Dataset Information

Multiple Membrane Transporters and Some Immune Regulatory Genes are Major Genetic Factors to Gout.

ABSTRACT: Gout is a common form of inflammatory arthritis caused by hyperuricemia and the deposition of Monosodium Urate (MSU) crystals. It is also considered as a complex disorder in which multiple genetic factors have been identified in association with its susceptibility and/or clinical outcomes. Major genes that were associated with gout include URAT1, GLUT9, OAT4, NPT1 (SLC17A1), NPT4 (SLC17A3), NPT5 (SLC17A4), MCT9, ABCG2, ABCC4, KCNQ1, PDZK1, NIPAL1, IL1?, IL-8, IL-12B, IL-23R, TNFA, MCP-1/CCL2, NLRP3, PPARGC1B, TLR4, CD14, CARD8, P2X7R, EGF, A1CF, HNF4G and TRIM46, LRP2, GKRP, ADRB3, ADH1B, ALDH2, COMT, MAOA, PRKG2, WDR1, ALPK1, CARMIL (LRRC16A), RFX3, BCAS3, CNIH-2, FAM35A and MYL2-CUX2. The proteins encoded by these genes mainly function in urate transport, inflammation, innate immunity and metabolism. Understanding the functions of gout-associated genes will provide important insights into future studies to explore the pathogenesis of gout, as well as to develop targeted therapies for gout.

SUBMITTER: Zhu W

PROVIDER: S-EPMC6062909 | biostudies-literature | 2018

REPOSITORIES: biostudies-literature

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Multiple Membrane Transporters and Some Immune Regulatory Genes are Major Genetic Factors to Gout.

Zhu Weifeng W Deng Yan Y Zhou Xiaodong X

The open rheumatology journal 20180724

Gout is a common form of inflammatory arthritis caused by hyperuricemia and the deposition of Monosodium Urate (MSU) crystals. It is also considered as a complex disorder in which multiple genetic factors have been identified in association with its susceptibility and/or clinical outcomes. Major genes that were associated with gout include <i>URAT1, GLUT9, OAT4, NPT1 (SLC17A1), NPT4 (SLC17A3), NPT5 (SLC17A4), MCT9, ABCG2, ABCC4, KCNQ1, PDZK1, NIPAL1, IL1β, IL-8, IL-12B, IL-23R, TNFA, MCP-1/CCL2, ...[more]

PMID: 30123371

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Project description:OBJECTIVE:Many population studies have shown that maternal prenatal nutrition deficiency may increase the risk of neurodevelopmental disorders in their offspring, but its potential transcriptomic effects on brain development are not clear. We aimed to investigate the transcriptional regulatory interactions between genes in particular pathways responding to the prenatal nutritional deficiency and to explore their effects on neurodevelopment and related disorders. RESULTS:We identified three modules in rat hippocampus responding to maternal prenatal nutritional deficiency and found 15 key genes (Hmgn1, Ssbp1, LOC684988, Rpl23, Gga1, Rhobtb2, Dhcr24, Atg9a, Dlgap3, Grm5, Scn2b, Furin, Sh3kbp1, Ubqln1, and Unc13a) related to the rat hippocampus developmental dysregulation, of which Hmgn1, Rhobtb2 and Unc13a related to autism, and Dlgap3, Grm5, Furin and Ubqln1 are related to Alzheimer's disease, and schizophrenia. Transcriptional alterations of the hub genes were confirmed except for Atg9a. Additionally, through modeling miRNA-mRNA-transcription factor interactions for the hub genes, we confirmed a transcription factor, Cebpa, is essential to regulate the expression of Rhobtb2. We did not find singificent singals in the prefrontal cortex responding to maternal prenatal nutritional deficiency. CONCLUSION:These findings demonstrated that these genes with the three modules in rat hippocampus involved in synaptic development, neuronal projection, cognitive function, and learning function are significantly enriched hippocampal CA1 pyramidal neurons and suggest that three genetic regulatory subnetworks and thirteen key regulating genes in rat hippocampus perturbed by a prenatal nutrition deficiency. These genes and related subnetworks may be prenatally involved in the etiologies of major brain disorders, including Alzheimer's disease, autism, and schizophrenia. METHODS:We compared the transcriptomic differences in the hippocampus and prefrontal cortex between 10 rats with prenatal nutritional deficiency and 10 rats with prenatal normal chow feeding by differential analysis and co-expression network analysis. A network-driven integrative analysis with microRNAs and transcription factors was performed to define significant modules and hub genes responding to prenatal nutritional deficiency. Meanwhile, the module preservation test was conducted between the hippocampus and prefrontal cortex. Expression levels of the hub genes were further validated with a quantitative real-time polymerase chain reaction based on additional 40 pairs of rats.

Project description:ObjectiveTo explore the regulatory functions of ceRNA networks in the nosogenesis of gout and search for potential therapeutic targets.MethodsWe searched the GEO database and downloaded the lncRNA microarray chipset GSE160170. This matrix series was analyzed to yield differentially expressed lncRNAs and mRNAs. Then, the correlations between lncRNAs and miRNAs were obtained by comparing the highly conserved miRNA families. The predicted miRNA-regulating mRNAs were matched to the differentially expressed mRNAs from the chipset analyses to obtain miRNA-mRNA interactions. Next, we used the Cytoscape software to model ceRNA networks and the STRING database to determine their protein-protein interactions. The R software was used to algorithmically screen the functional pathways of key PPI modules in the ceRNA networks.ResultsA total of 354 lncRNAs (140 downregulated and 214 upregulated) and 693 mRNAs (399 downregulated and 294 upregulated) were differentially expressed between the gout group and the healthy group. The ceRNA network of differentially expressed lncRNAs contained 86 lncRNAs (35 downregulated and 51 upregulated), 29 miRNAs, and 57 mRNAs. The processes identified in the GO enrichment analysis included gene transcription, RNA polymerase II transcription, and the regulation of cell growth and apoptosis. The pathways identified in the KEGG enrichment analysis included IL-17, TNF, and MAPK signaling. Nine lncRNAs (AC104024, AC084082, AC083843, FAM182A, AC022819, FAM215B, AP000525, TTTY10, and ZNF346-IT1), eleven miRNAs (hsa-miR-1297, hsa-miR-17-5p, hsa-miR-429, hsa-miR-139-5p, hsa-miR-449c-5p, hsa-miR-125a-5p, hsa-miR-125b-5p, hsa-miR-23b-3p, hsa-miR-217, hsa-miR-363-3p, and hsa-miR-20b-5p), and nine mRNAs (JUN, CASP2, PMAIP1, FOS, TNFAIP3, MAP3K8, BTG2, NR4A2, and DUSP2) were identified in the exploration of the key modules.ConclusionCharacterization of ceRNA networks could be a promising approach for better understanding the pathogenesis of gout, with the TTTY10/hsa-miR-139-5p/AP-1 axis likely to be of clinical significance.

Dataset Information

Multiple Membrane Transporters and Some Immune Regulatory Genes are Major Genetic Factors to Gout.

Publications

Multiple Membrane Transporters and Some Immune Regulatory Genes are Major Genetic Factors to Gout.

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