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MicroRNAs as tools to predict glucocorticoid response in inflammatory bowel diseases.

ABSTRACT: In spite of the introduction in therapy of highly effective biological agents, glucocorticoids (GCs) are still employed to induce remission in moderate to severe inflammatory bowel diseases (IBD), but considerable inter-individual differences in their efficacy and side effects have been reported. The effectiveness of these drugs is indeed very variable and side effects, particularly severe in pediatric patients, are common and often unpredictable: the understanding of the complex gene regulation mediated by GCs could shed light on the causes of this variability. In this context, microRNAs (miRNAs) represent a new and promising field of research. miRNAs are small non-coding RNA molecules that suppress gene expression at post-transcriptional level, and are fine-tuning regulators of diverse biological processes, including the development and function of the immune system, apoptosis, metabolism and inflammation. Emerging data have implicated the deregulated expression of certain miRNA networks in the pathogenesis of autoimmune and inflammatory diseases, such as IBD. There is a great interest in the identification of the role of miRNAs in the modulation of pharmacological response; however, the association between miRNA and GC response in patients with IBD has not yet been evaluated in a prospective clinical study. The identification of miRNAs differently expressed as a consequence of GC treatment in comparison to diagnosis, represents an important innovative approach that could be translated into clinical practice. In this review we highlight the altered regulation of proteins involved in GC molecular mechanism by miRNAs, and their potential role as molecular markers useful for predicting in advance GC response.

SUBMITTER: De Iudicibus S

PROVIDER: S-EPMC3848142 | biostudies-literature | 2013 Nov

REPOSITORIES: biostudies-literature

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MicroRNAs as tools to predict glucocorticoid response in inflammatory bowel diseases.

De Iudicibus Sara S Lucafò Marianna M Martelossi Stefano S Pierobon Chiara C Ventura Alessandro A Decorti Giuliana G

World journal of gastroenterology 20131101 44

In spite of the introduction in therapy of highly effective biological agents, glucocorticoids (GCs) are still employed to induce remission in moderate to severe inflammatory bowel diseases (IBD), but considerable inter-individual differences in their efficacy and side effects have been reported. The effectiveness of these drugs is indeed very variable and side effects, particularly severe in pediatric patients, are common and often unpredictable: the understanding of the complex gene regulation ...[more]

PMID: 24307788

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Project description:In this review, we provide an update on genome-wide association studies (GWAS) in inflammatory bowel disease (IBD). In addition, we summarize progress in defining the functional consequences of associated alleles for coding and noncoding genetic variation. In the small minority of loci where major association signals correspond to nonsynonymous variation, we summarize studies defining their functional effects and implications for therapeutic targeting. Importantly, the large majority of GWAS-associated loci involve noncoding variation, many of which modulate levels of gene expression. Recent expression quantitative trait loci (eQTL) studies have established that the expression of most human genes is regulated by noncoding genetic variations. Significant advances in defining the epigenetic landscape have demonstrated that IBD GWAS signals are highly enriched within cell-specific active enhancer marks. Studies in European ancestry populations have dominated the landscape of IBD genetics studies, but increasingly, studies in Asian and African-American populations are being reported. Common variation accounts for only a modest fraction of the predicted heritability and the role of rare genetic variation of higher effects (ie, odds ratios markedly deviating from 1) is increasingly being identified through sequencing efforts. These sequencing studies have been particularly productive in more severe very early onset cases. A major challenge in IBD genetics will be harnessing the vast array of genetic discovery for clinical utility through emerging precision medical initiatives. In this article, we discuss the rapidly evolving area of direct-to-consumer genetic testing and the current utility of clinical exome sequencing, especially in very early onset, severe IBD cases. We summarize recent progress in the pharmacogenetics of IBD with respect to partitioning patient responses to anti-TNF and thiopurine therapies. Highly collaborative studies across research centers and across subspecialties and disciplines will be required to fully realize the promise of genetic discovery in IBD.

Project description:Background & aimsA subset of patients with inflammatory bowel diseases (IBD) have continuously active inflammation, leading to a high number of complications and high direct health care costs (diagnostic tests, medications, and surgeries) and indirect costs (reduced employment and productivity and fewer opportunities for activities). Identifying these high-risk patients and providing effective interventions could produce better outcomes and reduce costs. We used prior year data to create IBD risk models to predict IBD-related hospitalizations, emergency department visits, and high treatment charges (>$30,000/year) in the subsequent year.MethodsWe performed a retrospective study of medical records from all patients with IBD treated at the University of Michigan Hospital from fiscal years 2013-2015. We selected clinical variables from the prior year and tested their abilities to predict 3 adverse outcomes (IBD-related hospitalizations, emergency department visits, and treatment charges >$30,000/year) in the subsequent year. Individual patients were only included once in the data set. We created a multivariate model that was based on a 70% randomly selected cohort (1005 patients) and validated the model on the other 30% (425 patients). Logistic regression was used for bivariate and multivariate analyses.ResultsFactors that predicted high-cost outcomes included the presence of psychiatric illness, use of corticosteroids, use of narcotics, low levels of hemoglobin, and high numbers of IBD-related hospitalizations. In the validation cohort, the model predicted IBD-related hospitalizations, emergency department visits, and high charges in the following year with receiver operating characteristic curve values of 0.751, 0.738, and 0.744, respectively.ConclusionsWe identified 5 factors that can effectively identify patients with IBD at high risk for hospitalization, emergency department visits, and high treatment charges in the next year. These patients should be closely monitored and aggressively managed.

Project description:Natural and synthetic glucocorticoids (GCs) are widely employed in a number of inflammatory, autoimmune and neoplastic diseases, and, despite the introduction of novel therapies, remain the first-line treatment for inducing remission in moderate to severe active Crohn's disease and ulcerative colitis. Despite their extensive therapeutic use and the proven effectiveness, considerable clinical evidence of wide inter-individual differences in GC efficacy among patients has been reported, in particular when these agents are used in inflammatory diseases. In recent years, a detailed knowledge of the GC mechanism of action and of the genetic variants affecting GC activity at the molecular level has arisen from several studies. GCs interact with their cytoplasmic receptor, and are able to repress inflammatory gene expression through several distinct mechanisms. The glucocorticoid receptor (GR) is therefore crucial for the effects of these agents: mutations in the GR gene (NR3C1, nuclear receptor subfamily 3, group C, member 1) are the primary cause of a rare, inherited form of GC resistance; in addition, several polymorphisms of this gene have been described and associated with GC response and toxicity. However, the GR is not self-standing in the cell and the receptor-mediated functions are the result of a complex interplay of GR and many other cellular partners. The latter comprise several chaperonins of the large cooperative hetero-oligomeric complex that binds the hormone-free GR in the cytosol, and several factors involved in the transcriptional machinery and chromatin remodeling, that are critical for the hormonal control of target genes transcription in the nucleus. Furthermore, variants in the principal effectors of GCs (e.g. cytokines and their regulators) have also to be taken into account for a comprehensive evaluation of the variability in GC response. Polymorphisms in genes involved in the transport and/or metabolism of these hormones have also been suggested as other possible candidates of interest that could play a role in the observed inter-individual differences in efficacy and toxicity. The best-characterized example is the drug efflux pump P-glycoprotein, a membrane transporter that extrudes GCs from cells, thereby lowering their intracellular concentration. This protein is encoded by the ABCB1/MDR1 gene; this gene presents different known polymorphic sites that can influence its expression and function. This editorial reviews the current knowledge on this topic and underlines the role of genetics in predicting GC clinical response. The ambitious goal of pharmacogenomic studies is to adapt therapies to a patient's specific genetic background, thus improving on efficacy and safety rates.

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MicroRNAs as tools to predict glucocorticoid response in inflammatory bowel diseases.

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MicroRNAs as tools to predict glucocorticoid response in inflammatory bowel diseases.

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