated. Although allergic diseases are inheritable, genetic variance alone cannot explain the notable increase in the prevalence of allergic diseases over a short period of time in recent decades. Recently, research focus has been shifting to epigenetic factors, such as non‑coding RNAs. Circular RNAs (circRNAs) are involved in the pathogenesis of various diseases. The aim of the present study was to further elucidate the etiology of allergic asthma by analyzing aberrantly expressed circRNAs in a murine asthma model. A mouse model of house dust mite allergen‑induced asthma was established, and the qualified libraries were sequenced using next‑generation sequencing. The expression levels of circRNAs were validated by reverse transcription‑quantitative PCR (RT‑qPCR) analysis. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analyses were performed for biological pathway classification and enrichment analysis of the aberrantly expressed circRNAs. In addition, the interaction network of the differentially expressed circRNAs and microRNAs (miRNAs) was constructed using Cytoscape. By next‑generation sequencing, a total of 150 circRNAs were revealed to be upregulated and 130 were downregulated in the murine asthma model group compared with in the control group. GO and KEGG analyses demonstrated that the differentially expressed circRNAs were mainly involved in processes such as 'autoimmune disease', 'cell adhesion molecules (CAMs)' and 'endocytosis', among others. The expression levels of six circRNAs, namely three upregulated (circ_0000909, circ_0000629 and circ_0000455) and three downregulated (circ_0001454, circ_0000723 and circ_0001389) circRNAs, were validated by RT‑qPCR. In conclusion, the analyses suggested that circRNAs performed critical functions via endocytosis (such as macrophage endocytosis), cell adhesion molecules and lipid metabolism in allergic asthma. The interaction network revealed that certain miRNAs that may serve a role in asthma could be regulated by the differentially expressed circRNAs.

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Evaluation of polymorphisms in predicted target sites for micro RNAs differentially expressed in endometriosis.

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Evaluation of polymorphisms in predicted target sites for micro RNAs differentially expressed in endometriosis.

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