Gene Expression and Thiopurine Metabolite Profiling in Inflammatory Bowel Disease – Novel Clues to Drug Targets and Disease Mechanisms?
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{"title"=>"Gene Expression and Thiopurine Metabolite Profiling in Inflammatory Bowel Disease - Novel Clues to Drug Targets and Disease Mechanisms?", "type"=>"journal", "authors"=>[{"first_name"=>"Sofie", "last_name"=>"Haglund", "scopus_author_id"=>"36839420700"}, {"first_name"=>"Sven", "last_name"=>"Almer", "scopus_author_id"=>"7006744450"}, {"first_name"=>"Curt", "last_name"=>"Peterson", "scopus_author_id"=>"7402987799"}, {"first_name"=>"Jan", "last_name"=>"Söderman", "scopus_author_id"=>"37096214000"}], "year"=>2013, "source"=>"PLoS ONE", "identifiers"=>{"issn"=>"19326203", "pui"=>"368409470", "doi"=>"10.1371/journal.pone.0056989", "sgr"=>"84874309873", "scopus"=>"2-s2.0-84874309873", "pmid"=>"23437289"}, "id"=>"5698c795-1703-3daa-837a-88b392cc937f", "abstract"=>"BACKGROUND AND AIMS: Thiopurines are effective to induce and maintain remission in inflammatory bowel disease (IBD). The methyl thioinosine monophosphate (meTIMP)/6-thioguanine nucleotide (6-TGN) concentration ratio has been associated with drug efficacy. Here we explored the molecular basis of differences in metabolite profiles and in relation to disease activity. METHODS: Transcriptional profiles in blood samples from an exploratory IBD-patient cohort (n = 21) with a normal thiopurine S-methyltransferase phenotype and meTIMP/6-TGN ratios >20, 10.0-14.0 and ≤4, respectively, were assessed by hybridization to microarrays. Results were further evaluated with RT qPCR in an expanded patient cohort (n = 54). Additionally, 30 purine/thiopurine related genes were analysed separately. RESULTS: Among 17 genes identified by microarray-screening, there were none with a known relationship to pathways of purines/thiopurines. For nine of them a correlation between expression level and the concentration of meTIMP, 6-TGN and/or the meTIMP/6-TGN ratio was confirmed in the expanded cohort. Nine of the purine/thiopurine related genes were identified in the expanded cohort to correlate with meTIMP, 6-TGN and/or the meTIMP/6-TGN ratio. However, only small differences in gene expression levels were noticed over the three different metabolite profiles. The expression levels of four genes identified by microarray screening (PLCB2, HVCN1, CTSS, and DEF8) and one purine/thiopurine related gene (NME6) correlated significantly with the clinical activity of Crohn's disease. Additionally, 16 of the genes from the expanded patient cohort interacted in networks with candidate IBD susceptibility genes. CONCLUSIONS: Seventeen of the 18 genes which correlated with thiopurine metabolite levels also correlated with disease activity or participated in networks with candidate IBD susceptibility genes involved in processes such as purine metabolism, cytokine signaling, and functioning of invariant natural killer T cells, T cells and B cells. Therefore, we conclude that the identified genes to a large extent are related to drug targets and disease mechanisms of IBD.", "link"=>"http://www.mendeley.com/research/gene-expression-thiopurine-metabolite-profiling-inflammatory-bowel-disease-novel-clues-drug-targets", "reader_count"=>18, "reader_count_by_academic_status"=>{"Professor > Associate Professor"=>1, "Researcher"=>1, "Student > Ph. D. Student"=>5, "Student > Master"=>4, "Student > Bachelor"=>4, "Lecturer > Senior Lecturer"=>1, "Professor"=>2}, "reader_count_by_user_role"=>{"Professor > Associate Professor"=>1, "Researcher"=>1, "Student > Ph. D. Student"=>5, "Student > Master"=>4, "Student > Bachelor"=>4, "Lecturer > Senior Lecturer"=>1, "Professor"=>2}, "reader_count_by_subject_area"=>{"Biochemistry, Genetics and Molecular Biology"=>1, "Agricultural and Biological Sciences"=>7, "Medicine and Dentistry"=>6, "Sports and Recreations"=>1, "Chemistry"=>1, "Immunology and Microbiology"=>1, "Pharmacology, Toxicology and Pharmaceutical Science"=>1}, "reader_count_by_subdiscipline"=>{"Medicine and Dentistry"=>{"Medicine and Dentistry"=>6}, "Chemistry"=>{"Chemistry"=>1}, "Sports and Recreations"=>{"Sports and Recreations"=>1}, "Immunology and Microbiology"=>{"Immunology and Microbiology"=>1}, "Agricultural and Biological Sciences"=>{"Agricultural and Biological Sciences"=>7}, "Biochemistry, Genetics and Molecular Biology"=>{"Biochemistry, Genetics and Molecular Biology"=>1}, "Pharmacology, Toxicology and Pharmaceutical Science"=>{"Pharmacology, Toxicology and Pharmaceutical Science"=>1}}, "reader_count_by_country"=>{"Chile"=>1}, "group_count"=>1}

Scopus | Further Information

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Figshare

  • {"files"=>["https://ndownloader.figshare.com/files/1005045"], "description"=>"a<p>Reverse transcription qPCR data, in the expanded patient cohort (n = 54), of genes showing significant results either in a Spearman rank order correlation analysis or in a Mann-Whitney U-test. Significant group differences are indicated in bold. Abbreviations: R20; meTIMP/6-TGN concentration ratio >20, Median; median metabolizer, R4; meTIMP/6-TGN concentration ratio ≤5.7.</p>", "links"=>[], "tags"=>["qpcr", "genes", "metabolite"], "article_id"=>665669, "categories"=>["Biological Sciences", "Chemistry", "Genetics", "Pharmacology"], "users"=>["Sofie Haglund", "Sven Almer", "Curt Peterson", "Jan Söderman"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0056989.t004", "stats"=>{"downloads"=>1, "page_views"=>7, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Relative_gene_expression_levels_RT_qPCR_data_of_purine_thiopurine_related_genes_vs_metabolite_profiles_a_/665669", "title"=>"Relative gene expression levels (RT qPCR data) of purine/thiopurine related genes <i>vs.</i> metabolite profiles.<sup>a</sup>", "pos_in_sequence"=>0, "defined_type"=>3, "published_date"=>"2013-02-21 01:34:29"}
  • {"files"=>["https://ndownloader.figshare.com/files/962792"], "description"=>"<p>Scatterplots illustrating the co-variation between the relative gene expression levels of the genes with the most significant correlation coefficients with the concentration of A) 6-TGN, B) meTIMP or C) the meTIMP/6-TGN concentration ratio.</p>", "links"=>[], "tags"=>["genes", "means", "microarray", "qpcr"], "article_id"=>632774, "categories"=>["Biological Sciences", "Chemistry", "Genetics", "Pharmacology"], "users"=>["Sofie Haglund", "Sven Almer", "Curt Peterson", "Jan Söderman"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0056989.g001", "stats"=>{"downloads"=>0, "page_views"=>1, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Scatterplots_of_genes_identified_by_means_of_microarray_screening_RT_qPCR_data_/632774", "title"=>"Scatterplots of genes identified by means of microarray screening (RT qPCR data).", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2013-02-22 09:06:47"}
  • {"files"=>["https://ndownloader.figshare.com/files/1004984"], "description"=>"a<p>Genes that showed a significant correlation (<i>P</i><0.05) between relative gene expression levels (RT qPCR data) and the concentration of 6-TGN, meTIMP or the meTIMP/6-TGN concentration ratio in the expanded patient cohort (n = 54).</p>b<p>None of the genes selected by means of their potential relationship with the mechanism, metabolism or transport of purines/thiopurines fulfilled the established significance level (<i>P</i><0.001) in the microarray data.</p>", "links"=>[], "tags"=>["correlations", "qpcr", "metabolite", "expanded"], "article_id"=>665607, "categories"=>["Biological Sciences", "Chemistry", "Genetics", "Pharmacology"], "users"=>["Sofie Haglund", "Sven Almer", "Curt Peterson", "Jan Söderman"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0056989.t003", "stats"=>{"downloads"=>1, "page_views"=>6, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Spearman_rank_correlations_RT_qPCR_data_vs_metabolite_data_a_in_the_expanded_patient_cohort_of_purine_thiopurine_related_genes_b_/665607", "title"=>"Spearman rank correlations (RT qPCR data <i>vs.</i> metabolite data)<sup>a</sup>, in the expanded patient cohort, of purine/thiopurine related genes.<sup>b</sup>", "pos_in_sequence"=>0, "defined_type"=>3, "published_date"=>"2013-02-21 01:33:27"}
  • {"files"=>["https://ndownloader.figshare.com/files/1005083"], "description"=>"a<p>The regression model is based on the expanded patient cohort (n = 54), using the natural logarithm of the meTIMP concentration as dependent variable and the gene expression levels (dC<sub>T</sub> values) of <i>PLCB2</i> and <i>TPMT</i> and glucocorticosteroid and 5-ASA therapy as independent variables. A higher dC<sub>T</sub> value is associated with a lower gene expression level. <i>R<sup>2</sup></i> = 0.35, <i>P</i> = 2×10<sup>−4</sup>.</p>", "links"=>[], "tags"=>["linear", "regression"], "article_id"=>665706, "categories"=>["Biological Sciences", "Chemistry", "Genetics", "Pharmacology"], "users"=>["Sofie Haglund", "Sven Almer", "Curt Peterson", "Jan Söderman"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0056989.t006", "stats"=>{"downloads"=>5, "page_views"=>2, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_A_multiple_linear_regression_model_for_the_concentration_of_meTIMP_a_/665706", "title"=>"A multiple linear regression model for the concentration of meTIMP.<sup>a</sup>", "pos_in_sequence"=>0, "defined_type"=>3, "published_date"=>"2013-02-21 01:35:06"}
  • {"files"=>["https://ndownloader.figshare.com/files/1005025"], "description"=>"a<p>The regression model is based on the expanded patient cohort (n = 54), using the natural logarithm of the meTIMP/6-TGN concentration ratio as dependent variable and the gene expression levels (dC<sub>T</sub> values) of <i>CD1D</i>, <i>PLCB2</i>, <i>NT5E</i>, <i>TPMT</i>, <i>TUSC2</i>, and glucocorticosteroid therapy as independent variables. A higher dC<sub>T</sub> value is associated with a lower gene expression level. <i>R<sup>2</sup></i> = 0.46, <i>P</i> = 3×10<sup>−5</sup>.</p>", "links"=>[], "tags"=>["linear", "regression"], "article_id"=>665646, "categories"=>["Biological Sciences", "Chemistry", "Genetics", "Pharmacology"], "users"=>["Sofie Haglund", "Sven Almer", "Curt Peterson", "Jan Söderman"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0056989.t005", "stats"=>{"downloads"=>1, "page_views"=>3, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_A_multiple_linear_regression_model_for_the_meTIMP_6_TGN_concentration_ratio_a_/665646", "title"=>"A multiple linear regression model for the meTIMP/6-TGN concentration ratio.<sup>a</sup>", "pos_in_sequence"=>0, "defined_type"=>3, "published_date"=>"2013-02-21 01:34:06"}
  • {"files"=>["https://ndownloader.figshare.com/files/963011", "https://ndownloader.figshare.com/files/963046", "https://ndownloader.figshare.com/files/963100", "https://ndownloader.figshare.com/files/963151", "https://ndownloader.figshare.com/files/963234", "https://ndownloader.figshare.com/files/963296", "https://ndownloader.figshare.com/files/963367"], "description"=>"<div><p>Background and Aims</p><p>Thiopurines are effective to induce and maintain remission in inflammatory bowel disease (IBD). The methyl thioinosine monophosphate (meTIMP)/6-thioguanine nucleotide (6-TGN) concentration ratio has been associated with drug efficacy. Here we explored the molecular basis of differences in metabolite profiles and in relation to disease activity.</p> <p>Methods</p><p>Transcriptional profiles in blood samples from an exploratory IBD-patient cohort (n = 21) with a normal thiopurine S-methyltransferase phenotype and meTIMP/6-TGN ratios >20, 10.0–14.0 and ≤4, respectively, were assessed by hybridization to microarrays. Results were further evaluated with RT qPCR in an expanded patient cohort (n = 54). Additionally, 30 purine/thiopurine related genes were analysed separately.</p> <p>Results</p><p>Among 17 genes identified by microarray-screening, there were none with a known relationship to pathways of purines/thiopurines. For nine of them a correlation between expression level and the concentration of meTIMP, 6-TGN and/or the meTIMP/6-TGN ratio was confirmed in the expanded cohort. Nine of the purine/thiopurine related genes were identified in the expanded cohort to correlate with meTIMP, 6-TGN and/or the meTIMP/6-TGN ratio. However, only small differences in gene expression levels were noticed over the three different metabolite profiles. The expression levels of four genes identified by microarray screening (<i>PLCB2</i>, <i>HVCN1</i>, <i>CTSS</i>, and <i>DEF8</i>) and one purine/thiopurine related gene (<i>NME6</i>) correlated significantly with the clinical activity of Crohn’s disease. Additionally, 16 of the genes from the expanded patient cohort interacted in networks with candidate IBD susceptibility genes.</p> <p>Conclusions</p><p>Seventeen of the 18 genes which correlated with thiopurine metabolite levels also correlated with disease activity or participated in networks with candidate IBD susceptibility genes involved in processes such as purine metabolism, cytokine signaling, and functioning of invariant natural killer T cells, T cells and B cells. Therefore, we conclude that the identified genes to a large extent are related to drug targets and disease mechanisms of IBD.</p> </div>", "links"=>[], "tags"=>["thiopurine", "metabolite", "profiling", "inflammatory", "bowel", "clues", "targets"], "article_id"=>632976, "categories"=>["Biological Sciences", "Chemistry", "Genetics", "Pharmacology"], "users"=>["Sofie Haglund", "Sven Almer", "Curt Peterson", "Jan Söderman"], "doi"=>["https://dx.doi.org/10.1371/journal.pone.0056989.s001", "https://dx.doi.org/10.1371/journal.pone.0056989.s002", "https://dx.doi.org/10.1371/journal.pone.0056989.s003", "https://dx.doi.org/10.1371/journal.pone.0056989.s004", "https://dx.doi.org/10.1371/journal.pone.0056989.s005", "https://dx.doi.org/10.1371/journal.pone.0056989.s006", "https://dx.doi.org/10.1371/journal.pone.0056989.s007"], "stats"=>{"downloads"=>4, "page_views"=>33, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/Gene_Expression_and_Thiopurine_Metabolite_Profiling_in_Inflammatory_Bowel_Disease_Novel_Clues_to_Drug_Targets_and_Disease_Mechanisms__/632976", "title"=>"Gene Expression and Thiopurine Metabolite Profiling in Inflammatory Bowel Disease – Novel Clues to Drug Targets and Disease Mechanisms?", "pos_in_sequence"=>0, "defined_type"=>4, "published_date"=>"2013-02-22 09:08:15"}
  • {"files"=>["https://ndownloader.figshare.com/files/1004968"], "description"=>"a<p>Genes that showed a significant correlation (<i>P</i><0.05) between relative gene expression levels (RT qPCR data) and the concentration of 6-TGN, meTIMP or the meTIMP/6-TGN concentration ratio in the expanded patient cohort (n = 54).</p>b<p>Significant (<i>P</i><0.001) positive (P) or negative (N) correlations observed in the microarray data of the explorative patient cohort (n = 21) are indicated.</p>", "links"=>[], "tags"=>["correlations", "qpcr", "metabolite", "expanded", "genes", "microarray"], "article_id"=>665586, "categories"=>["Biological Sciences", "Chemistry", "Genetics", "Pharmacology"], "users"=>["Sofie Haglund", "Sven Almer", "Curt Peterson", "Jan Söderman"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0056989.t001", "stats"=>{"downloads"=>1, "page_views"=>16, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Spearman_rank_correlations_RT_qPCR_data_vs_metabolite_data_a_in_the_expanded_patient_cohort_of_genes_identified_by_microarray_screening_/665586", "title"=>"Spearman rank correlations (RT qPCR data <i>vs.</i> metabolite data)<sup>a</sup>, in the expanded patient cohort, of genes identified by microarray screening.", "pos_in_sequence"=>0, "defined_type"=>3, "published_date"=>"2013-02-21 01:33:06"}
  • {"files"=>["https://ndownloader.figshare.com/files/962833"], "description"=>"<p>Scatterplots illustrating the co-variation between the relative gene expression levels of the genes with the most significant correlation coefficients with the concentration of A) 6-TGN, B) meTIMP or C) the meTIMP/6-TGN concentration ratio.</p>", "links"=>[], "tags"=>["genes", "proven", "thiopurines", "qpcr"], "article_id"=>632819, "categories"=>["Biological Sciences", "Chemistry", "Genetics", "Pharmacology"], "users"=>["Sofie Haglund", "Sven Almer", "Curt Peterson", "Jan Söderman"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0056989.g002", "stats"=>{"downloads"=>0, "page_views"=>4, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Scatterplots_of_genes_selected_for_a_proven_or_potential_relationship_to_thiopurines_RT_qPCR_data_/632819", "title"=>"Scatterplots of genes selected for a proven or potential relationship to thiopurines (RT qPCR data).", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2013-02-22 09:07:04"}
  • {"files"=>["https://ndownloader.figshare.com/files/962905"], "description"=>"<p>Interactions between candidate IBD susceptibility genes and genes identified as correlated with meTIMP, 6-TGN and/or the meTIMP/6-TGN concentration ratio (marked with an orange star).</p>", "links"=>[], "tags"=>["genetics and genomics", "Computational biology", "pharmacology", "Gastroenterology and hepatology"], "article_id"=>632885, "categories"=>["Biological Sciences", "Chemistry", "Genetics", "Pharmacology"], "users"=>["Sofie Haglund", "Sven Almer", "Curt Peterson", "Jan Söderman"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0056989.g003", "stats"=>{"downloads"=>2, "page_views"=>106, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Protein_protein_network_analysis_STRING_database_/632885", "title"=>"Protein-protein network analysis; STRING database.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2013-02-22 09:07:34"}
  • {"files"=>["https://ndownloader.figshare.com/files/1005063"], "description"=>"a<p>The regression model is based on the expanded patient cohort (n = 54), using the natural logarithm of the 6-TGN concentration as dependent variable and the gene expression level (dC<sub>T</sub> value) of <i>TUSC2</i>, and glucocorticosteroid and 5-ASA therapy as independent variables. A higher dC<sub>T</sub> value is associated with a lower gene expression level. <i>R<sup>2</sup></i> = 0.27, <i>P</i> = 0.001.</p>", "links"=>[], "tags"=>["linear", "regression"], "article_id"=>665687, "categories"=>["Biological Sciences", "Chemistry", "Genetics", "Pharmacology"], "users"=>["Sofie Haglund", "Sven Almer", "Curt Peterson", "Jan Söderman"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0056989.t007", "stats"=>{"downloads"=>4, "page_views"=>4, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_A_multiple_linear_regression_model_for_the_concentration_of_6_TGN_a_/665687", "title"=>"A multiple linear regression model for the concentration of 6-TGN.<sup>a</sup>", "pos_in_sequence"=>0, "defined_type"=>3, "published_date"=>"2013-02-21 01:34:47"}
  • {"files"=>["https://ndownloader.figshare.com/files/1005003"], "description"=>"a<p>Reverse transcription qPCR data, in the expanded patient cohort (n = 54), of genes showing significant results either in a Spearman rank order correlation analysis or in a Mann-Whitney U-test. Significant group differences are indicated in bold. Abbreviations: R20; meTIMP/6-TGN concentration ratio >20, Median; median metabolizer, R4; meTIMP/6-TGN concentration ratio ≤5.7.</p>", "links"=>[], "tags"=>["qpcr", "genes", "microarray", "metabolite"], "article_id"=>665629, "categories"=>["Biological Sciences", "Chemistry", "Genetics", "Pharmacology"], "users"=>["Sofie Haglund", "Sven Almer", "Curt Peterson", "Jan Söderman"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0056989.t002", "stats"=>{"downloads"=>1, "page_views"=>7, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Relative_gene_expression_levels_RT_qPCR_data_of_genes_identified_by_microarray_screening_vs_metabolite_profiles_a_/665629", "title"=>"Relative gene expression levels (RT qPCR data) of genes identified by microarray screening <i>vs.</i> metabolite profiles.<sup>a.</sup>", "pos_in_sequence"=>0, "defined_type"=>3, "published_date"=>"2013-02-21 01:33:49"}

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Relative Metric

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