Literature DB >> 36262825

Identification of Differentially Expressed microRNAs Associated with Ischemic Stroke by Integrated Bioinformatics Approaches.

Shengqiang Jiang1,2, Jie Wu1,2, Yan Geng2,3, Yuting Zhang3, Yupeng Wang3, Jinrong Wu3, Chunqu Lu4, Guoxuan Luo2, Jie Zan2,3, Yong Zhang1,2.   

Abstract

Ischemic stroke (IS) is one of the leading causes of disability and mortality worldwide. This study aims to find the crucial exosomal miRNAs associated with IS by using bioinformatics methods, reveal potential biomarkers for IS, and investigate the association between the identified biomarker and immune cell pattern in the peripheral blood of IS patients. In this study, 3 up-regulated miRNAs (hsa-miR-15b-5p, hsa-miR-184, and hsa-miR-16-5p) miRNAs in the serum exosomes between IS patients and healthy controls from GEO database (GSE199942) and 25 down-regulated genes of peripheral blood mononuclear cells of IS patients from GSE22255 were obtained with the help of the R software. GO annotation and KEGG pathway enrichment analysis showed that the 25 down-regulated genes were associated with coenzyme metabolic process and were mainly enriched in the N-glycan biosynthesis pathway. Furthermore, we performed the LASSO algorithm to narrow down the above 25 intersected genes, and identified 8 key genes which had a good diagnostic value in discriminating IS patients from the healthy controls analyzed with ROC curve. CIBERSORT algorithm indicated that the abundance of M0 macrophages and resting mast cells was significantly lower than that of the control group. The spearman correlation analysis showed that STT3A was negatively correlated with the proportion of follicular helper T cells, activated NK cells and resting dendritic cells. Finally, GSE117064 showed that has-miR-16-5p was more advantageous for diagnosing stroke. In conclusion, hsa-miR-15b-5p, hsa-miR-184, and hsa-miR-16-5p are identified as specific related exosomal miRNAs for IS patients. These genes may provide new targets for the early identification of IS.
Copyright © 2022 Shengqiang Jiang et al.

Entities:  

Year:  2022        PMID： 36262825      PMCID： PMC9576445          DOI： 10.1155/2022/9264555

Source DB:  PubMed          Journal:  Int J Genomics        ISSN： 2314-436X            Impact factor:   2.758


1. Introduction

Ischemic stroke (IS) is one of the leading causes of disability and mortality worldwide and accounts for 80% of all strokes [1]. Intravenous thrombolysis is the only approved treatment strategy for acute IS by FDA [2]. Due to the short treatment time window within 4.5 h of onset and the high risk of hemorrhage, the thrombolysis rate in IS patients is very low [3], suggesting early diagnosis is extremely critical. Nowadays, clinical diagnosis of IS mainly relies on magnetic resonance imaging and computed tomography [4]. However, most community medical institutions lack the testing equipment, and the brain imaging examinations are relatively expensive, which limits the clinical diagnosis of IS [5]. Thus, developing new diagnostic markers and therapeutic targets for IS are urgently needed. microRNAs (miRNAs) are a class of small and noncoding RNA, which regulate gene expression through silencing target genes and play important roles in the nervous system diseases, such as traumatic brain injury, spinal cord injury, subarachnoid hemorrhage, and IS [6-8]. For example, miR-31 inhibits traumatic brain injury-triggered neuronal cell apoptosis by regulating hypoxia-inducible factor-1A/vascular endothelial growth factor A axis [7]. miR-672-3p promotes functional recovery in rats with contusive spinal cord injury by inhibiting ferroptosis suppressor protein 1 [8]. Nowadays, more and more studies identify that some aberrant expressed circulating miRNAs in the serum, which are identified via bioinformatics methods, could be used as potential candidates for disease diagnosis. For example, Hsa-miR-484, hsa-miR-185-5p, hsa-miR-340-5p, hsa-miR-146a-5p, and hsa-miR-195-5p have a prognostic value in breast cancer patients treated with integrative interventions, including diet and physical activity [9]. Specific alteration of 20 miRNAs has a direct association with pesticide exposure and the development of neurodegenerative diseases [10]. Hsa-miR-181a-3p, hsa-miR-214-3p, hsa-miR-18a-5p, and hsa-miR-938 are positively related to the IL-6 signaling pathway activation in various cancers [11]. 14 potentially important miRNAs are identified as IS diagnostic signatures via bioinformatics method combined with logistic regression analysis [12]. Whereas circulating miRNAs in the serum are generally affected by the different pathophysiological conditions and circulating ribonucleases [13], there are still short of reliable prognostic or diagnostic blood biomarkers. Exosomes are spherical extracellular nanovesicles with a bilayer lipid structure for the outer membrane, defined by a diameter of 30–100 nm [14]. Exosomes contain proteins, mRNAs, and miRNAs and play essential roles in intercellular communication [15]. Due to their high stability, serum exosomal miRNAs are considered to be powerful non-invasive biomarkers in many diseases, including breast cancer, pancreatic ductal adenocarcinoma, and hepatocellular carcinoma [16-18]. Recently, Tong et al. [19] found that miR-151a-5p, miR-24, mir-485-5p, mir-331-5p, and mir-214 were upregulated with statistical significance in both the serum exosome and cerebrospinal fluid exosomes, and may be considered as a biomarker for the diagnosis of Parkinson's disease. In this study, we attempt to identify the crucial exosomal miRNAs associated with IS by using bioinformatics methods, reveal potential biomarkers for IS, and investigate the association between the identified biomarker and immune cell infiltration in IS.

2. Materials and Methods

2.1. Data Sources

The data were downloaded from the Gene Expression Omnibus (GEO) database (http://www.ncbi.nlm.nih.gov/geo). The inclusion and exclusion criteria for these data sets were as follows. Inclusion criteria: (i) data sets containing miRNA and mRNA expression levels of IS patients; (ii) data sets reporting miRNAs expression levels of both IS patient and healthy patient; and (iii) data sets containing miRNA expression data of at least 5 IS samples and 5 controls. Exclusion criteria: (i) data sets containing exclusively IS sample and (ii) data sets containing miRNAs expression levels of animal models, cell lines or other in vitro experiments. GSE199942 included the miRNA expression profiles of serum exosomes in five acute IS patients and five healthy controls detected by RNA-seq using llumina HiSeqTM 2500. GSE22255 included the gene expression profiling in peripheral blood mononuclear cells (PBMCs) of 20 IS patients and 20 sex- and age-matched controls using Affymetrix microarrays. GSE16561 included the gene expression profiles of peripheral whole blood RNA from 39 IS patients and 24 healthy controls. GSE117064 included the microRNA profiles of 1785 samples, which consist of 173 of CVD patients, 1612 of non-CVD control using microarrays. PMC8702168 included the miRNA expression profiles of human stroke brain tissue in five acute IS patients and three non-stroke controls detected by RNA-seq using Illumina NextSeq 500. All the data sets used in this study could be available on GEO data sets.

2.2. Analysis of Differentially Expressed miRNAs and Genes

The differentially expressed miRNAs from GSE199942 were obtained using the edgeR package [20]. The differentially expressed genes from GSE22255 were obtained using the limma package [21]. The P value <0.05 was used as threshold for nominally significant differential expression. gplot2 and pheatmap packages were used to draw the volcanic maps and heat maps, respectively.

2.3. Sankey Diagram of the miRNAs-mRNAs Network

The miRNAs-mRNAs network was drawn using the “ggalluvial” package of R software.

2.4. GO and KEGG Analysis

Gene ontology (GO) functional enrichment and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway were performed using the “clusterProfiler” R package [22]. P value <0.05 was considered the criterion for statistical significance.

2.5. Evaluation of Immune Cell Abundance

The gene expression profiling of GSE22255 was used to compare immune cell abundance in the peripheral blood of 20 IS patients and 20 healthy controls. The “CIBERSORT” algorithm was used to calculate the relative proportions of 22 types of immune cells [23]. Significant alterations in immune cells were identified using the Wilcoxon test at P < 0.05. The “ggcorrplot” package was used to visualize the results of correlation between immune cells.

2.6. Diagnostic Value of Differentially Expressed Genes in IS

The receiver operating characteristic (ROC) curve analysis is often used to determine the best diagnostic threshold for a diagnostic method. Generally, the area under the curve (AUC) value of >0.7 obtained from ROC curve analysis is considered to have a good predictive value [24].

3. Results

3.1. Identification of Differentially Expressed Exosomal miRNAs Related to IS

In this study, we analyzed the differentially expressed miRNAs in serum exosomes between IS patients and healthy controls from GSE199942 data sets, and found that 35 upregulated and 24 downregulated miRNAs (Table 1). The expression of these miRNAs is shown in Figures 1(a) and 1(b). Furthermore, the differentially expressed serum exosomes miRNAs were intersected with those differentially expressed miRNAs from freshly removed human stroke brain tissue [25], and three upregulated miRNAs were obtained: hsa-miR-15b-5p, hsa-miR-184, and hsa-miR-16-5p (Figures 1(c) and 1(d)).
Table 1

The differentially expressed miRNAs in serum exosomes between IS patients and healthy controls from GSE199942 data sets.

GeneslogFClogCPM P ValueFDRChange
hsa-miR-45114.01777513.15193110.0003910.1276672Up
hsa-miR-450a-5p2.36085314.750.00187180.2345272Up
hsa-miR-15b-5p1.87015655.68244970.00275740.2345272Up
hsa-miR-187-3p6.04097993.63702480.00287320.2345272Up
hsa-miR-44883.1070225.14011730.00490580.2367778Up
hsa-miR-30a-5p2.460329210.2023890.00518250.2367778Up
hsa-miR-3688-3p4.51277811.92195090.00548930.2367778Up
hsa-miR-30a-3p2.34924787.31374970.00571830.2367778Up
hsa-miR-519b-5p5.55156392.28563430.00677650.2367778Up
hsa-miR-523-5p5.55156352.28563430.00677690.2367778Up
hsa-miR-522-5p5.55152362.28563430.00681490.2367778Up
hsa-miR-518e-5p5.551472.28563430.00686640.2367778Up
hsa-miR-519c-5p5.55145372.28563430.00688220.2367778Up
hsa-miR-519a-5p5.55138482.28563430.00694910.2367778Up
hsa-miR-23a-3p1.39001298.91372210.00731520.2367778Up
hsa-miR-223-3p1.69909386.59243470.00761460.2367778Up
hsa-miR-12624.76793631.84184620.00903330.2564662Up
hsa-miR-1843.92838663.48733810.00964320.2623126Up
hsa-let-7g-3p4.7771191.83496660.0108460.2623126Up
hsa-miR-503-5p1.46372555.97198430.0116940.2727198Up
hsa-miR-2115-3p3.35989632.57556350.01412690.3180986Up
hsa-miR-365a-3p3.37513443.19586650.02101960.4111132Up
hsa-miR-365b-3p3.37521763.19586650.02133120.4111132Up
hsa-miR-143-3p1.310620212.3402440.02321670.4123441Up
hsa-miR-140-3p1.100650413.623170.02399550.4123441Up
hsa-miR-4677-3p2.65116542.77538440.02470740.4136901Up
hsa-miR-708-3p1.58378764.8998950.02688260.4341984Up
hsa-miR-518d-5p4.59331271.77068090.02844910.4341984Up
hsa-miR-520c-5p4.59329671.77068090.02848860.4341984Up
hsa-miR-526a4.59325491.77068090.02859190.4341984Up
hsa-miR-16-5p1.181193710.0140530.02954330.4384491Up
hsa-miR-873-5p2.73028293.65443560.03059880.4440228Up
hsa-miR-218-5p1.6730554.87193180.03272280.4546377Up
hsa-miR-542-3p1.7027244.00296470.03874680.4914672Up
hsa-miR-501-5p2.64086561.93044820.04660.5261696Up
hsa-miR-185-5p–0.99593414.1610130.05117420.5569459No significant change
hsa-miR-206–1.3927415.74629870.06334470.6573682No significant change
hsa-miR-7113-5p3.80997031.66120460.06525890.6573682No significant change
hsa-miR-509-3-5p3.34645992.10642680.06703690.6573682No significant change
hsa-miR-548ad-5p1.59152794.23046390.06794660.6573682No significant change
hsa-miR-548ae-5p1.59152354.23046390.06844970.6573682No significant change
hsa-miR-1070.96472057.85669260.0698410.6573682No significant change
hsa-miR-6511b-5p–1.9091833.26213640.07168490.6573682No significant change
hsa-miR-6741-3p–2.2649892.29295630.07231310.6573682No significant change
hsa-miR-145-3p1.03984946.72405290.07234870.6573682No significant change
hsa-miR-204-3p1.64785425.2089780.07284230.6573682No significant change
hsa-miR-330-3p–0.8693867.17905010.07312150.6573682No significant change
hsa-miR-4762-3p–2.7991182.00769360.07543120.6573682No significant change
hsa-miR-589-5p0.86365026.14292560.07737010.6573682No significant change
hsa-miR-671-3p–1.0410895.14095410.07906740.6573682No significant change
hsa-miR-323b-3p2.22656373.02135460.07929160.6573682No significant change
hsa-miR-125a-5p–1.1123567.76783990.07983320.6573682No significant change
hsa-miR-141-3p–2.5778722.36672620.08009670.6573682No significant change
hsa-miR-3913-5p1.09226744.84461920.08138340.6573682No significant change
hsa-miR-378c–1.3333669.24488390.08148840.6573682No significant change
hsa-miR-744-5p–0.7978289.55633710.08229310.6573682No significant change
hsa-miR-148a-5p–1.1023755.65354380.08422960.6573682No significant change
hsa-miR-5193–2.9965551.73410560.0843130.6573682No significant change
hsa-miR-1224-5p–1.3338085.02872360.08568650.6573682No significant change
hsa-miR-1298-5p2.12718152.45418490.08632590.6573682No significant change
hsa-miR-548ay-5p1.4805353.46988450.08859520.6573682No significant change
hsa-miR-326–1.4902043.24920.08886160.6573682No significant change
hsa-miR-4755-5p–1.9634282.98187390.08897110.6573682No significant change
hsa-miR-331-5p1.36015363.33888490.08912020.6573682No significant change
hsa-miR-27a-5p0.91835896.58580810.09147640.6573682No significant change
hsa-miR-3928-3p–1.2718815.10733890.09309950.6573682No significant change
hsa-miR-509-3p3.10730882.47489860.09352760.6573682No significant change
hsa-miR-3157-3p1.64744042.53547580.09392050.6573682No significant change
hsa-miR-6810-5p–4.8127791.80994670.09414760.6573682No significant change
hsa-miR-27a-3p1.01440349.78331950.09462880.6573682No significant change
hsa-miR-15b-3p1.87011933.3805780.09688370.6590269No significant change
hsa-miR-34a-5p4.16864581.60791170.09770920.6590269No significant change
hsa-miR-3130-3p1.50385183.60046640.0994970.6590269No significant change
hsa-miR-371a-5p–4.3373541.63136310.09955310.6590269No significant change
hsa-miR-1292-5p–1.0331455.80122750.10072790.6590269No significant change
hsa-miR-214-3p1.69976022.98037980.10177580.6590269No significant change
hsa-miR-1307-3p–0.86251310.957750.10193220.6590269No significant change
hsa-miR-12461.068577211.1201330.10603790.6612336No significant change
hsa-miR-6747-3p–2.4033271.99047870.10871320.6612336No significant change
hsa-miR-6857-3p–2.3131141.84542110.10937970.6612336No significant change
hsa-miR-6859-5p–1.2934823.01404160.10991690.6612336No significant change
hsa-miR-2277-3p–4.4861881.6844030.11049250.6612336No significant change
hsa-miR-1273h-3p–1.0244394.77443060.11251730.6612336No significant change
hsa-miR-4489–1.6526562.81154040.11572860.6612336No significant change
hsa-miR-2110–0.7633999.5335660.11601440.6612336No significant change
hsa-miR-582-3p0.96925916.87174130.11788040.6612336No significant change
hsa-miR-4211.13338573.76034650.11796840.6612336No significant change
hsa-miR-6808-3p–1.8642982.03410990.1182890.6612336No significant change
hsa-miR-6855-5p2.32068252.69201970.11851410.6612336No significant change
hsa-miR-30d-3p1.96583832.23801370.11857740.6612336No significant change
hsa-miR-548g-3p2.13659631.92773460.12029410.6612336No significant change
hsa-miR-4632-5p–4.4384521.66466510.12060230.6612336No significant change
hsa-miR-223-5p1.032683810.9945970.12236150.6612336No significant change
hsa-miR-148b-3p0.85718429.11758560.12309290.6612336No significant change
hsa-miR-511-5p–0.9542877.69622270.12339120.6612336No significant change
hsa-miR-3120-5p–1.5695493.1895440.12389890.6612336No significant change
hsa-miR-6807-5p–1.684452.76563620.12580880.6612336No significant change
hsa-miR-7706–0.8009768.13641830.12598730.6612336No significant change
hsa-miR-6877-5p–0.978644.03466950.12817990.6612336No significant change
hsa-miR-6867-5p–4.4203871.63993480.1287130.6612336No significant change
hsa-miR-654-3p1.47164824.0584580.12927710.6612336No significant change
hsa-miR-532-3p1.33452663.05794250.13109350.6612336No significant change
hsa-miR-139-5p–0.7639618.79830530.13110840.6612336No significant change
hsa-miR-150-5p–0.9517214.57762610.13150270.6612336No significant change
hsa-miR-29c-3p1.5905682.93742160.13218380.6612336No significant change
hsa-miR-216b-5p2.23739782.2036770.13259360.6612336No significant change
hsa-miR-182-5p0.96614188.88975240.13337840.6612336No significant change
hsa-miR-422a–1.0784674.62985080.13380460.6612336No significant change
hsa-miR-598-5p–2.6666131.57353920.1346770.6612336No significant change
hsa-miR-5001-5p–2.5515532.03696420.13704730.6620332No significant change
hsa-miR-134-5p–0.9807169.42155160.13734060.6620332No significant change
hsa-miR-12842.41454062.19685350.13788130.6620332No significant change
hsa-miR-3150a-3p–2.8117731.56347350.13904330.6627395No significant change
hsa-miR-363-3p0.70737629.10435110.14135060.6688546No significant change
hsa-miR-1228-5p–1.5837185.62672190.15101840.6974406No significant change
hsa-miR-451b1.55565342.3416550.15134680.6974406No significant change
hsa-miR-4690-3p–1.5853322.31226930.15460860.6974406No significant change
hsa-miR-44921.88907492.69085750.15561860.6974406No significant change
hsa-miR-22-5p0.71134847.50086180.15644730.6974406No significant change
hsa-miR-382-3p2.66187061.88842540.15693760.6974406No significant change
hsa-miR-1268a–1.3440743.51730160.1572150.6974406No significant change
hsa-miR-130b-5p–1.3498465.53683020.15731530.6974406No significant change
hsa-miR-1908-5p–0.8683765.32057330.15750610.6974406No significant change
hsa-miR-13233.17542721.74996440.15871520.6974406No significant change
hsa-miR-142-5p0.924594310.7469010.15914030.6974406No significant change
hsa-miR-202-5p–2.1482192.10916040.16118120.7016757No significant change
hsa-miR-3614-5p0.82358815.102390.16282950.7029907No significant change
hsa-miR-4734–2.3886632.05939320.16363640.7029907No significant change
hsa-miR-500a-3p0.81909936.92276090.16712410.7088167No significant change
hsa-miR-6837-3p2.33387041.53371010.16716350.7088167No significant change
hsa-miR-1251-5p3.91765011.53416430.17145350.7155546No significant change
hsa-miR-1303–1.5555322.65599090.17162890.7155546No significant change
hsa-miR-6729-5p–1.5903272.6585340.17256840.7155546No significant change
hsa-miR-3164–1.408142.5424410.17479910.7155546No significant change
hsa-miR-4686–2.7121781.76712510.17548590.7155546No significant change
hsa-miR-199a-5p–0.8083275.1437260.17663250.7155546No significant change
hsa-let-7i-5p0.670520313.7323160.17673540.7155546No significant change
hsa-miR-98-5p1.00034125.43526180.17751890.7155546No significant change
hsa-miR-148a-3p0.943564616.2903350.17888680.7166447No significant change
hsa-miR-424-5p1.89402642.21987140.18088030.7189678No significant change
hsa-miR-4738-3p–0.9278434.94219830.18166870.7189678No significant change
hsa-miR-548av-5p1.80259982.57862820.18452220.7226147No significant change
hsa-miR-548k1.80266042.57862820.18509140.7226147No significant change
hsa-miR-10b-5p0.986576313.4901420.18694940.7226147No significant change
hsa-miR-6894-5p–2.4249551.62339220.18742970.7226147No significant change
hsa-miR-502-3p0.79055246.72115640.18812330.7226147No significant change
hsa-miR-548d-5p1.2438272.86000410.19065090.728041No significant change
hsa-miR-197-5p2.56812161.55695660.1938980.7361359No significant change
hsa-miR-3177-3p–0.8276884.38284170.20480540.7701355No significant change
hsa-miR-483-3p–1.9744562.22118160.20521220.7701355No significant change
hsa-miR-44431.4411882.01313360.2090350.7769258No significant change
hsa-miR-450b-5p1.27731843.62551820.20940110.7769258No significant change
hsa-miR-3944-5p–1.9172861.66162470.21246540.7809496No significant change
hsa-miR-378a-3p–0.69355313.5292090.21345820.7809496No significant change
hsa-miR-1268b–1.2537012.8354880.21407350.7809496No significant change
hsa-miR-1301-3p–0.6724486.39650390.21531590.7811183No significant change
hsa-miR-23b-3p0.83172056.71901260.21667840.7817181No significant change
hsa-let-7f-5p0.981304412.7717150.22033570.7827953No significant change
hsa-miR-323a-3p1.54215092.9337770.22068170.7827953No significant change
hsa-miR-146a-3p–1.4717242.83360030.22298310.7827953No significant change
hsa-miR-3615–0.56001711.590870.22315730.7827953No significant change
hsa-miR-3653-3p1.78846592.89437710.226650.7827953No significant change
hsa-miR-4750-5p2.19884622.28826480.22701040.7827953No significant change
hsa-miR-30b-5p–1.1739842.81233670.22811710.7827953No significant change
hsa-miR-4685-3p1.70021632.35987040.22841970.7827953No significant change
hsa-miR-29a-3p0.62965727.10611010.22857090.7827953No significant change
hsa-miR-338-5p0.98310615.15412940.22896460.7827953No significant change
hsa-miR-409-5p–2.4550291.86603020.23039490.7835825No significant change
hsa-miR-6735-5p–1.1133512.72528620.23586950.7980454No significant change
hsa-miR-451a0.69226917.3080790.23857710.8030457No significant change
hsa-miR-543–0.7868275.84795380.24408160.8039067No significant change
hsa-miR-320a–0.81534217.4506790.2448790.8039067No significant change
hsa-miR-9-5p–1.3712763.5878570.24594020.8039067No significant change
hsa-miR-4669–1.5951445.86937760.24634950.8039067No significant change
hsa-miR-423-5p0.942799214.8185820.2474310.8039067No significant change
hsa-miR-505-5p–1.2712113.17836290.24833590.8039067No significant change
hsa-miR-433-3p–0.8475413.96455980.24948750.8039067No significant change
hsa-miR-378f–0.7110485.40205750.25067520.8039067No significant change
hsa-miR-369-5p1.48647542.46927210.25106320.8039067No significant change
hsa-miR-2355-3p–1.150723.77394930.25114390.8039067No significant change
hsa-miR-203a-3p–1.0094012.95502790.25243440.8040958No significant change
hsa-miR-324-5p–1.1598042.78222150.25395810.8050225No significant change
hsa-miR-6866-5p1.215842.67713940.25869370.8156615No significant change
hsa-miR-146b-5p–0.5062910.0583820.25981260.8156615No significant change
hsa-miR-6850-5p–1.3009323.58139080.26217240.8191319No significant change
hsa-miR-6805-5p1.6855671.92144730.26607180.8253837No significant change
hsa-miR-1288-3p0.71954333.78221210.26981330.8253837No significant change
hsa-miR-671-5p–1.325282.76357740.26984850.8253837No significant change
hsa-miR-31981.14730642.83459480.27072230.8253837No significant change
hsa-let-7g-5p0.684577311.3755670.27323240.8253837No significant change
hsa-miR-15a-5p1.19489873.68488850.27407720.8253837No significant change
hsa-miR-125b-5p–0.7320387.84266420.27418470.8253837No significant change
hsa-miR-1304-3p0.90435262.91665870.27807660.8253837No significant change
hsa-miR-1307-5p0.90638195.22430530.27963020.8253837No significant change
hsa-miR-1304-5p0.77626744.53056690.28023730.8253837No significant change
hsa-let-7a-3p0.93309174.81543460.28309360.8253837No significant change
hsa-let-7c-5p0.68757798.81675550.28614860.8253837No significant change
hsa-miR-501-3p0.50044238.05750920.28676480.8253837No significant change
hsa-miR-45041.03506082.53260260.28725580.8253837No significant change
hsa-miR-6740-5p–1.5811231.73439980.28855720.8253837No significant change
hsa-miR-548ah-3p–1.3043423.31975060.28907540.8253837No significant change
hsa-miR-548ah-5p1.92948961.70389120.28935560.8253837No significant change
hsa-miR-483-5p–0.9305617.5649090.29140310.8253837No significant change
hsa-miR-660-5p0.70754084.28822360.29142570.8253837No significant change
hsa-miR-21-3p0.95423212.41572150.29314740.8253837No significant change
hsa-miR-3934-5p–1.2127192.70025450.29332180.8253837No significant change
hsa-miR-636–0.9648913.85631120.29356470.8253837No significant change
hsa-miR-548o-3p0.6819336.07712910.2939880.8253837No significant change
hsa-miR-6847-5p–1.8498931.8003030.2945090.8253837No significant change
hsa-miR-548e-3p1.68746982.81395970.29584370.825581No significant change
hsa-miR-548aq-3p1.06581742.53636060.29885530.8304362No significant change
hsa-miR-548p–1.2827762.57488820.30251630.8347429No significant change
hsa-miR-224-5p–0.8157625.42590380.30296180.8347429No significant change
hsa-miR-6842-3p–0.540626.41819740.306620.8353266No significant change
hsa-miR-6842-5p–1.101073.13502160.30670380.8353266No significant change
hsa-miR-664a-5p–0.5116497.56910250.30701130.8353266No significant change
hsa-miR-29b-3p0.91357123.38570840.31041690.8410881No significant change
hsa-miR-47921.62819131.76705140.31320490.8451357No significant change
hsa-miR-374b-5p1.14942072.79769080.31617450.8482237No significant change
hsa-miR-548ar-3p2.03686421.72913850.31736620.8482237No significant change
hsa-miR-101-3p0.509177712.222810.31904730.8482237No significant change
hsa-miR-19b-3p–0.5136617.86911280.31954520.8482237No significant change
hsa-miR-138-5p1.7468352.94301730.32225190.8519453No significant change
hsa-miR-127-5p1.33999191.93871150.32382210.8526446No significant change
hsa-miR-6767-5p–1.2154242.66487080.32608740.8551609No significant change
hsa-miR-378g–0.6752234.94050710.32963510.8602968No significant change
hsa-miR-1291–1.0524213.06565290.33143690.8602968No significant change
hsa-miR-340-5p0.59215067.14479210.33199820.8602968No significant change
hsa-miR-27b-3p0.56060849.23279370.33542140.865732No significant change
hsa-miR-133a-3p–1.0105862.7950730.33823560.8695584No significant change
hsa-miR-3180-3p–0.8465833.85980080.34111220.8701843No significant change
hsa-miR-3180–0.8465823.85980080.34114420.8701843No significant change
hsa-miR-548f-3p1.06617863.27496080.34815260.8846056No significant change
hsa-miR-454-3p1.57228451.8749250.35276710.8870067No significant change
hsa-miR-3605-5p0.82218273.58290530.35285110.8870067No significant change
hsa-miR-36560.95755666.4010010.35414520.8870067No significant change
hsa-miR-200c-3p–0.7122894.396080.35503010.8870067No significant change
hsa-miR-4668-5p1.3920881.62407170.35588940.8870067No significant change
hsa-miR-125a-3p0.53996495.17150310.35929550.8870821No significant change
hsa-miR-44491.59545641.93204230.35945720.8870821No significant change
hsa-miR-409-3p–0.5432169.76194620.36136280.8870821No significant change
hsa-miR-191-5p–0.43383810.6199170.36161480.8870821No significant change
hsa-miR-378b–0.8808432.20214480.3638230.8870821No significant change
hsa-miR-7704–0.9841223.39577060.36414250.8870821No significant change
hsa-miR-221-5p–1.0027643.49541760.36739520.8870821No significant change
hsa-miR-25-5p–0.4931495.60918140.36794070.8870821No significant change
hsa-miR-425-3p0.5418835.31046130.36814590.8870821No significant change
hsa-miR-4533–1.7605732.12541060.37040920.8888605No significant change
hsa-miR-933–0.9591652.33753050.37530030.8888605No significant change
hsa-let-7a-5p0.649732212.9758140.37534050.8888605No significant change
hsa-miR-4470–0.8925242.81220580.376950.8888605No significant change
hsa-miR-2278–1.7666991.87787930.37704780.8888605No significant change
hsa-miR-486-5p–0.45793916.6860460.38320730.8888605No significant change
hsa-miR-3940-3p–1.4080481.66087320.38328430.8888605No significant change
hsa-miR-3187-3p–0.8921372.59216950.38557470.8888605No significant change
hsa-miR-44970.73927053.60146120.38708670.8888605No significant change
hsa-miR-199b-5p0.98364113.06200570.38806510.8888605No significant change
hsa-miR-619-5p0.79148853.69301730.39191010.8888605No significant change
hsa-miR-486-3p–0.5271639.29471090.39220850.8888605No significant change
hsa-miR-877-5p0.8871422.78355250.39366750.8888605No significant change
hsa-miR-26a-5p–0.43852612.0349810.39416450.8888605No significant change
hsa-miR-130a-3p0.79318393.4524870.39622620.8888605No significant change
hsa-miR-5189-3p–1.8777461.58503350.39793360.8888605No significant change
hsa-miR-219a-1-3p0.61665563.92891590.39856450.8888605No significant change
hsa-miR-3613-5p1.04868123.43537810.39904070.8888605No significant change
hsa-miR-6868-3p1.57841151.832750.39931110.8888605No significant change
hsa-miR-43260.50593124.6958750.39969360.8888605No significant change
hsa-miR-142-3p–0.5399925.27611150.39995010.8888605No significant change
hsa-miR-188-5p–1.7720541.83302910.40037390.8888605No significant change
hsa-miR-628-3p–0.8154033.53649410.40201940.8888605No significant change
hsa-miR-3163–1.7724861.73363990.40391950.8888605No significant change
hsa-miR-6734-5p–0.7852772.78965610.40393290.8888605No significant change
hsa-miR-450a-2-3p1.43172921.75965010.4049950.8888605No significant change
hsa-miR-181a-2-3p0.50759865.43326870.40736370.8888605No significant change
hsa-miR-95-3p0.85445313.15195620.40839020.8888605No significant change
hsa-miR-197-3p–0.4494935.82764890.40953430.8888605No significant change
hsa-let-7d-3p–0.567878.82932060.4098230.8888605No significant change
hsa-miR-1343-3p–0.9465812.51332190.4110810.8888605No significant change
hsa-miR-28-5p–0.6213884.6300080.41748680.8997323No significant change
hsa-miR-4746-5p–0.4868394.76261530.42122210.9022778No significant change
hsa-miR-766-5p–0.7376943.37272110.4220330.9022778No significant change
hsa-miR-215-5p–0.4806047.11617660.42495660.9022778No significant change
hsa-miR-5584-5p–1.3797731.78465950.4250090.9022778No significant change
hsa-let-7e-5p–0.463965.72918920.42678140.9022778No significant change
hsa-miR-204-5p1.05626793.14460460.42808740.9022778No significant change
hsa-miR-505-3p1.01153242.20079870.43111190.9022778No significant change
hsa-miR-3960–0.8203233.02524960.43125140.9022778No significant change
hsa-miR-769-5p0.41313476.3285320.4341830.9022778No significant change
hsa-miR-574-5p0.51653054.41206080.43461840.9022778No significant change
hsa-miR-4745-5p1.10351721.88345070.43517740.9022778No significant change
hsa-miR-6826-5p–1.5498231.66799060.43742850.9022778No significant change
hsa-miR-6873-3p–1.8542911.84344490.43753160.9022778No significant change
hsa-miR-1255a–1.4927191.84635840.43891870.9022778No significant change
hsa-miR-196a-5p1.58973581.72112080.43939410.9022778No significant change
hsa-miR-541-3p1.65964731.5370370.44331410.9048498No significant change
hsa-miR-411-5p–1.0765072.20874150.44351090.9048498No significant change
hsa-miR-5010-3p–0.8832362.71594180.44480370.9048498No significant change
hsa-miR-627-5p–0.9185253.62527890.44661780.9057188No significant change
hsa-miR-1285-3p0.39455647.18308840.45172630.9132424No significant change
hsa-miR-190b–0.9639082.6771740.45450070.9144084No significant change
hsa-miR-100-5p0.42004139.59219160.45600860.9144084No significant change
hsa-miR-361-5p0.5350134.80838030.45650410.9144084No significant change
hsa-miR-5187-5p–0.8674992.90178730.45915330.9148355No significant change
hsa-miR-147b–0.5893514.46677790.46233710.9148355No significant change
hsa-miR-937-3p–0.9743851.93539140.4643010.9148355No significant change
hsa-miR-6510-3p1.01742611.76192310.46441560.9148355No significant change
hsa-miR-939-5p–0.6972564.09958990.46512440.9148355No significant change
hsa-miR-378h–0.7916172.32606910.46587310.9148355No significant change
hsa-miR-2171.30214981.90501080.46652410.9148355No significant change
hsa-miR-7641–0.4680294.93669520.46901130.9154936No significant change
hsa-miR-548av-3p0.471146.2522220.47335180.9154936No significant change
hsa-miR-6741-5p0.59492074.17143290.4753080.9154936No significant change
hsa-miR-654-5p–0.4645144.84001680.47639950.9154936No significant change
hsa-miR-200b-3p0.70911445.01076980.47660570.9154936No significant change
hsa-miR-1255b-5p–0.4513045.60569010.47792320.9154936No significant change
hsa-miR-491-5p0.93131272.24976780.47894450.9154936No significant change
hsa-miR-25-3p0.348973614.278370.47910030.9154936No significant change
hsa-miR-941–0.4094368.26144030.4802180.9154936No significant change
hsa-miR-12780.74814352.83171470.48087950.9154936No significant change
hsa-miR-136-3p1.13335582.0802220.48562820.9218466No significant change
hsa-miR-651-5p0.82967412.88578990.48939420.9261983No significant change
hsa-miR-2115-5p–0.6541343.85682410.49471840.9261983No significant change
hsa-miR-125b-1-3p–0.7100742.58218460.49518710.9261983No significant change
hsa-miR-432-5p0.5194595.77323120.49737340.9261983No significant change
hsa-miR-370-3p–0.4492918.52314890.49955610.9261983No significant change
hsa-miR-30e-3p0.43030926.20127460.50154770.9261983No significant change
hsa-miR-4664-3p0.69642192.92129320.50269160.9261983No significant change
hsa-miR-199b-3p0.39839557.74128340.50287770.9261983No significant change
hsa-miR-199a-3p0.39839577.74128340.50291590.9261983No significant change
hsa-miR-3135a0.847272.2651360.5032140.9261983No significant change
hsa-miR-200b-5p–1.0187362.43453790.50418330.9261983No significant change
hsa-miR-485-5p–0.4525215.31785140.50578170.9261983No significant change
hsa-miR-7854-3p0.56683724.12618320.50635950.9261983No significant change
hsa-miR-6500-3p1.84579381.57899950.51020980.9267524No significant change
hsa-miR-342-5p–0.3711017.97578910.51177930.9267524No significant change
hsa-miR-4429–0.4869076.55450030.51282560.9267524No significant change
hsa-miR-106b-3p0.29716589.69627240.51355980.9267524No significant change
hsa-miR-1468-5p–0.431494.43149040.51388610.9267524No significant change
hsa-miR-192-5p–0.38926810.9070.51517790.9267524No significant change
hsa-miR-30b-3p–0.7486552.23924320.51997140.9326946No significant change
hsa-miR-200a-3p0.60847556.00343140.52255110.9326946No significant change
hsa-miR-99b-3p0.44259545.29623110.52420530.9326946No significant change
hsa-miR-125b-2-3p–0.4959674.20761810.52525650.9326946No significant change
hsa-miR-128-3p–0.41372211.3839020.52623590.9326946No significant change
hsa-miR-92b-3p–0.4328075.47865380.5270510.9326946No significant change
hsa-miR-143-5p0.62690913.08705240.52976080.9335995No significant change
hsa-miR-39110.93204732.74157640.53042180.9335995No significant change
hsa-miR-103a-3p0.305439110.3547310.5324890.933819No significant change
hsa-miR-30c-2-3p0.84254852.17526550.53544840.933819No significant change
hsa-miR-495-3p0.52917275.46755320.53645520.933819No significant change
hsa-miR-26a-2-3p1.51988741.60293440.5375990.933819No significant change
hsa-miR-126-3p–0.30727312.4131480.53947430.933819No significant change
hsa-miR-3682-3p0.81435842.10604390.54073250.933819No significant change
hsa-miR-4448–0.8761611.56481660.54325240.933819No significant change
hsa-miR-132-5p0.42505664.38400810.54362330.933819No significant change
hsa-miR-93-3p–0.5913152.84805140.54454390.933819No significant change
hsa-miR-32-3p1.43284081.7613570.54970120.933819No significant change
hsa-miR-20a-5p0.37788387.20584720.55027760.933819No significant change
hsa-let-7i-3p–1.3222391.87907770.55057620.933819No significant change
hsa-miR-329-3p1.00609241.84287530.55172860.933819No significant change
hsa-miR-493-5p1.09141512.07293940.55279740.933819No significant change
hsa-miR-6878-5p–0.962071.82759460.55472830.933819No significant change
hsa-miR-151a-3p–0.2703915.0426130.55475180.933819No significant change
hsa-miR-92a-1-5p–0.9316992.28044790.55630170.933819No significant change
hsa-miR-46600.95677592.22838560.55760350.933819No significant change
hsa-miR-4753-5p0.81886792.33542970.55771730.933819No significant change
hsa-miR-340-3p–0.5254084.26399040.56195480.9344595No significant change
hsa-miR-34c-5p–0.9097241.66551840.56218010.9344595No significant change
hsa-miR-10b-3p0.46651914.88836030.56239290.9344595No significant change
hsa-miR-4661-5p0.52124493.07500910.57075370.9441812No significant change
hsa-miR-32-5p0.56113413.12758750.57113570.9441812No significant change
hsa-miR-452-5p–0.3587466.02193010.57335420.9444801No significant change
hsa-miR-548j-3p–0.7538822.61906970.57421830.9444801No significant change
hsa-miR-148b-5p–0.6656222.46644560.57565550.9444801No significant change
hsa-miR-1180-3p–0.274829.02817030.57748780.9448464No significant change
hsa-miR-17-3p–0.9751261.89032050.57877270.9448464No significant change
hsa-miR-3127-5p0.58021732.63557280.58319930.9496986No significant change
hsa-miR-195-5p0.74328782.50186880.58822750.9555039No significant change
hsa-miR-6515-5p0.4809453.63037550.59777440.9686022No significant change
hsa-miR-12940.34636514.93233710.60059490.9707635No significant change
hsa-miR-6514-5p0.61986552.40062830.60286920.9720336No significant change
hsa-miR-7850-5p–1.0244762.14573570.6046710.9725373No significant change
hsa-miR-132-3p–0.5232323.06405870.60917890.9773803No significant change
hsa-miR-5581-3p–1.1186941.70233920.61087620.9777013No significant change
hsa-miR-6786-3p–0.8200011.85401610.61536520.9824779No significant change
hsa-miR-24-1-5p–0.5887332.49939690.6172750.9831234No significant change
hsa-miR-296-3p0.61981842.70346050.62007190.9851751No significant change
hsa-miR-598-3p0.67287582.25668530.62366780.9884833No significant change
hsa-miR-4646-5p–0.5408472.29127290.62627760.9902161No significant change
hsa-miR-4440–0.5901122.27935660.63890040.998528No significant change
hsa-miR-1273 h-5p–0.4239213.7907860.63914110.998528No significant change
hsa-miR-576-3p–0.2376878.73406720.64040480.998528No significant change
hsa-miR-45160.53847991.82707860.64440290.998528No significant change
hsa-miR-28-3p–0.2163849.23620650.64630920.998528No significant change
hsa-miR-140-5p0.36915164.34508040.64755970.998528No significant change
hsa-miR-4781-3p–0.7666541.96005320.64788830.998528No significant change
hsa-miR-320b–0.31876313.643760.64908340.998528No significant change
hsa-miR-4726-5p–1.1150351.93218520.65063760.998528No significant change
hsa-miR-615-3p0.49955485.29575990.65134570.998528No significant change
hsa-miR-44371.12385671.70133770.65213910.998528No significant change
hsa-miR-185-3p–0.2755835.40417650.65470880.998528No significant change
hsa-miR-1250-5p–0.4602753.12922870.65726770.998528No significant change
hsa-miR-532-5p0.202434210.4635050.65728830.998528No significant change
hsa-miR-3620-5p0.53274812.17305180.65812880.998528No significant change
hsa-miR-6862-5p0.73397341.65785420.65835560.998528No significant change
hsa-miR-339-5p0.35993483.54203690.66013040.998528No significant change
hsa-miR-193b-3p0.83553951.83482190.66035390.998528No significant change
hsa-miR-24-3p0.211912712.4836150.66194220.998528No significant change
hsa-miR-361-3p0.19673878.92902520.66303330.998528No significant change
hsa-miR-4487–1.1508091.56979530.66367380.998528No significant change
hsa-miR-548 am-3p0.51512262.96106650.66725880.998528No significant change
hsa-miR-335-3p0.40410493.41631320.66996150.998528No significant change
hsa-miR-4840.2296378.23030320.67010360.998528No significant change
hsa-miR-320d0.32037038.77208330.67086870.998528No significant change
hsa-let-7d-5p0.27110849.26645150.67169540.998528No significant change
hsa-miR-196b-5p0.43297912.75833640.67675310.998528No significant change
hsa-miR-27b-5p0.5585642.79125710.67888340.998528No significant change
hsa-miR-1287-5p0.36756213.72488610.68083770.998528No significant change
hsa-miR-92a-3p–0.25264713.8377650.68251840.998528No significant change
hsa-miR-1273c–0.5525222.47816650.68296090.998528No significant change
hsa-miR-22-3p–0.18138912.4470270.68533610.998528No significant change
hsa-miR-766-3p0.56141172.04063060.68555550.998528No significant change
hsa-miR-6503-3p–0.3002073.79723930.68607940.998528No significant change
hsa-miR-1285-5p0.99502261.64543970.68648920.998528No significant change
hsa-miR-181c-3p0.42928272.69015740.68658360.998528No significant change
hsa-miR-44670.5934212.53656320.69027731No significant change
hsa-miR-642a-3p–0.4754323.2181890.69403721No significant change
hsa-miR-3605-3p–0.6591322.47707230.69592271No significant change
hsa-miR-3120-3p–0.3252193.14885790.69868961No significant change
hsa-miR-1273d–0.3907832.85242220.70065831No significant change
hsa-miR-222-3p0.20871158.7331340.70301741No significant change
hsa-miR-181b-5p0.22306567.82561680.70937481No significant change
hsa-miR-45080.285009710.4247080.71041691No significant change
hsa-miR-548u–0.5643021.98144850.71057771No significant change
hsa-miR-99b-5p0.19506439.44669710.71232011No significant change
hsa-miR-12610.62356881.68847820.71264221No significant change
hsa-miR-381-3p–0.2306755.28898090.71600371No significant change
hsa-miR-504-5p0.65952511.8402550.71635791No significant change
hsa-let-7f-1-3p–0.4560752.67975660.72479341No significant change
hsa-miR-18a-3p–0.4437583.33363270.72603521No significant change
hsa-miR-6180.41278252.98917590.7269831No significant change
hsa-miR-3138–0.749131.82681810.73098191No significant change
hsa-miR-328-3p–0.1721316.75136950.73203521No significant change
hsa-miR-6806-3p0.37067073.26658150.73294871No significant change
hsa-miR-144-3p–0.1901365.92845790.73395611No significant change
hsa-miR-12700.5207362.00350590.73600311No significant change
hsa-miR-4659b-3p–0.9173161.59456080.7363331No significant change
hsa-miR-514a-3p0.66445751.76271730.73646871No significant change
hsa-miR-4654–0.6395382.28145970.74282391No significant change
hsa-miR-79760.22802994.05529380.74313021No significant change
hsa-miR-873-3p0.29947084.22328170.74610151No significant change
hsa-miR-424-3p0.17113237.2134380.74663181No significant change
hsa-miR-942-3p–0.570662.27594550.75202991No significant change
hsa-miR-214-5p0.4314212.53257430.75351771No significant change
hsa-miR-610–0.3835322.74638280.753931No significant change
hsa-miR-186-5p–0.14693910.2104790.75535951No significant change
hsa-miR-629-5p0.169518911.2647910.75701341No significant change
hsa-miR-205-5p–0.4554822.21632670.75750521No significant change
hsa-miR-1538–0.3778362.47731780.75819751No significant change
hsa-miR-4742-3p–0.5744251.96564150.76165091No significant change
hsa-miR-152-3p–0.1747237.87559730.76390431No significant change
hsa-miR-1260b–0.2319884.02587880.7648171No significant change
hsa-miR-191-3p–0.258573.611250.76625291No significant change
hsa-miR-12900.17213728.29027430.76720011No significant change
hsa-miR-3158-3p–0.15083410.6370150.76726921No significant change
hsa-miR-128-1-5p0.50004032.07667890.76826681No significant change
hsa-miR-42860.51626471.84431750.77484521No significant change
hsa-miR-335-5p0.19355975.83161060.77602721No significant change
hsa-miR-210-3p–0.1962575.32674140.77678071No significant change
hsa-miR-26b-5p0.17819767.66481120.7790131No significant change
hsa-miR-7-5p0.133792311.0934450.78296571No significant change
hsa-miR-3691-5p0.3796012.19074580.78578471No significant change
hsa-miR-99a-5p–0.15037213.5698670.78886861No significant change
hsa-miR-183-5p0.17127028.48130480.79175231No significant change
hsa-miR-6821-5p–0.4926811.82365720.79971481No significant change
hsa-miR-6750-5p–0.2565612.97910130.80274271No significant change
hsa-miR-18a-5p0.53120051.90859350.80392161No significant change
hsa-miR-3679-5p–0.500481.96578910.80706121No significant change
hsa-miR-345-5p–0.1260437.11035770.80757581No significant change
hsa-miR-155-5p0.18976885.32611390.80804941No significant change
hsa-miR-659-5p–0.1767874.48250360.80898721No significant change
hsa-miR-4772-5p–0.3840252.21723990.81238321No significant change
hsa-miR-576-5p–0.3178233.44461280.81606071No significant change
hsa-miR-6829-5p0.65732331.68035280.81622841No significant change
hsa-miR-5189-5p–0.2647123.69693120.81978241No significant change
hsa-miR-4797-3p0.49772171.57064560.8207531No significant change
hsa-miR-378d0.15987436.47448160.82218081No significant change
hsa-miR-151a-5p–0.189853.77195240.82317261No significant change
hsa-miR-320c–0.15948610.9179390.82353171No significant change
hsa-miR-106b-5p–0.1385435.33410270.8242241No significant change
hsa-miR-379-5p0.2220084.58389070.82613511No significant change
hsa-miR-20b-5p–0.138324.86495190.82702141No significant change
hsa-miR-1273f0.27242472.5875970.82929211No significant change
hsa-let-7b-5p–0.1078413.3251420.82992651No significant change
hsa-miR-3140-3p–0.3521472.09327230.83086511No significant change
hsa-miR-145-5p0.17944924.35112820.83211141No significant change
hsa-miR-548ap-5p0.26004832.0135020.83254451No significant change
hsa-miR-181a-3p–0.2107373.05544960.83339321No significant change
hsa-miR-378i–0.121088.79994960.83569991No significant change
hsa-miR-3199–0.4643731.99238270.83750081No significant change
hsa-miR-3127-3p–0.6228971.80054860.8398741No significant change
hsa-miR-429–0.3491532.55108790.84538631No significant change
hsa-miR-374a-5p0.22645043.089390.84936381No significant change
hsa-miR-382-5p0.10952126.94169820.85134191No significant change
hsa-miR-6761-5p0.6236791.54953840.8515641No significant change
hsa-miR-6875-5p0.52116681.94003190.85157981No significant change
hsa-miR-423-3p–0.08161111.8724070.85511711No significant change
hsa-miR-60870.58226171.60758620.85540711No significant change
hsa-miR-6882-5p0.51914951.57871260.85633171No significant change
hsa-miR-3196–0.5497641.56109050.85973651No significant change
hsa-miR-96-5p0.20175213.50279270.86046981No significant change
hsa-miR-339-3p–0.1011567.38903870.86105931No significant change
hsa-miR-30e-5p–0.0801269.47713370.86192781No significant change
hsa-miR-23a-5p–0.1522713.54463310.86531281No significant change
hsa-miR-46570.29775582.20538270.86551211No significant change
hsa-miR-4741–0.3336541.77722740.86783811No significant change
hsa-miR-574-3p–0.1379524.59919810.86852751No significant change
hsa-miR-493-3p–0.12035.61544890.8692641No significant change
hsa-miR-455-5p–0.1574624.05151210.87127331No significant change
hsa-miR-4747-5p–0.6615221.75324460.87360841No significant change
hsa-miR-31790.67397581.53721340.87393231No significant change
hsa-miR-374a-3p0.30153781.71773520.87806221No significant change
hsa-miR-378a-5p0.29666642.44214760.87911341No significant change
hsa-miR-760–0.0938725.95053120.88034341No significant change
hsa-miR-4639-5p–0.4731421.60209460.88136411No significant change
hsa-miR-31760.14166032.6330190.88299531No significant change
hsa-miR-3124-5p–0.1733893.12592510.88445191No significant change
hsa-miR-625-3p–0.1070026.39897750.88452031No significant change
hsa-miR-3150b-3p–0.095925.01805380.88502721No significant change
hsa-miR-4466–0.2519131.82755560.88572441No significant change
hsa-miR-106a-5p0.14048813.92838780.88758241No significant change
hsa-miR-24-2-5p–0.0760835.91032130.88842911No significant change
hsa-miR-12540.14209863.16687220.8891561No significant change
hsa-miR-10a-5p–0.09212711.2620340.88920131No significant change
hsa-miR-17-5p–0.0787096.52551910.88968581No significant change
hsa-miR-330-5p–0.0828625.91351670.8897761No significant change
hsa-miR-3074-5p0.29563171.90121050.89003591No significant change
hsa-miR-136-5p0.18043243.12087970.89618271No significant change
hsa-miR-324-3p–0.1335593.00588110.89999551No significant change
hsa-miR-550a-3-5p0.06422576.57963740.90140261No significant change
hsa-miR-26b-3p–0.3079552.00101250.90211221No significant change
hsa-miR-4498–0.3345581.74913140.90611821No significant change
hsa-miR-331-3p0.27047662.01276790.90779981No significant change
hsa-miR-579-5p–0.2454582.63888520.90808541No significant change
hsa-miR-195-3p0.10677414.20953030.91043021No significant change
hsa-miR-365b-5p0.27076651.95952750.91052691No significant change
hsa-miR-3909–0.3078871.97039240.91471021No significant change
hsa-miR-146a-5p–0.04981312.1375340.9152021No significant change
hsa-miR-3064-5p0.23253212.11061260.91633361No significant change
hsa-miR-625-5p0.36274391.89578840.91653561No significant change
hsa-miR-499a-5p0.06958464.79891120.91835911No significant change
hsa-miR-548q–0.430381.81649820.91986131No significant change
hsa-miR-5009-5p–0.0852353.92493930.92116421No significant change
hsa-miR-44730.18097761.96477360.92291541No significant change
hsa-miR-616-3p–0.1486832.35644930.92511341No significant change
hsa-miR-1260a0.12456253.38670940.92682891No significant change
hsa-miR-127-3p–0.0573087.70988320.92801091No significant change
hsa-miR-10a-3p0.2019662.41650850.92851911No significant change
hsa-miR-942-5p–0.0505385.75541590.93040111No significant change
hsa-miR-3150a-5p–0.2480332.18404620.93334781No significant change
hsa-miR-5010-5p–0.1896892.3508880.93451511No significant change
hsa-miR-19a-3p0.06687185.54691390.93496231No significant change
hsa-miR-46470.10210533.75807730.93614561No significant change
hsa-miR-30c-5p–0.05086.84280240.9376091No significant change
hsa-miR-221-3p0.03994298.24074370.93922161No significant change
hsa-miR-30d-5p–0.0373412.7887920.94175391No significant change
hsa-miR-200a-5p0.21007912.9142630.94178151No significant change
hsa-miR-4732-5p–0.0493046.26717870.94291881No significant change
hsa-miR-372-3p0.12243693.88806730.94389891No significant change
hsa-miR-93-5p–0.037247.5797070.94480461No significant change
hsa-miR-550a-5p0.03950626.15471690.94749481No significant change
hsa-miR-21-5p–0.03049511.735240.9477891No significant change
hsa-miR-342-3p0.04795214.65904610.95501051No significant change
hsa-miR-23b-5p–0.0682613.88070560.956381No significant change
hsa-miR-3190-3p0.13267342.94808060.95714011No significant change
hsa-miR-363-5p0.13313892.99216040.95848561No significant change
hsa-miR-874-3p–0.0748643.62639680.95932451No significant change
hsa-miR-4755-3p–0.0804793.13702780.96040281No significant change
hsa-miR-1-3p–0.0364187.17981750.96321191No significant change
hsa-miR-126-5p–0.0653054.00844070.96478031No significant change
hsa-miR-652-3p–0.0293455.91222460.96635231No significant change
hsa-miR-129-5p–0.0282946.98213230.96753281No significant change
hsa-miR-16-2-3p–0.0275238.8119070.96832081No significant change
hsa-miR-1306-3p–0.0314425.77171780.9703661No significant change
hsa-miR-92b-5p–0.046484.40999620.97245631No significant change
hsa-miR-194-5p0.0221137.91644170.97273061No significant change
hsa-let-7b-3p0.04378953.48389390.97349181No significant change
hsa-miR-130b-3p–0.0258124.15043860.97718691No significant change
hsa-miR-584-5p–0.0150479.19855010.97744081No significant change
hsa-miR-151b0.02436524.21123580.97873141No significant change
hsa-miR-181a-5p–0.01028210.9394460.98200321No significant change
hsa-miR-6852-5p0.0188144.59476720.98626411No significant change
hsa-miR-425-5p0.00625138.96398750.98960491No significant change
hsa-miR-181d-5p–0.0086515.018253611No significant change
hsa-miR-516b-5p–0.1026282.819071111No significant change
hsa-miR-641–0.0978432.270386811No significant change
hsa-miR-1273a–0.3421871.540993611No significant change
hsa-miR-548j-5p0.22381241.935619411No significant change
hsa-miR-548az-5p0.1321752.232959811No significant change
hsa-miR-371b-5p0.34747161.600509711No significant change
hsa-miR-6716-3p0.33155851.592339811No significant change
hsa-miR-4306–0.3288551.590447911No significant change
hsa-miR-6839-5p0.29734051.692811111No significant change
hsa-miR-6774-5p–0.2536021.540093811No significant change
hsa-miR-6818-5p–0.2347821.88261811No significant change
hsa-miR-6781-5p0.22342651.536186811No significant change
hsa-miR-4800-5p0.21543582.014541411No significant change
hsa-miR-365a-5p0.18276951.777959911No significant change
hsa-miR-500b-3p0.16435852.039601811No significant change
hsa-miR-5810.16378641.996926211No significant change
hsa-miR-6501-5p0.14223511.706718411No significant change
hsa-miR-494-3p–0.1318721.77249511No significant change
hsa-miR-556-5p–0.130521.738435811No significant change
hsa-miR-6780a-5p0.12351971.98260411No significant change
hsa-miR-6815-5p–0.0749962.433705111No significant change
hsa-miR-50960.07287142.329442311No significant change
hsa-miR-5003-3p–0.0705532.037079511No significant change
hsa-miR-4724-5p0.06905481.704881911No significant change
hsa-miR-431-5p0.06336662.275235511No significant change
hsa-miR-664b-5p–0.0622522.053089311No significant change
hsa-miR-3122–0.0607051.737748311No significant change
hsa-miR-36900.04404393.098556811No significant change
hsa-miR-30c-1-3p–0.0379411.868458811No significant change
hsa-miR-3675-5p0.03773251.912371111No significant change
hsa-miR-6733-5p–0.0242921.594861811No significant change
hsa-miR-4433b-3p–0.0148774.828172211No significant change
hsa-miR-412-5p–0.0052982.410213511No significant change
hsa-miR-29c-5p–0.0011972.704549311No significant change
hsa-miR-144-5p–0.0002544.026345111No significant change
hsa-miR-375–2.90792810.6212114.83E-083.16E-05Down
hsa-miR-885-3p–5.2739852.40018320.00123260.2345272Down
hsa-miR-122-5p–2.15982117.226280.00255470.2345272Down
hsa-miR-4433b-5p–2.2743284.52276630.00266410.2345272Down
hsa-miR-4446-3p–1.7113384.69007480.00704620.2367778Down
hsa-miR-885-5p–4.1349222.50153120.00840430.2494538Down
hsa-miR-362-5p–4.250442.11849630.01005740.2623126Down
hsa-miR-150-3p–1.4622536.40668430.0104930.2623126Down
hsa-miR-3173-5p–2.2546042.67844230.01692410.3683817Down
hsa-miR-139-3p–1.4297496.62995380.01826710.3847879Down
hsa-miR-378e–2.9475713.60081840.02176260.4111132Down
hsa-miR-193b-5p–1.5259967.07637640.02203520.4111132Down
hsa-miR-4435–2.0385392.53926220.02392510.4123441Down
hsa-miR-3191-3p–3.1123642.26003130.03244870.4546377Down
hsa-miR-4665-5p–1.7863674.01037890.03519450.4787914Down
hsa-miR-1249-3p–4.3666911.63614650.03677610.4900979Down
hsa-miR-1299–2.2319418.51187650.03775540.4914672Down
hsa-miR-6884-5p–1.815154.26705090.03913670.4914672Down
hsa-miR-1247-5p–4.906651.87845320.04075620.5021471Down
hsa-miR-4732-3p–1.1080726.60872680.042290.5113961Down
hsa-miR-320e–1.9942685.44740590.04551230.5261696Down
hsa-miR-146b-3p–1.4064134.61727670.0466920.5261696Down
hsa-miR-6511a-5p–3.2617562.13367660.04673480.5261696Down
hsa-miR-193a-5p–1.20292611.1551220.04893390.5415905Down
Figure 1

Scanning differentially expressed miRNAs. (a) Differentially expressed miRNAs in GSE199942. |LogFC| >1 and P value <0.05 were set to screen. (b) Heatmap of the differentially expressed miRNAs in GSE199942. (c) Venn diagram representing the intersection of up-regulated expressed miRNAs in the 2 data sets (GSE199942 and PMC8702168). (d) Venn diagram representing the intersection of down-regulated expressed miRNAs in the 2 data sets (GSE199942 and PMC8702168).

3.2. Construction of miRNA-mRNA Network

Next, we analyzed the potential targets of the three differentially expressed serum microvesicles miRNAs by miRWalk, and found a total of 593 genes may be co-regulated by at least two of the three miRNAs, of which 192 genes were co-targeted by hsa-miR-15b-5p and hsa-miR-16-5p, 250 genes were co-targeted by hsa-miR-15b-5p and hsa-miR-184, 92 genes were co-targeted by hsa-miR-16-5p and hsa-miR-184, and 59 genes were co-targeted by the three miRNAs (Figures 2(a) and 2(b) and Table 2). Given that miRNA negatively regulates the expressions of its targets, we further intersected the 593 prediction genes with the downregulated-expressed genes of PBMCs of IS patients from GSE22255 [26], and obtained 25 genes (Figure 2(c)). The expression of the 25 intersected genes was shown in Figure 2(d). Then, the network containing 3 miRNAs and 25 mRNAs was visualized by the “ggallouvial” package of R software and was shown in Figure 3.
Figure 2

Construction of miRNA-mRNA Network. (a) The miRNA-target gene network for differentially expressed miRNAs. (b) Venn diagram showing the overlap among the predicted targets of the differentially expressed miRNAs. (c) Venn diagram showing the overlap between down-regulated expressed genes and predicted targets of the differentially expressed miRNAs. (d) Heat map of the 25 intersected genes.

Table 2

Target genes of the three miRNAs.

Potential targets of hsa-miR-15b-5pPotential targets of hsa-miR-16-5pPotential targets of hsa-miR-184Potential targets of hsa-miR-15b-5p AND hsa-miR-16-5p NOT hsa-miR-184Potential targets of hsa-miR-15b-5p AND hsa-miR-184 NOT hsa-miR-16-5pPotential targets of hsa-miR-16-5p AND hsa-miR-184 NOT hsa-miR-15b-5pPotential targets of hsa-miR-15b-5p AND hsa-miR-16-5p AND hsa-miR-184
CPDEXT1STRADASTAMBPL1TASORCCDC80RAB30
USP14RNF157BCAT2DCAF12L2ELP2LIPHBCL11A
SETD5PDLIM7STX6CTSCPI4K2AOPN3ZMAT3
SESN1NCOA6TLCD3ARCC2FAM204APHKG2NEK10
TTPALNCS1FTCDMCRIP1CYB561D1SLC4A8PPP2R2B
GLS2UBE2J1CHST14GFI1BNOP9XRRA1CDRT1
GALK2PHACTR4MAP4K4CUL3CTDP1IST1BEST3
DCLRE1CPPM1DERVV-1RAB44TSHZ2ZFAND5MTA3
CRADDTRIP12SYNE3UBE2V1RAI14DIXDC1MPI
TSPYL5FBXW7ZNF707FRMD6RBBP4SURF4TMEM106A
B3GAT1RPS14DLX1CLOCKCBX5RAD9BTMCC3
SNRKDHX33RNF38RAB3IPTBCDZRANB3SNX19
PRAMEF8TMEM143M1APSTT3ASTK24RUBCNLPARP15
AKR1B15DEPDC1BHSPA12APDK1JAKMIP3CCL4L2TFRC
MBPIRAK3MTMR10HPCAL4SSBP2RXRADLK1
VASH1MRTFASLC16A3TTC1NFATC2ACP2TBC1D7
OTUB1DDX6EFCAB14TLE4SHTN1CYSLTR2GPR63
SMURF1IKZF3JOSD1GOT2CDH19EZH1SON
ODF2LVPS50RAB21USP49DNAJC10C1orf21SLC9A7
PTPRJSLC4A7RETSATADD1CSNK1A1HNRNPDLBTBD9
SORDKIF18BSHQ1CALML4ORAI2CCDC115XKR4
VPS9D1GPR161QRSL1RCL1SCIMPNFKBIDNOPCHAP1
CORINCD274CYCSNADK2IGSF9BGNB1LZNF597
HSPA13SOCS2MDM1CPEB1AMOTL2SLC30A7PANK2
KRR1MCUUBR4POLHCEP43CREB1MOB1B
IL3PGRSYT13TRERF1ARFGAP1TMEM183ASYT9
COX19PTGS1PTPAPRDM5NCAPHSNX1UBE2D3
RPGRCCDC177CDC25BMYO6FSD2GJD3NRP2
CHIC1KCNMA1KLRB1ACER3GNA13FBXW8NCKAP1
AGAP3SLC39A1KPNA1TPD52L1ADNPCNTN5MBD1
PHTF2VWA2PLAGL2ARHGEF12USP47MTMR11AREL1
CD209DUOXA1CCL4SLMAPFAM107BBIRC3KIAA1549L
NR4A1KCNJ15SDC1NKAIN3XRN1AK4RALGPS1
YOD1ZNF468ASTN1MBNL2EIF4E3TLR6SUSD6
DNAI4GDNFRAB7AARPP19PTCD2TMEM154WAPL
SLC12A2ZKSCAN8PCYT1ADCUN1D1LYSMD4RNF150ZBTB20
TBC1D16NUP155TROAPTGFATPD52FHIP1ACNNM2
ZBTB18FBXL7HMX2HEMK1EYA1SEMA4DAP5S1
MARCHF8FRS2CERT1PCDH9KIF6KSR1JPH1
AMZ1EDIL3CCT3ACSL4CECR2RBFOX2MS4A7
ZNF75ALYPLA1LAPTM5B3GNT2CTBP2SEC14L5MASP1
SLC2A10ATP7ARPGRIP1LRACGAP1CERS3CDC42BPACTSH
STPG4GNA12TPRA1PIAS1DHFRZBTB5KIF3B
THRAGAPVD1NHEJ1STSTMCC2ASXL1GFRA1
CD164L2CDV3EN1ZNF436TTC39AIRF2BP1CD6
BCL6POLR1BCHRNA7OR14J1SLC9B2RAB23ZBTB43
GINS1RIMS2LIN52TRIM56CD55KLHL3TBL1XR1
GRM5ZNF341ZC2HC1CSH3BGRL2CCL28GALNT7SOD2
TCEAL6GUCD1PPP1R18PSD2ZNF639GSPT2FLRT2
EPSTI1RBM7PARP9GPR174MLECUBE2WZNF544
YTHDF1TMEM132BP2RX6FOXP1KRBA2TXLNGB4GALT1
EYA3SUMO3KLF6RPL13LNPKUBFD1BRWD1
ZNF217THSD4CNDP1GBP4NAT9EIF5A2RNLS
SMC1ACENPWMBTD1PALM2AKAP2ZFP90ABOSCN3B
GABPB2AIG1ZNF517MACROD2ARHGEF6GALNT1SLC6A4
KLHDC7AVEGFASMIM10L1IRAG1SETD7FMR1RBM23
DCXITPRID2CEP350ALKBH3MRTFBRAB3BGLRX
ADAMTS17STK32ADIDO1GIT2TNFAIP8L3SLAMF1TGFBR3
PEX26DMPKLPCAT3YWHAZPLCB3SRPK1CCNT2
TNNI1TTC7ASPP1CHMP4CUVSSASTC1
FHDC1PHLPP2COMMD7FAM241ABNC2PDXK
GUCY1A1COPG2AMPD2RDH12ENTPD6ARL3
ZNF74POLDIP2KLHL36ABHD2RPS6KA2KIF2A
PRMT8NBR1MPZGPR26PLEKHO2XPR1
GDAP1L1HNRNPRCHFRSEMA6DAPOL6ONECUT2
PEX5LZNF417SMC6ZNF398ZNF442PTBP3
RNF165EIF4BSTOML1ANAPC16GABARAPL1PDK3
RIT1WNT8AABRMALT1THAP2KLC1
ZNF382ANKRD42PAX1CSNK2A1PCDHA4RGS4
SLC20A2RAB11FIP4LIFPAK5MRPS5MANBA
FGF1RPL10GPD1IL21RRBM48TRA2A
GRIA1USP6ZNF451ORC4TMEM164USP25
HMBSMED20ATP5F1ABTLAZBED3METTL8
ZNF501ZNF827BOD1L2UBE2IZBTB37CAMK4
MSH2PLEKHG3ITPRID1MRRFRSPO3TACC1
CLPBCCNJLEFTUD2PEDS1-UBE2V1ADOLOC112694756
PKD2L2TSHZ1EPS15L1SERTAD3B3GALNT1FAM149A
SLC9A8AAMDCRPS3PLPP6STX1BHECTD4
NOL10AGO1CALCOCO2GAB1EXOSC6IRAK2
TSNCHCHD7PTGES3LXKR5CNTNAP5FXN
PDPK1CARD19ZNF484SART3OTUD7ASLC11A2
CDX2SALL4CDS1IFT140MBNL3HMGXB4
FAM13AAK2SMC2POU2F1MTO1ZXDC
ZNF211GMEB1UNC45BKIF5CKCNK10WTIP
PSME3ZNF326PLEKHB2NCBP2RHBDL3NCBP3
CREMZDHHC23CTCFLSIAH1BACE2ATXN1
TBC1D2KIF1AANKRD46LRRC63TOR1AIP2CACNB4
MGST1MATN4G6PC1PRKAG3SKA3TTC39B
ZNF850DICER1RXRBMGST2ZNF641RAB3GAP1
PSMD5SPHKAPCDK2AP1SEMA3ACCNYL1PEG10
CDC42EP3FCRL2STOMSREBF1ZNF555MAMLD1
PSMD11COG3KLF7SMAD2ST6GALNAC3GFOD1
CHD2SESN2NFIXCHEK1PRICKLE1
PCED1ASYT15ZNF512GLYCTKMRPL42
CALCRLTSSK6SEMA4FUTP25APBB2
ITGBL1C19orf44PUS7LNEK6LSM11
CEP57L1SLITRK6RCN2SULT1B1CLVS1
SZRD1RTL6AAGABCCDC144APGM2L1
SRGAP2BTCHPSTK25KIAA0408OR7D2
KIF27NTPCRRAB4APHACTR2PSMF1
SLIT3PRXL2AKCNT1AAK1GPAT4
ITPRIPLCORLRRC14KIF1BHNF4A
PRKAR1ADCTN5RPS6KB1SNX13LDLRAD4
LZTFL1PARD6BCHD4DENND5ACUX1
HOMER1USP32BBXANAPC13ZNF778
ZNF550CBR4ELF2INTUZNF605
WDR72ZNF587ZNF891DCAF8UBE2L6
FMN1SEC22CPOTEICNR1GPRIN3
ANKRD62TRIM4GANABGOLGA7CNNM3
RFPL4AL1LMLNCLCC1RAB9BDSTYK
SDHCFGF5LMCD1ERAP1GAS7
SLC38A1KRASPTPN5RGS3QKI
ACVR2ATPGS1CARHSP1CDC37L1NFASC
MYBL2LUZP1LILRA1EPB41L4BRNF213
RANGAP1PLEKHG4BACTN2SLC35E3RPRD1B
FBXL4FCRL3PHYKPLNUP107LRRC3B
REXO4DNAJB6RHOHSPC25RUBCN
JRKKCNG3COBLL1TAOK1NPY4R2
DPF3RUNDC3BMDM2HOXD11ADCYAP1R1
ZNHIT3AKAP7MON2SRPRBSEC22A
MAP2K4MSI2GPATCH11PELI2FBXO3
SMAP1CD151CRNKL1PROK2CLUH
UPK1AMRPL30SSTR3XPNPEP3ZNF701
SLC35C2APOBEC3FELNTMEM38ACBFA2T2
MCM8TNFRSF10BPHBTTC13EIF2AK2
RFX3SVIPHEPHGALNT12REEP1
SSH2HGSNATPYCR1RBFAMMS22L
PPP2R5EAMER1OSCARCCDC134EML1
WFDC1TLCD4ARPINDLSTALDH1L2
ZFP37PGBD4MDH2HSPA4MTERF4
FAM243AMETTL15KCTD14KPNA4TRAK1
H6PDNATD1GOLGA8MNDUFB5PTCHD4
ARSLIP6K1GOLGA8HRAD51DTTBK1
FAM107ABEST4GOLGA8KSRP19NCOA2
HEY1HYAL1ZNF343VSNL1ZNF276
TRIB1ZNF791BTBD3ACOX3NHSL2
CIBAR1LNX2HHLA2MPDZMKLN1
ZFYVE16ZDHHC14ZCCHC17GPRC5ACELF2
VOPP1KMT2CSLC66A3PRDX6MAPRE2
FKBP9RASSF2KIAA1217PPARABMP10
LRRC49TEDDM1CCNYCCDC6FAM131B
SLC36A4RDH10RASGEF1AKARS1PTDSS1
SLC2A14DCUN1D3MTSS1NFIBMRPL19
RALGPS2CNKSR3AP1S1ABI2ARNT2
PKNOX1DNAJC5GUSP8EIF1ZNF652
MRS2ARL10EIF3JLANCL1ZNF507
TUBGCP3JAZF1LRRC28CAPZA2ZHX3
PPIL6SPDYE1UTP15POLD3SAMHD1
TMEM179GATCFAM234ADBF4OPA1
RNF217TUBOPRM1FAF1FAM169A
CIITATMEM26FAM168APXMP4YPEL5
RNGTTCMTM4TAF1BRCA1DNAJC27
KIAA0513SRPK2DTX3PGLSSHC3
RNPS1SP8VTA1NUPR1ADD2
SYNPO2MACC1TRIM40EPN1TMEM127
NTMT1ATF4MON1BTRHDEPRR11
FARP1PXDC1MLLT3PNISRRSBN1
FSD1LCREB3L2ACSL1CX3CR1STRBP
XKR9NAIF1BORASMIM10L2BPAG1
IQCERINLCRISPLD1SPDYE11ERMAP
CLTCAPOOLPCMTD1SPDYE17KLHL7
ELP4LONRF2CBR1C4orf54WDR5B
DNM1CIBAR2CNOT6LATP2B1ADCY2
ABCA8NHLRC1DCAF10PTAR1PDP2
PLAGL1SIAH3PTTG1IPSPDYE14ZBTB4
FAM104ATPD52L2HECW1SPDYE8EPB41L5
PRMT7MOB4KIF17SPDYE15ADCY1
CEACAM7GPX1JADE1SPDYE9INIP
IGF1RCLEC12BCOL4A6SPDYE13XYLT1
WASF3GADL1CYFIP1MCTP2LMBR1
CDC27NEBLSNTG1IMPG1HHIP
CCR1YKT6TMEM9CASRHAPLN4
MIER3ETV1CST3CD44KLHL18
CCDC125ARFGEF2CSF1RREEP3VCPIP1
C1orf43ANO6DBNDD1OR4N5HAPLN1
MAMSTRPAFAH2TMEM273OR6B1AFF2
ZNF546PPP6R3VSTM1BIRC5FNTA
TSEN15KLHDC2RMND5BSOGA3KLRD1
LYPLAL1LOC102723728ZNF585AKATNAL1PRKAR2B
SYT7TXN2LAIR1MECRPRPS1
CDK19GPR55DLDCSKMTQSOX1
EYA4KCNK9ZNF761TFKCNK5
TRPM7KIAA1958UHRF1ATG9ABMPR1A
HMGB3PGAP2SEMA3BRAP1GAP2SPTLC2
DEFB134NWD1TIMM23BPAK3IDE
TMEM198COL20A1MYADMSLC2A5SMAD4
HAUS3SLC30A3CDIN1CCDC85CINHBC
PRKACAITPR1SLC35E2BPTPRQLPP
ZBTB26SAV1ZNF304ANKRD34CDCAF7
CEP20WNT10BCYB561D2ANKRD33BPITPNA
PRKAG2TUT4SH2B3TK2UQCRB
GPX8POTEB3ZBTB8ACXADRSEC24B
SERPINB13MTMR9RELRAB35
MAP4K2TTC34KLRF1SLC2A3
ELMOD1SNX27MTRZNF81
TNS1CEBPZOSCDH18PHLDA1
SENP5PLEKHM3RUFY3PITPNB
NEURL1BING5SGK1WBP2
CPEB4TMCC1CLNS1ADSE
GCLMTPRG1MYCNMCTS1
PGPEP1SH3RF2CA12DBNL
SLC38A7HEY2SEPTIN9HDAC9
THY1HNF4GLYRM7CTSO
BLOC1S6HPSE2ZNF131ARL17B
RHOASCAPERHSPBP1KCNJ5
LOXPLEKHJ1CNGA3PPT1
ZNF331PRIMA1CIRBPVMA21
TRAM1ATP2B3FRMD8SLFN12L
PPM1LSLC4A4ZNF562LRCH3
ZKSCAN5SLC6A11KMT5BOTUD4
LZTS2SLC25A15EMSYZNF577
NINLTENM1DLG2MAPKAPK5
CCDC157NPTXRNUDT4ADPRHL1
ZFP1SMUG1CADM1NBEAL1
TRAPPC4CRCPNDST1ZNF142
STK32CGOLIM4ZBTB44SPECC1
OPCMLHERPUD1ERC1RNASE10
RILPL1EEF1AKMT4-ECE2TMEM98SFMBT2
CAMKVDAZAP2UMAD1OR10A6
NRXN1TSC22D2AAMPBMP7
U2SURPTRILACHESLC26A4
FASTECPR2CEP97GABRA1
BNIP2PPM1ESMIM21GUCY1A2
LPGAT1RRP1BVBP1HTR4
MCF2LWDR43CD226OPRD1
WDR82OTUD3OLFM2PTGIS
TTYH3KIF13BLMOD3IL17REL
NDFIP1VPS39HMG20AOR8D1
LRRC27ANGEL1KRCC1SPIN3
DDHD1AHCYL2CYRENFAM102B
CYRIATMEM158ZNF236SNX30
TXNDC5UBXN7QDPRSERF2
APOLD1GPX7DAPP1YTHDC1
OR2J2MED15CCT5HIGD1A
ANP32EPHF20L1TGFBR1VSIG4
AMMECR1LRTRAFTCF12AUTS2
TRAPPC9IRAK4ZYG11AAP4S1
MARVELD1A4GNTUPRTARHGEF3
CACNG8NCKIPSDDYNAPCALU
CCNB1PAX5ST8SIA5KCTD1
PCDHGA6TRIT1LIPGNEMP2
CAPRIN2TENT5CPIK3C3SIN3A
PLXNA1THUMPD1PHC3PDCD6IP
EIF1ADHIF1ANZNF24STX3
LLPHSLC30A6SYT17SRSF10
DDI2POLR3BSS18TMEM178B
COG8EFHC1SSR3RUNX1T1
MSANTD4GOLPH3LZNF346SLC28A3
JAGN1PARVANME6TMEM235
KRTAP4-4SLC47A1NAA50TAF1C
TRIM63UQCC1MGME1
PAPOLACMTR2AURKB
MAFGMINDY1MYMX
SFT2D3CHST11CCDC141
ZC3H10GABRQSPC24
SYAP1DISC1BLCAP
SPPL2AWDR4CTSB
ITIH5ERBINARIH2
SPRYD3FBXO42CDKN2AIP
PRPF38AANKIB1THAP6
TMEM241WDR44BCL2L1
KRTAP4-11VSIG10AQP7
SYNE1CHST7SLC35E4
ZCCHC3HMCESZNF532
SLC45A3STOX2BICRAL
PMLCDC42SE1FHL2
SMDT1CLDN2LSAMP
CDC14BJPH2FAM216B
CFAP91AICDAPRCP
MVB12BSERINC1NUMB
DISP2TBC1D14BCAS3
TPD52L3ZBTB2DMAC2
FGF13TRPM3MED28
CDH7BMP5KDM7A
CORO2AMTMR3ATXN3
WDR7CLDN1OR2H1
AZIN2DMTF1C1QTNF3
ZFP91PSAT1PHACTR1
MYLKADAM22ADAMTS12
TEKT1FOXA2SFXN3
BSNDOPTNSLC25A28
FBXO32PRSS22CDK13
SLC36A1IPPKDNAL1
COL9A1DDX50CRISPLD2
PTPN2IRF2BPLGRWD1
C20orf96RPAP2CACNG6
CST9LPRR5LESYT3
SRXN1CNR2KLF16
WFDC10ACOL4A1PCBP2
ASB16CTSGTMEM245
COLEC12FCN1ZIC4
DPP8HOXD10ZNRF3
UBE3BLY75ZNRF1
INPP5KMN1LRRC8C
ZFP82NMBRHSDL2
HPCAL1OMGCCDC77
PANK1PFDN5ARFGAP2
GLB1L2PIM1MEGF11
ZNF251PREPSPIRE2
MARCHF9MAPK13CNFN
CMTM7PSMB2KBTBD8
ARL11SCN9ABOK
DDX31ITSN1NT5C1A
BCL2L11SH3GL2ST6GAL2
NFAT5SLC7A2ZNF594
SPATA17SPARCSLITRK2
VANGL1MAP3K7USP38
NRXN3VCLMFSD14B
SPPL3ZNF84INA
MAPK9HMGA2TXNDC17
SREK1TAF15ZNF496
DNAAF8RANBP3ADGRA2
TSTD2DGKEZNF514
PPTC7DENRCEP89
CLDN14ASAP2PDGFB
TBC1D2BARHGEF7TSLP
MAPK1IP1LMBD2GTPBP10
ATP6V1C2EFNB2NKD1
ZFYVE27COL12A1CNP
C15orf40DMP1GABRG3
NIPA1FOXE1ADAM19
CMTM3ILF3TNKS1BP1
UROC1RAD9ADMAC1
FAM76BRAB11ALARP1
GLT1D1VAPBGADD45GIP1
SEPTIN10MAGI1RFT1
KLHL23IER2SLC2A13
EFHBDHX8ELFN2
SPICE1SERPINI1WDFY2
FAM91A1CD80NIBAN1
FAM124ACDX4ARTN
UBQLNLSKILKLHDC3
C18orf25ARHGAP6NAA15
PIGMNCOR2TRIM6
DIRAS1SPTLC1BORCS5
AFG1LELLBRD4
PDCD4RRAGABANP
WFDC5TCFL5B3GALT6
APOBEC3ALMO4TMEM41A
TIGD1HNMTSLC46A1
CACNG5SRP72DYNLL2
HS6ST2WASF2SIRPA
FOXP2ZHX1SOCS4
OSBPL9DUSP12MUCL3
RPUSD2KLF12DBN1
C1orf158DNPEPWRNIP1
C1orf216GTF3C4TSPAN18
JMYMRASSYCE1
APOBEC3DKPNA6SNAP25
CEP128SEC61A1WIPF2
ZNF362SNX12GSX2
SNRNP48NRBP1PLCD3
TBCELOSTM1CCBE1
ELAPOR2TRPS1BMPER
SCUBE3HNRNPH3MED22
TMEM18UROSRORA
TMEM268PISDZNF845
TNPO1NEK9DHRS1
MFSD4BMETTL21AFOXP4
ODF2CCDC40TLR4
LTO1CEP78MPLKIP
HS6ST3ZNF383CANT1
CREBRFFBLIM1ANKRD54
CALHM5MGAT4CA1CF
C10orf67ZNF843MS4A6E
MEIS2GCKKCNH5
SKP1NT5C3AYWHAB
CAMK2BDCHS2ODAD1
CAMK2GLOC102723996NACC2
ELF1DEPDC4ZNF558
RELNC9orf85CCDC13
IFNLR1MIOSKLK11
ABCA12LOC102724488ZFC3H1
NFATC3TFDP2VSTM4
SLC38A11GIGYF1ANKRD23
REM2SH3D19ZNF25
CCDC171NFILZGLYATL2
RNF152RNFT2NSMCE1
SLC9A9SPDYE21SENP8
ZNF619LCA5LOSBPL3
SLC30A8OR6C4DBF4B
SPATA19TTC28TRAF6
CNTN1ESR2CRYZL1
KRT73ING2SNX15
MT1ENCF1IPMK
EXOC8TPP1TCEAL7
C5orf51NEU1ORAI3
PIGNPCSK1TADA2B
PDLIM2SLC10A2RAB42
PATJCYP3A7TRMT61A
STX12GRIN2BPIK3AP1
LYNX1IGF2RAGBL1
RETREG3TSR3CDYL2
RASSF3NOMO3PRXL2B
SPTBN1OR2T33TBX15
LCE1EOR5A1TMEM237
SPINT4OR56A4UGT3A1
SLC25A42OR56B1C5orf24
TRIML1OR4N4ZNF664
FBXO27IGSF3UBE2U
SCYL3GP2CNIH3
DCAF4CISD2ARL6IP6
NCOA3PLPPR5PPM1K
GJA5DNTTMOSPD2
NF2DAPL1SDE2
ZSCAN22CORO1BBBS12
APAF1ZNF181SGMS2
ENOX2AP1G1CDC20B
GATD1CYB5RLDCP2
TMEM255BMAFSNX31
ANKDD1ANGRNDAND5
TPRG1LELMO1NANP
VSX2DEDDAMER2
ERGMINDY2MTURN
IRF2BP2SLC6A3COL22A1
DTNBP1JADE3MAGI3
TMEM107G6PC2PXT1
CYP26C1POLR2J3ZFP3
HNRNPA3MID1IP1SLC35G1
ZBTB41GXYLT1ERI1
RNF41PACS2APCDD1L
RNF138KIF13AZCCHC24
TREML4SYNPOB4GALNT2
G3BP1IGF1MED19
ZNF621PABPC4LNUP50
FAM83HPLAAT3LCORL
NHLRC2ROBO2CACUL1
CCDC172INSYN2BZFPM1
DRAXINMEF2AADGRF1
LHFPL4AGFG1RASGRP4
TDRD1PIK3IP1ATP2A2
BCAS4RPS24RASAL2
ACACAZNF880NMNAT2
LCN6SPDYE6CAMK2A
DZIP1CCDC81TRIM39
ISM2PLEKHD1RC3H1
ILDR2COG5CSF1
KCNRGZSCAN12MMAA
CACNB2C10orf105KCNH1
ZMYM3SPDYE2BLIN9
ENOSF1NEU4USH1G
SMIM10L2AUBAP1PTCHD1
SYNJ1ASTN2TTBK2
GRB2FBXL20PLBD2
UGT1A6CENPOKLHDC8B
ECI2KATNA1TYSND1
PRAMEATG13ANKRD52
ENSAEHFZNF776
FREM2BACE1RIMKLA
LRRC75AGHRPDZD8
BEND4PARNRABL3
TMPRSS11FGFOD2SLC41A1
TEX19CDC5LPSMD12
ADAMTSL3NKX3-1CCDC50
ZC3H14SEC14L3
EEF1AKMT2ZPLD1
ANO5DDX51
TMED8APTX
WNK1XG
ANKRD44PTPMT1
KDM2BZNF792
PEAK1PRR18
PCGF2FGF14
RECQL5PSMD13
RAE1FAM171B
METTL6PKHD1L1
UBE2E1ASB6
SACSSOX5
SNX9GPR119
SYNJ2CCDC190
ARHGAP5ZDHHC21
DRAM1IQUB
MICU1HPS5
ADARPIK3R1
SUSD4UBXN2A
FOSL2OPN5
CHIC2CERS2
TRIM2C20orf203
DELE1SKA2
MYLK4CTDSP1
EMP2GPX6
ACTN4GDF7
RPS6KA3DLGAP4
DLG3ADCY5
PHKA1RNF14
AGPSFBXO25
LOC401040SRRM4
TTC23LKRIT1
MKRN1COPS8
STX17CD96
NIPSNAP3BMLX
PLA2G15HIPK1
TMEM131LSRC
NR3C2EMB
ARHGAP25C19orf54
GALNT16RUFY4
RIMBP2LRIT3
DMBT1LANCL3
INPP5FSTIMATE
ZC3H12CGJB7
HMGCRVWC2
KAZNSULF2
CACYBPKRTAP10-4
NFIAKRTAP10-5
TMEM234MKNK2
EFCAB2HOMER2
ABCC5POLQ
SNCACDC25A
SUPT3HMAFA
EXOSC2STAMBP
RAPGEF3SF1
TARBP2IYD
GRTP1MBLAC2
NTRK3IER5L
TVP23AOR2V2
TTLL6NAALADL2
SOCS7PAOX
NPEPPSFAM199X
GOSR2NIPAL1
ZC3H4SPRYD4
ARHGEF9MAP6
SHROOM4PATE2
AGKSIGLEC15
MLLT10SLC25A24
ENAHPRRC2C
EIF5ANYAP2
TCEA2USP37
HECW2CDK15
RBM5HSPBAP1
LIMD1PI4K2B
B3GNT3ABI1
UQCRQSLC1A2
MOCS3IDH3A
MCATGLP2R
OR1A1NKIRAS2
STRN3RARA
DNTTIP2FOSB
FAM120AZNF324B
NOS1APPDCD5
TCAF1GMEB2
KIAA0586CRELD2
TOMM20CHCHD5
LCMT2PDS5B
TOX4SLC66A2
RHOBTB1ACAD8
SRGAP3FAM172A
HELZKIAA0319L
NLGN4YMEF2D
NAV3STAT1
CNKSR2TTC21B
FASTKD2SNCB
STK38LMAFK
TNIKCACNA1C
GGA2LRP6
SPARTSETD1B
TTLL12LITAF
SEPTIN8CCNP
RCOR1PGLYRP4
CYLDADAM23
CUX2GABBR1
HAUS5GRB10
RRP8CEP152
BRI3HACD3
CCDC28AMPHOSPH6
C2CD2PAFAH1B1
CRELD1POU2F2
DNM3THOP1
LSM14ATNNC2
FAM184BPPM1F
WWC3BIRC6
RRP7AACTR8
COL5A3PDE10A
KRT76ATG14
ST8SIA3POMT2
ZMYND10SRGAP1
RWDD1CEP290
GALZDHHC6
ABHD5SPOCK2
DHRS7ZMYM1
RLIMGNG4
RAB10BIN3
MRTO4PPIH
HECACHRM3
DCTN4PODN
CYB5R4NPHP4
NLKTLR5
AKAP11CYP27A1
CAB39EAF2
WBP11TGFBR2
GULP1BAP1
RAPGEFL1ADGRL3
ZDHHC2LARP1B
PHF20OGFRL1
BET1LAGFG2
UFM1FGFR1
CYRIBTUSC3
C21orf91ANKS6
EPHB2SNAPC3
BAIAP2ASAH2
NPTNCPT1A
PLXNA3RBMS2
LEPROTDCAF5
PARP14PNPO
TRIM44SMIM5
DIRAS2PIGL
KIF21BABHD12
ZNF280DTAB3
GDAP2GALNT11
LRRFIP2ASPH
UHRF1BP1CC2D2B
CASZ1RPS6KA1
NSD3CNTN2
DEPDC1TNRC6C
SARS2TXNL1
PIGXIL18R1
GID8TIGIT
TTC38UBL4A
VPS37CCLEC4M
TMEM248ADAM28
IFT57CAPN6
CCDC186TNFAIP8
PRPF38BSND1
ANO10TMOD2
ARMC1TMEM97
KLHL11SOX8
N4BP2HERC3
SBNO1KIAA0040
ARL8BPHF14
MACO1EDEM1
MOB1AAQR
RCOR3SECISBP2L
TMEM19ZNF536
C5orf22RNF144A
AGPAT5SERTAD2
LIN7CEPM2AIP1
SYNJ2BPPLPPR4
BEX1KBTBD11
GPALPP1ADNP2
CHST12CILK1
RBBP6ADGRL1
CTTNBP2NLZNF365
SLC30A10RPH3A
OTULINLSV2C
SPATA6TNRC6B
UGT1A10RAD54L2
UGT1A8PHF3
UGT1A7LARP4B
UGT1A5TRIM9
FGF20FBXO28
TCIMMINAR1
SAR1APOFUT2
RAD18MGRN1
CMC2ADCY6
NIT2SASH1
OTUD7BDPY19L1
DTWD1ESYT1
CDC42SE2PHF24
TULP4SRGAP2
ARRB1ZNF10
MNTSPEF1
SLC39A10CAMSAP1
ENTPD7ATL3
XPNPEP1NOL11
PLXDC1RAB11FIP5
ADCK1DKK3
LYRM1NUDT13
SELENONTRIM33
NHSL1TPPP3
NDRG4UBE2D4
RHOJKLF13
HEG1FIS1
AARS2HDGFL3
MIB1INSIG2
TRMT5SUFU
CCDC191IKZF2
ZFP28AK3
MEAK7PCYOX1
SLC7A14ACP6
LZTS1ANKFY1
UGT1A9SCLY
TMSB4XKLF3
RNASELERGIC2
NEUROD4SLC25A37
NTN4ZNF771
RBM25FZD3
BCRSIX4
PBOV1SPA17
ADAM12CPSF2
FAM3ANAGK
TWNKOTUD5
MCL1SAMD9
ZNF148GIPC2
LAMTOR3FERMT1
KCNK13NUP62CL
KCNK12BIVM
NAPBCWC25
CLSPNRPP25
TSPYL2NHP2
CLSTN2PHIP
RAB38ZNHIT6
PDFARGLU1
NCAPGATG2B
ABCG8MANSC1
NSD1NODAL
GREM2RIC8B
ATPAF1CCDC198
CERKCKAP2
NIBAN2UBA6
BCL11BBRF2
C8orf33SPTLC3
FUNDC2SLC39A9
C1orf116FOXJ2
TMPRSS3TMEM242
PRRG3ASAP1
MBOAT7ZC4H2
TMEM43CEP41
DSC3AJAP1
ADIPOR2PCDHB14
GALNT14PCDHB15
EFCAB1PDE7B
TUT7ERRFI1
RTL10HOXC5
VPS37BSSH1
SNIP1CCSER2
IQCA1TMX3
MOB3BING3
ATP8B4SEPTIN3
ACTR5PPP1R37
FBXO17HOXD8
POF1BLRRC8A
DOCK5C21orf62
GFM1SERTAD4
ASRGL1ACRV1
NYNRINFEM1C
CENPAC5orf15
CKS1BINCENP
SLC31A1COQ8A
DR1ZMIZ1
DRP2SLC24A2
DSG2PCNP
FGF4LYZL6
FRKTHAP11
GABRR2RTN4
GFPT1RCN3
GLULKIAA1143
GNAQGATAD2B
GTF2E2LRRC47
GTF2F1USP31
KDRNLN
LAMA4CCPG1
LAMC1NLGN4X
LIFRMTUS1
NDUFA4COG6
NEO1PCDH19
NPTX1RTL9
OR1D2NUFIP2
OR3A1IFT80
PPP2R1BRELCH
PRPSAP1SHROOM3
PSMD7CALCOCO1
PTPN3PLXNA4
RAP2BGNAO1
RBL1ZNF253
RGS12ZNF250
RYKART4
SBF1CCAR2
SH3BP2LY6G5B
ST8SIA1IL21
SOX11FGA
SSR2ITM2B
SYN2TIA1
TAC1NXF3
NFE2L1MRPL17
TEFVIPAS39
TRPC1STEEP1
UBE2G1EPB41L4A
UBE2NERAP2
VLDLRNXN
WEE1SUDS3
WNT2VPS52
ZNF177GPR135
SNNPRRX1
ULK1SLC13A3
VAPAMRPS11
GCM1INTS3
TRADDZBTB10
CDS2ZNF426
CCN4DSC2
MBD4PSTPIP2
KYNUWNT2B
USP13FYCO1
INPP4ANKAP
EIF4EBP2RIC3
AKAP6MPZL1
ATF6BMAP7D3
ELF3NAA35
ETV5YRDC
FGF10LRRK1
VEGFDASB13
FOXA3TXNDC15
MYT1SNX22
PEX14L2HGDH
GET1SCD5
COILNAA25
LIN7AIFT74
DCLK1CLU
PIWIL1GOT1
B4GALT5HOXB5
UBE4AIDO1
KCNK6IFNA8
SH3BP5LRPAP1
PCYT1BLSS
AKAP5SH2D1A
SEC22BMARCKS
MYO1EMCC
NDUFA9MSR1
NFKBIL1NFX1
SNU13NOVA2
OXA1LOAS1
SCDPAPPA
ZMYM4PBX2
ADAMTS4PDCD2
THRAP3PDGFRB
CLEC2BPDK2
FOXL1PLN
GPR15POLA2
HAS2PPP2CA
PRKAB2PPP6C
CCL13PRKACG
AKT3PRKCB
MLANAPSMA4
HOXA11PTMA
IFNGR2PTPN4
LAMC2PTPRG
SOX3RAC2
VAMP7CCL22
FARSBXCL1
ABCC4SDC4
SAP18SFRP4
GOLGA3SHB
MAP1BSLC6A1
CD164SLC18A2
ALKBH1SSR1
HTR3BSUPT4H1
HS3ST3B1TFAP2B
CITED2TRAPPC10
NTSTNNC1
ORC2TRHR
PAX9TXK
ENPP1UBE2B
PHKG1UBE2V2
PRKAA2WNT5A
NCOR1ZIC1
RBM14ZNF141
TRIM38BSN
EIF3MBFSP2
ARL6IP5CUL4A
MTHFSTPST2
PAICSSMARCA5
P3H4GPR65
POLR3FPARG
GNAI3NIPSNAP1
HIC1TP63
PVRAOC3
HBS1LCHRD
MTHFD2IRS2
MMP24KAT2B
NUDT3ST13
SUGT1RNF8
DNAJB2FKBP5
AP3M2GMFB
CKAP4SLC1A1
TMED10SNRPD3
RAB31USP2
ZFHX3CHST2
IDH3BGDA
RASGRF2ARHGDIA
DDX52ELAVL2
ADAMTS5ETFDH
NISCHFOXD2
CEP250HNRNPC
SEC23IPSCO1
RNF139PIAS2
KLHL2RABEP1
MMEATG12
BRD3RPS6KA5
ATP1B4ASIC3
ELL2B4GALT6
CHRM5BAG5
CLDN12APBA3
TIMM10BCDH6
KCND2DOCK3
LDOC1GABRE
MYCBPKCNC3
PRNDKCND3
POLMNUCB2
CDIP1ABCD4
OR10H1TLE1
PAX8AKAP17A
CNTNAP2EXOG
PRKAR2AABL1
PMS2ATP5MC2
NUTF2CBL
CDKL5CBX2
ZNF197FOXN3
ZEB1CRK
CSTF1CRKL
HMBOX1ERBB4
LRP10HSPA1A
PLEKHA7CNOT9
SRGAP2CZRANB2
ASB1KCNE3
MOKCFL1
TIMELESSITK
POLA1KRT6B
CYB561TAF11
POU6F1VDAC3
AKT2RNF103
LRRC7TSPAN5
CMC1CNIH1
TMEM72SPRY3
CEP83MLLT6
DLGAP2MMP16
DYRK1AMTF1
ARHDAC4
ZNF525PRICKLE3
TBC1D5NRGN
HSPB7PRKG1
ICA1DNAJC3
SLC8A1HOXB13
C13orf42VTI1B
DAZAP1CRTAP
CTXND1AGPAT1
PSME3IP1TGOLN2
BRAFERF
BRD3OSPSMC4
EPM2ATRIM27
DIO3DYNLT3
TCAF2EXOC5
PDE1ADCTN6
NR3C1FUT9
MGAT1KIF1C
FAM243BHPSE
TENT4BSPIN1
KLHL33ABLIM1
DAB1FKTN
GPRC5CSCML1
KPNA5KRT38
CACNA2D1ZBTB33
FAT3ATF7
ALDH5A1ZFP36L2
FGFRL1CALM1
AKAP12ATE1
POLR3GKAT7
CTXN2ZXDA
CRYBG1ERG28
FBXO41RNF2
TMEM217PMF1
DNASE1L2ABL2
STXBP1PSEN1
PNPLA1AP4E1
LOC100133315DGAT1
PDE8BADAT1
XIAPAP3M1
IRS4ARL5A
HNRNPCL3DDAH1
PRRC2BCCNDBP1
TDRPDNAI1
AGTR2FBXL3
DTNAFBXW2
USP54FBXO7
ELAVL1TRIM32
GATMMLYCD
HSBP1OGA
ID4SLC35A3
IFRD1MORF4L2
CEACAM1TRAM2
BTG1OR2A5
COL4A4PITPNC1
ERCC6TINF2
SHHYWHAG
ITGB3DNAJC15
JAK3VPS4A
KCNA1RBM15B
PRNPEEF2K
SOX9BLNK
TGFBISNX8
THBDPCDHB1
TPM1GREM1
BLMHRAX
IL2RANRG1
UGT1A1LIG3
EPXCRIPT
CRXTOM1L1
BCL2FAM156B
CHRNB2CD99
GRM6ASAH2B
HTR1BNDUFA10
IL2RBADAL
KCNJ2PYCR3
OPRL1CALM3
PRRG1CTF1
RPL11NDEL1
RPL28DRG2
OR2A14SCYL2
PIM3GLDN
ASTLSAP130
ERICH3SMYD1
STUML3MBTL4
DUSP29USB1
BMFTOP2B
NRARPKLHL26
OR5M3ZNF287
GBAOR2J1
ZNF780BCHD1L
PLA2R1ZDHHC24
LMBRD2KIDINS220
NEXMIFGRAMD2B
USP20DGKB
DNAAF9NT5C2
C1QL3TIAM1
GOLGA7BPCDH15
SLC9A4TMEM269
CREB5ZNF214
OLA1CXCL8
KRTAP5-10NUDT4B
PABPC1L2AGOLGA8T
PLIN5CCDC163
DGKKRNF227
CARS1FRRS1
LGR6NAGA
BCL7ACYP4A11
YIPF5RAB41
CD34NOTCH2NLB
SLC35F1NOTCH2NLC
RGS7BPBAALC
MTUS2DLG1
ZNF704RGMB
ARL4ATTC8
FOXK1BCLAF3
TRIM71MAGT1
TESMINZNF479
TYW5ZBTB3
RSPO4ORMDL1
TMEM70GABRB2
LINS1HP1BP3
PABPC1L2BIKZF5
INSCGLI2
EIF4G2LRIG1
TTC14CNGA1
ZNF391BDKRB2
UBXN2BCHML
FAM110CATXN7L3
LDB3DMAC2L
CCDC88CFUT1
MYBL1GPRIN2
EPHA6OR7E24
CACTINKIAA1671
TMEM120BDPYSL3
ZNF112FXYD3
ARSAIRGQ
ZNF207OR56A1
RNF169HTT
TIFABERN1
SH3RF3GPC4
ZNF578GDI1
PIP4P1GSTA4
CNPY1MR1
RPP30ACTA2
PCMTD2AHR
SRRM3ARCN1
PRH2ARSD
TENT2ATP2B4
CFLARATP6V1C1
EIF4EPOLR3D
ZNF720CCND2
AKR1C2CD38
PAX7ENTPD1
SMIM13BCHE
ANXA2CD40LG
ATXN7L3BERCC8
VASH2SLC26A2
C1orf198GNAT1
CISD3LIPA
FAM13CMYL3
CROTNDP
ZNF534PDHA1
NSMAFPGK1
CCDC169SERPINA1
RFPL4APKP1
CASTOR2SLC5A1
PPP1R3GHOXA13
INTS9NOS1
UBE2QL1ADH6
NONOALDH2
SCRN1ATP4B
MTFR1CHRNB1
NCEH1CYP1A2
RBMXL1CYP11A1
STAU2GLRB
TLCD2GRIN2A
ATP5MGLPTGFR
ZNF268NCCRP1
TNFAIP8L1ZNF429
TRMT2BSPOPL
AMMECR1ARHGEF37
ZNF559-ZNF177CLDN18
CPEB2RABL2B
VITDYRK3
SEMA3EGRK6
SLITRK4ZNF774
NIT1KRTAP5-2
GIMD1OR1B1
ATP6V1FNBOR10H5
EFCAB13OR2L3
CCDC179OR4K17
ARPC4-TTLL3OR52E4
PHOSPHO2-KLHL23LRRC55
ST20-MTHFSOR10G3
BMP2PLCXD3
BMP3SLC25A25
CTSVWDR35
ANKRD12COA5
ELOCC1QL4
SLC19A1MXRA7
MFAP3SHE
CD99L2TTC7B
ZNF322ZC3H12B
ELOVL5MYPOP
RANBP6NUDT17
ZNF124OR2G6
TRA2BC2orf68
TRDNGDPGP1
Figure 3

Sankey diagram of the miRNA-mRNA Network in IS.

3.3. Enrichment Analysis of Differentially Expressed Genes

To explore the potential biological functions of the above downregulated-expressed 25 mRNAs, we performed GO annotation and KEGG pathway enrichment analysis. The enriched GO annotation included oxidoreduction coenzyme metabolic process, pyridine-containing compound metabolic process, and nicotinamide nucleotide metabolic process in the biological process (BP) category. Sin3 complex, oligosaccharyltransferase complex, and tetraspanin-enriched microdomain were included in the cellular component (CC) category. NAD+ kinase activity, oxidoreductase activity, and beta-1,3-galactosyltransferase activity were included in the molecular function (MF) category (Figure 4(a)). KEGG pathway analysis showed these genes were mainly involved in various types of N-glycan biosynthesis, nicotinate and nicotinamide metabolism, and pentose phosphate pathway (Figure 4(b)).
Figure 4

GO (a) and KEGG (b) analysis of the 25 intersected genes.

3.4. PPI Network Construction and Validation of Predictive Feature Biomarkers

We further analyzed the protein-protein interaction (PPI) network of the above 25 intersected genes by Genemania and identified the RB binding protein 4 (RBBP4) had the most interactions in the network (Figure 5(a)). Furthermore, we performed the LASSO algorithm to narrow down the above 25 intersected genes and identified eight key genes related to IS (Figure 5(b)). The eight genes were BCL11A, RNLS, UBFD1, STT3A, NADK2, GPR26, PPARA, and SAMHD1. Moreover, we used ROC curve to estimate the predictive value of the eight genes, and found that all of the eight genes had a certain diagnostic value in discriminating IS patients from the healthy controls, with an AUC of 0.7 (Figure 5(C)).
Figure 5

PPI network construction and validation of predictive feature biomarkers. (a) PPI network of the 25 intersected genes constructed by GENEMANIA. (b) A plot of biomarkers selection by LASSO regression algorithm. (c) ROC diagnostic curve for the eight genes selected by ASSO regression algorithm.

3.5. Immune Cell Patterns in the Peripheral Bloods of IS

Given that peripheral immune system has been shown to play crucial roles in the evolution of ischemic brain damage [27, 28], we further compared the different immune cell patterns of the peripheral bloods between IS patients and normal controls from GSE22255. As shown in Figures 6(a) and 6(b), M0 macrophages and resting mast cells were significantly decreased in the peripheral bloods of IS patients. M1 macrophages and activated mast cells were slightly increased in the IS group but had no significant difference compared to the normal control group (Figure 6(b)). Furthermore, we analyzed the correlation among the immune cells and found that monocytes were significantly positively correlated to M2 macrophages and significantly negatively correlated to activated NK cells and activated mast cells (Figure 7(a)). Moreover, we analyzed the correlation between the immune cells and the eight variables related to IS and found that STT3A was significantly negative-correlated to follicular helper T cells, activated NK cells and resting dendritic cells (Figure 7(b)).
Figure 6

Immune cell patterns in the peripheral bloods of IS samples. (a) The composition of immune cells in the peripheral bloods of IS patients. (b) Comparison of the indicated immune cell subtypes between stroke and normal control group. ∗P < 0.05.

Figure 7

Correlation analysis of immune cells in the peripheral bloods of IS. (a) The correlation between immune cells in IS samples. (b) The correlation between the eight key genes and immune cells. ∗P < 0.05, ∗∗P < 0.01, ∗∗∗P < 0.001.

3.6. Verification of the Diagnostic Efficacy of the Key miRNAs

GSE117064 were included in this study as the verification series to validate the diagnostic efficacy of the above three miRNAs. Has-miR-16-5p was more advantageous for diagnosing stroke than the other two miRNAs, as shown in Figure 8.
Figure 8

Verification of the diagnostic efficacy of the key miRNAs. ROC diagnostic curve for the three miRNAs.

4. Discussion

Stroke causes great burden on human health and the economy. Although prominent improvements in the early diagnosis and treatment of IS in the past decade, it is still a leading cause of death and disability. Thus, identifying new biomarkers for the early diagnosis of IS is essential. Recently, serum glutamic oxaloacetic transaminase is reported to may be utilized as predictor in detection of early neurological deterioration in acute IS [29]. Here, we first used the GEO data set to detect the differentially expressed exosomal miRNAs associated with IS and identified three miRNAs (hsa-miR-15b-5p, hsa-miR-184, and hsa-miR-16-5p) intersected with those differentially expressed miRNAs from freshly removed human stroke brain tissue [25]. Among the predicted target genes of the three differentially expressed exosomal miRNAs, 25 mRNAs were obtained by intersecting with differentially expressed genes from GSE22255. Then, we used LASSO algorithm to identify eight key genes related to IS, and further analyzed the independent prediction ROC curve. Subsequently, we analyzed the immune cell patterns in the peripheral bloods of IS patients and the correlation between the immune cells and the eight key genes as potential biomarkers for IS. Previous studies have reported the significance of the miRNAs, which were identified in our study. hsa-miR-15b-5p is highly expressed in the plasma of Alzheimer's disease (AD) patients, and could distinguish AD patients from normal controls [30, 31]. Besides, hsa-miR-15b-5p in the aqueous humour of patients with diabetic macular oedema shows a fold change greater than –50 in log2 values, compared to the control group [32]. In this study, we firstly identified hsa-miR-15b-5p is highly expressed in the exosomes of IS patients. Recently, hsa-miR-15b-5p is found to regulate the proliferation and apoptosis of human vascular smooth muscle cells [33]. However, the specific mechanism of action of hsa-miR-15b-5p in stroke is unclear, and needs further investigation. miR-16-5p is found to be highly expressed in the in serum and plasma of patients with colorectal cancer [34], and in the feces of patients with precancerous lesions [35]. Besides, hsa-miR-16-5p may be a good candidate for identification of predictive biomarkers of duloxetine response in patients with major depressive disorder who are responsive to duloxetine treatment [36], suggesting that hsa-miR-16-5p may play important roles in the nervous system disease. Consistently, we also found hsa-miR-16-5p is highly expressed in the serum of IS patients, and the specific role of hsa-miR-16-5p in IS needs further investigation. Hsa-miR-184 has been proposed as a biomarker for several cancers, including non-small cell lung, uterine corpus endometrial carcinoma, and oral squamous cell carcinoma [37-39], and brain-enriched hsa-miR-184 is downregulated in older adults with major depressive disorder [40]. Here, we identified that hsa-miR-184 is highly expressed in the serum of IS patients. Moreover, the co-regulated genes of the above three miRNAs were enriched in the N-glycan biosynthesis, nicotinate and nicotinamide metabolism, and pentose phosphate pathways. Interestingly, N-glycosylated immunoglobulin G has been shown to be associated with IS [41], and plasma N-glycans could as emerging biomarkers of cardiometabolic risk [42]. How the three miRNAs regulating N-glycan biosynthesis to affect the IS development would be explored in our following studies, and it could be a very interesting area. Peripheral immune cells interplay with the central nervous system, and play important roles in the brain development, and in the process of IS injury [43, 44]. The immune system is rapidly activated after IS, and peripheral immune cells migrate and infiltrate across the blood–brain barrier into the ischemic region to affect infarction progression and prognosis. Leukocytes are found to aggregate in the ischemic region of MCAO models as early as 30 min after occlusion [45]. Yilmaz et al. fond that CD4+ and CD8+ T cells are distributed in the brain tissue 24 h after IS onset, and act detrimental effects on post-ischemic cerebral immune responses [46]. In this study, we analyzed the different immune cell patterns of the peripheral bloods between IS patients and normal controls from GSE22255, and found M0 macrophages and resting mast cells were significantly decreased in the IS group, and pro-inflammatory M1 macrophages, and activated mast cells were slight increased, suggesting that the inflammatory responses were rapidly activated after stroke. Our result is consistent with recent study that CD11b + CD45+ and CD11b + Ly6G- monocytes and macrophages were greatly increased 3 days after cardiac arrest and resuscitation [47]. Mast cells are rapidly activated and release TNF-α and histamine to aggravate brain damage after IS [48, 49]. Among the eight key genes potentially targeted by the above three miRNAs identified in our study, STT3A, a catalytic subunit of the oligosaccharyltransferase, increases amyloid-β production by promoting N-glycosylation in the pathogenesis of Alzheimer's disease [50]. Besides, the expression level of STT3A was found to be negatively related to the biomarker expressions of M1 macrophages in breast cancer [51], indicating that STT3A may be involved in the regulating macrophage activation. Although the mechanism of regulating macrophages or mast cells has been extensively study, whether hsa-miR-15b-5p/hsa-miR-184/hsa-miR-16-5p-STT3A axis is involved in the regulating macrophages or mast activation in IS need further investigation. This study has some limitations. For example, our analytical data are derived from public database with relatively small sample sizes. Second, important analysis results need to be further validated with clinical samples. Further large-scale basic studies can be carried out to verify the conclusions of this study.

5. Conclusions

We for the first time conducted a comprehensive bioinformatics analysis and identified three serum exosomal miRNAs (hsa-miR-15b-5p, hsa-miR-184, and hsa-miR-16-5p), which may be involved in affecting the peripheral immune cell patterns of IS patients and might serve as promising diagnostic biomarkers. However, the specific pathogenesis and molecular targets still need to be further confirmed through molecular experiments.
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