Bioinformatics analysis reveals transcriptome and microRNA signatures and drug repositioning targets for IBD and other autoimmune diseases
Bioinformatics analysis reveals transcriptome and microRNA signatures and drug repositioning targets for IBD and other autoimmune diseases
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DOI：
10.1002/ibd.22958
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发表时间：
2012-12-01
影响因子：
4.9
通讯作者：
Tozeren, Aydin
中科院分区：
文献类型：
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作者：
Clark, Peter M.;Dawany, Noor;Tozeren, Aydin
背景：炎症性肠病(IBD)是一种涉及病原体感染、宿主免疫反应和肠道细胞生理改变的复杂疾病。在发达国家，IBD的发病率正以惊人的速度增长，有必要对IBD进行详细的分子描述。方法：我们使用大规模数据、生物信息学工具和高通量计算来获得克罗恩病(CD)和溃疡性结肠炎(UC)的基因和microRNA签名。结果：IBD中最高表达的基因与糖尿病(REG1A、REG1B)、细菌信号(TLRs、NLR)、先天免疫(DEFA6、IDO1、EXOSC1)、炎症(CXCLs)和基质降解(MMPs)相关。下调的基因编码紧密连接蛋白(CLDN8)、溶质转运体(SLCs)和黏附蛋白。UC较CD高表达的基因包括抗炎基因ANXA1、转运蛋白ABCA12、T细胞激活因子HSH2D和免疫球蛋白IGHV4-34。药物、氮、雄激素和雌激素的代谢受损，以及IBD中的脂类与特异性microRNA的增加相关。高表达的IBD基因构成了治疗胃肠道癌症、病毒感染和自身免疫性疾病(如类风湿性关节炎和哮喘)的药物靶点。结论：本研究提供了IBD亚型的临床相关基因水平及其与自身免疫性疾病的联系。这项研究确定了重新定位现有药物以管理IBD的候选药物。结合小鼠和人类的数据表明，B细胞反应的改变是IBD中涉及免疫防御其他方面的基因上调的原因，例如干扰素诱导的反应。
Background: Inflammatory bowel disease (IBD) is a complex disorder involving pathogen infection, host immune response, and altered enterocyte physiology. Incidences of IBD are increasing at an alarming rate in developed countries, warranting a detailed molecular portrait of IBD.Methods: We used large-scale data, bioinformatics tools, and high-throughput computations to obtain gene and microRNA signatures for Crohn's disease (CD) and ulcerative colitis (UC). These signatures were then integrated with systemic literature review to draw a comprehensive portrait of IBD in relation to autoimmune diseases.Results: The top upregulated genes in IBD are associated with diabetogenesis (REG1A, REG1B), bacterial signals (TLRs, NLRs), innate immunity (DEFA6, IDO1, EXOSC1), inflammation (CXCLs), and matrix degradation (MMPs). The downregulated genes coded tight junction proteins (CLDN8), solute transporters (SLCs), and adhesion proteins. Genes highly expressed in UC compared to CD included antiinflammatory ANXA1, transporter ABCA12, T-cell activator HSH2D, and immunoglobulin IGHV4-34. Compromised metabolisms for processing of drugs, nitrogen, androgen and estrogen, and lipids in IBD correlated with an increase in specific microRNA. Highly expressed IBD genes constituted targets of drugs used in gastrointestinal cancers, viral infections, and autoimmunity disorders such as rheumatoid arthritis and asthma.Conclusions: This study presents a clinically relevant gene-level portrait of IBD subtypes and their connectivity to autoimmune diseases. The study identified candidates for repositioning of existing drugs to manage IBD. Integration of mice and human data point to an altered B-cell response as a cause for upregulation of genes in IBD involved in other aspects of immune defense such as interferon-inducible responses.