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Identification of new biomarker candidates for glucocorticoid induced insulin resistance using literature mining
© Fleuren et al.; licensee BioMed Central Ltd. 2013
Received: 8 June 2012
Accepted: 2 January 2013
Published: 4 February 2013
Glucocorticoids are potent anti-inflammatory agents used for the treatment of diseases such as rheumatoid arthritis, asthma, inflammatory bowel disease and psoriasis. Unfortunately, usage is limited because of metabolic side-effects, e.g. insulin resistance, glucose intolerance and diabetes. To gain more insight into the mechanisms behind glucocorticoid induced insulin resistance, it is important to understand which genes play a role in the development of insulin resistance and which genes are affected by glucocorticoids.
Medline abstracts contain many studies about insulin resistance and the molecular effects of glucocorticoids and thus are a good resource to study these effects.
We developed CoPubGene a method to automatically identify gene-disease associations in Medline abstracts. We used this method to create a literature network of genes related to insulin resistance and to evaluate the importance of the genes in this network for glucocorticoid induced metabolic side effects and anti-inflammatory processes.
With this approach we found several genes that already are considered markers of GC induced IR, such as phosphoenolpyruvate carboxykinase (PCK) and glucose-6-phosphatase, catalytic subunit (G6PC). In addition, we found genes involved in steroid synthesis that have not yet been recognized as mediators of GC induced IR.
With this approach we are able to construct a robust informative literature network of insulin resistance related genes that gave new insights to better understand the mechanisms behind GC induced IR. The method has been set up in a generic way so it can be applied to a wide variety of disease networks.
Glucocorticoids (GCs) are often prescribed for the treatment of inflammatory diseases such as rheumatoid arthritis, asthma, inflammatory bowel disease and psoriasis[1–3]. Despite their excellent efficacy, usage is limited because of side-effects such as insulin resistance, glucose intolerance, diabetes, central adiposity, dyslipidemia, skeletal muscle wasting and osteoporosis[4–8].
GCs bind to the glucocorticoid receptor (GR), which then dimerizes and translocates to the nucleus where it influences gene transcription. Positive regulation of genes (transactivation) is mainly mediated by direct binding of the GR-GC complex to glucocorticoid response elements located in the regulatory region of a target gene. The GR-GC complex may also bind to negative glucocorticoid response elements, which leads to a negative regulation of genes (transrepression). It is believed that transrepression, in which proinflammatory genes are downregulated, is mainly responsible for the efficacy of GCs as anti-inflammatory drugs[5, 7], while transactivation might be responsible for the GC-induced adverse effects.
An important side effect is the development of insulin resistance (IR), because it is the onset of many metabolic diseases and conditions such as obesity, diabetes mellitus and hypertension. IR is a physiological condition in which a given concentration of insulin produces a less-than-expected biological effect. These biological effects are different depending on the tissue in which they occur. For instance, under IR conditions, fat and muscle cells fail to adequately respond to circulating insulin, which results in reduced glucose uptake, and subsequently higher glucose levels in blood[10, 11]. In liver cells the IR- effects can be seen in reduced glycogen synthesis and storage, and a failure to suppress glucose production and release into the blood.
One way by which GCs induce IR is by inhibition of the recruitment of GLUT4 glucose transporter, which results in reduced insulin-stimulated glucose transport in skeletal muscle. However, not all mechanisms involved in GC-induced side effects are not completely understood. To gain more insight into mechanisms behind GC induced IR, it is important to understand which genes play a role in the development of insulin resistance and which genes are affected by GCs.
It has been widely recognized that a system approach in which networks of genes in their functional context are studied, contributes to a better understanding of the mechanisms and pathways related to the disease and the drug effects[13–17]. To study a gene network related to a disease such as IR, a list of disease related genes as well as a notion of the interactions between these genes is needed.
Literature databases such as Medline contain many studies about IR and the molecular effects of synthetic glucocorticoids and thus are a good resource that can be used to create and study disease related gene networks.
The retrieval of relevant gene-disease associations out of the millions of abstracts in Medline is very labor intensive and thus a text mining system is needed to this in an automated fashion.
In previous work we reported about CoPub[18–20], a publicly available text mining system, which has successfully been used for the analysis of microarray data and in toxicogenomics studies[21–26]. CoPub calculates keyword co-occurrences in titles and abstracts from the entire Medline database, using thesauri for genes, diseases, drugs and pathways. We used this technology to develop CoPubGene, a rapid gene – disease network building tool. To evaluate the importance of genes in these networks we implemented a method to score the importance of genes in biological processes of interest by incorporating their functional neighborhood.
We used CoPubGene to create a network of genes related to insulin resistance and to evaluate the importance of the genes in this network for glucocorticoid induced metabolic side effects and anti-inflammatory processes.
By using this method, we identified several genes that already are considered markers of GC induced IR, such as phosphoenolpyruvate carboxykinase (PCK) and glucose 6 phosphatase, catalytic subunit (G6PC)[27, 28]. Even more importantly, we were able to identify genes involved in steroid synthesis that have not yet been recognized as mediators of GC induced IR.
List of available operations of the CoPub Web Service
Gene name, gene identifier
Biological identifier(s), with gene specific information
Each gene in CoPub belongs to an internal identifier (biological identifier). Get _genes converts the input gene to such a Biological identifier. This biological identifier serves as an input for subsequent operations.
Biological identifier(s), with keyword specific information
Retrieves for a set of keywords, the Biological identifiers to which these keywords belong in CoPub. These biological identifiers serve as an input for subsequent operations.
Given a Biological identifier, retrieves all abstracts in which the term occurs.
Get literature neighbours
Get _literature _neighbours
Given a Biological identifier, retrieves a list of keywords which are mentioned in the literature together with the input term.
Get enriched keywords
Get _enriched _keywords
List of gene identifiers
List of enriched keywords
For a list of genes, this operation calculates a keyword overrepresentation.
Get literature network
Get _literature _network
SVG / Cytoscape network
For a set of genes, the operation creates a network of genes.
List of categories
Returns a list of categories of terms in CoPub
List of microarrays
Returns a list of available Affymetrix chip names in CoPub.
Version of code and literature
Returns the version of the code and literature.
Retrieval of Gene-Disease associations
To create disease related gene networks, we used CoPubGene to retrieve gene-disease and gene-gene associations from Medline abstracts. Disease terms which had significant gene associations based on the R-scaled score (rs > 35) and literature count (lc > 5) in Medline abstracts, were extracted from the CoPub thesaurus.
Disease clustering was done in R (http://www.r-project.org) using the pvclust R package with “complete” setting for hierarchical clustering, based on correlation distance of R-scaled scores between genes and diseases, with 100 bootstrap replications. The hierarchical cluster was visualized using Denroscope. Additional gene set enrichment analysis against the GENETIC_ASSOCIATION_DB_DISEASE was done with the annotation server DAVID[30, 31].
Creation of IR gene network
CoPubGene was used to create a set of genes related to IR, by searching for associations between genes and IR in Medline abstracts using default values (rs > 30 and lc > 5). Subsequently the IR-gene network was created by connecting genes that had significant co-occurrences with each other.
Keyword enrichment analysis of IR related genes
Keyword enrichment analysis on the list of IR related genes was done against disease and drug terms from the CoPub database. Threshold values were chosen using default values.
Analysis of the IR gene network and calculation of neighbor score for genes
In which g1 is the R-scaled score of gene g with term d, and Ns is the literature score of its neighboring genes with term d. This latter score Ns is calculated using the R-scaled score of each neighboring gene of gene g with term d (g2, g3,.,gn) relative to its relation (R-scaled score) with gene g (rg2, rg3,.,rgn).
We developed CoPubGene by creating a number of web service operations that can be used to construct networks of genes based on their co-occurrences in Medline abstracts. These web service operations can be combined to answer a variety of biological questions (Table1). For example, the question “to what biological processes is this gene related?” can be answered by running the “get genes” and “get literature neighbours” functions. Using subsequently the “get references” function will return all the relevant pubmed entries in which the gene and keywords co-occur. By applying the “get keywords” and “get literature neighbours” functions one can retrieve all disease terms that are linked to a given drug term in the Medline abstract, or vice versa, retrieve all drug terms that are linked to a given disease term in abstracts. The networks that are created can be written to Cytoscape for downstream applications and visualizations. Also more advanced questions such as the construction of disease related gene networks, and subsequent calculation of keyword enrichment in this network can be addressed in an automatic way. In Table1 the available web service operations are shown.
Retrieval of gene-disease associations
Our aim was to get insight into the pathways and genes that are involved in insulin resistance, and the effect of glucocorticoids on this network. As a first step we created a list of genes associated with insulin resistance using CoPubGene. This yielded a list of 384 genes each of them connected to IR with an R scaled score (in Additional file1: Table S2A the top scoring genes with IR are shown, the full list is available in Additional file2: Table S2). To evaluate the quality of this list and to investigate whether this gene list is unique for IR or whether this list contains a large number of genes that are associated with multiple diseases we constructed a gene association list for all diseases in the disease thesaurus of CoPub, using similar parameter settings as used for construction of the IR gene list. This yielded a list of disease profiles with for each disease, a number of genes connected to that disease with an R scaled score. (Additional file1: Table S2 shows the results for a few selected diseases, the full table is available in Additional file2: Table S3).
Network of insulin resistance related genes
Annotation of the network with drugs and diseases terms
Over-represented drug and disease terms (P-value < 0.05)
Number of genes
Number of genes
Diabetes mellitus,type 2
Cancer of breast
There are several top scoring over-represented terms that are related to metabolic diseases, e.g. ‘diabetes mellitus’, ‘obesity’, ‘diabetes mellitus, type 2’ and ‘hyperinsulinemia’ (Table2B). The fact that these terms are high scoring is expected since we constructed the gene network based on the keyword insulin resistance. However we also found diseases that share a common origin with insulin resistance such as cardiovascular disease (Table2B). The most interesting high scoring term for our particular research question was the non-metabolic term ‘inflammation’, which was represented in the network by genes such as IL6, IL18, IL1RA, SOCS1, SOCS3, CCL2 and CCR2. Several of these genes have been mentioned in studies to be involved in the development of metabolic diseases. For instance, elevated levels of IL6 in subjects with obesity and diabetes showed an association between insulin resistance and IL6. Studies in mice showed that CCR2 deficiency or antagonism of this receptor resulted in attenuation of systemic insulin resistance and development of obesity, hence suggesting a modulating role of CCR2 in this[39, 40].
These results show that even with an unbiased data driven construction of a gene network, the relation between IR, dexamethasone and inflammation is discovered based on the genes that play a role in these effects. We subsequently highlighted the genes in the IR network that are related to inflammation and dexamethasone (Figure2).
Genes linked to inflammation and glucocorticoids in the context of insulin resistance
The majority of the genes in Figure3 are directly involved in important metabolic processes such as gluconeogenesis (PCK2, G6PC, PC and GCG), glycolysis (GCK, GCG), glucose uptake, lipid metabolism (ACACA, CHPT1, GPD1) and carbohydrate metabolism (GPD1). Other ones are directly involved in insulin signaling (GIP, IGF2, IPF1, IAPP).
Sex steroid physiology in relation to insulin resistance
Additional topological analysis of the sub-network using cytohubba revealed that IGF1R, HSD11B2, IGF2 and SHBG have a high betweenness centrality, i.e. they have many shortest paths going through them, analogous to major bridges and tunnels on a high map. Studies show that such a bottle necks play important roles in biological networks[44, 45].
CYP19A1 encodes for an aromatase which is responsible for the aromatization of androgens into estrogens, thus influencing the androgen to estrogen balance. Several studies showed that an imbalance between androgen and estrogen balance because of aromatase deficiency resulted in the development of symptoms related to the metabolic syndrome[46–49]. The fact that dexamethasone can regulate aromatase activity[50–52], suggests a role of aromatase in GC induced IR.
CYP17A1 is a key regulator of androgen synthesis and catalyzes the reactions in which pregnenolone and progesterone are converted into their 17-alpha-hydroxylated products and subsequently into Dehydroepiandrosterone (DHEA). A decline in DHEA and also its sulfated ester (DHEA-S) has been suggested to be causally linked to insulin resistance and obesity[53–56]. The possible inhibitory effects of dexamethasone on Cyp17a1[57, 58] suggests a role in GC induced IR by this gene.
CYP21A2 is a cytochrome P450 enzyme coding for the 21-hydroxylase that is involved in the biosynthesis of the steroid hormones aldosterone and cortisol. A defect in this gene leads to Congenital adrenal hyperplasia (CAH) in which there is a disbalance in cortisol and aldosterone secretion. CAH patients are characterized by insulin resistance, lower insulin sensitivity and hyperinsulinemia[43, 59–61]. Some studies indicate that the development of IR is because of GC treatment in this patient group[62–64]. Whether these patients develop IR because of CAH and deficiency of 21-hydroxylase, or because of the fact that they are often treated with synthetic GCs need to be elucidated.
Genes involved in osteoporosis
Another side effect of GC treatment is the development of glucocorticoid induced osteoporosis (GIOP). GIOP is characterized by reduced bone mineral density (BMD), decreased bone mass and disturbance of the bone matrix, leading to increased susceptibility to fractures. We applied CoPubGene to deduce important genes involved in GIOP by analyzing top scoring genes with OP (in total 131 genes associated with OP were found, see Additional file2: Table S5; the network of these top scoring genes with relations to dexamethasone and inflammation is shown in Additional file6: Figure S3. The majority of the genes are involved in bone remodeling and resorption (TNFRSF11A, TNFRSF11B, TNFSF11, SP7 ,CTSK), in bone mineralization (PTH, Klotho, VDR, Calca, BGLAP) or are part of the wnt signaling pathway that is involved in the regulation of bone formation (SOST, DKK1, LRP5, LRP6). Among these genes are known biomarkers of GIOP such as osteoprotegerin (encoded by TNFRSF11B) and the ligand RANK-L (encoded by TNFS11). Here we also searched for genes with a low score with inflammation. Several of these genes in the set, such as BGLAP, COL1A1 and SP7 are affected by GCs[68–72], have low associations with inflammation and therefore are interesting biomarker candidates for GIOP.
In the work presented here we used Medline abstracts to study mechanisms and genes involved in glucocorticoid induced insulin resistance. We created CoPubGene, a number of web service operations that can be used to retrieve relevant gene-disease, gene-drug and gene-gene associations out of Medline abstracts, using the CoPub technology.
The clustering of disease terms based on their associations with genes in Medline abstracts showed that CoPubGene is able to generate a list of specific IR genes that can be used for further analysis, and that this method also can be used to generate a variety of other gene disease associations. We used this clustering to evaluate the quality of disease related gene lists, generated using a text mining approach, because to our knowledge there is no real gold standard data set that covers a sufficient range of gene-disease associations that can be used. Databases such as OMIM and the KEGG disease database only cover a sub range of diseases which makes these datasets difficult to use in this type of evaluation.
Next, we studied the IR genes in their functional context, by including genes with which they co-occur in Medline abstracts. In this gene network we focused on genes that are strongly linked to dexamethasone and less strongly to inflammation. These genes are thought to be more exclusively related to GC induced IR and therefore might be interesting markers for this effect.
However, all of them are to a certain extent related to inflammation, either directly or indirectly by their neighbors, which suggests that these genes cannot be used as an exclusive marker for GC induced IR. This might have consequences for the search of dissociating compounds, i.e. compounds which only have the immune suppressive properties and not the unwanted side effects. Instead the search should focus on compounds that show a reduced effect on the expression of these IR genes.
The majority of the IR genes that have a low literature neighbor score for inflammation (< 25) and a high score for dexamethasone (literature neighbor score > 25) code for enzymes and hormones directly involved in important metabolic processes, such as glycolysis, gluconeogenesis, glucose uptake and lipid metabolism. All these processes are tightly regulated by insulin. This suggests that at a first instance, the search for mechanisms of GC induced IR should be focused on these processes.
Additionally, we also identified a sub network of genes involved in sex steroid synthesis that to our knowledge, not have been recognized yet as mediators of GC induced side effects. Key enzymes involved in steroid synthesis, i.e. CYP17A1, CYP21A2 and CYP19A1 keep the balance between several steroids, and an impairment of this balance could possibly result in metabolic disturbances such as IR. Additional topological analyses could further prioritize this sub-network for follow-up studies to determine the influence of GCs on sex steroid synthesis and the relation to IR. In such a study one could look at the influence of GCs on the balance between the steroids in combination with their influence on insulin stimulated glucose uptake in glucose sensitive tissues such as adipose and muscle tissue.
Using CoPubGene we are able to construct an informative literature network of IR related genes by only using information from Medline abstracts. Our approach revealed genes, that on a first glance were not considered to be involved in GC induced IR and thus gave new insights that might lead to a better understanding of the mechanisms behind GC induced IR.
Author WF was supported by the Biorange project (BR4.2) “A Systems Bioinformatics Approach For Evaluating And Translating Drug-Target Effects In Disease Related Pathways” of NBIC.
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