Abstract
Background and AimsThiopurines 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.MethodsTranscriptional 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.ResultsAmong 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.ConclusionsSeventeen 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.
Highlights
Ulcerative colitis (UC) and Crohn’s disease (CD) are chronic remitting and progressive inflammatory bowel diseases (IBD)
Ten patients with methyl thioinosine monophosphate (meTIMP)/6-TGN concentration ratios .20 (R20) were included in a microarray analysis, as were four patients with metabolite ratios corresponding to the median metabolite ratio and seven patients displaying a profile with a metabolite ratio #4 and 6-TGN $100 pmol/86108 red blood cells (RBC) (R4)
Genes Identified by Microarray Screening - analysis of variance (ANOVA) Four genes that were differently expressed over metabolite profiles were identified in the explorative patient cohort using the stringent filtering of microarray data (P,0.001); FAM46A, SLX1A, TGOLN2, UBE2A and included in the analyses with RT qPCR (Table S3)
Summary
Ulcerative colitis (UC) and Crohn’s disease (CD) are chronic remitting and progressive inflammatory bowel diseases (IBD). Two main metabolite groups are produced; the phosporylated thioguanine nucleotides (6-TGNs) which comprise thioguanosine mono-, diand triphosphates, and methylated thioinosine phosphates measured as meTIMP [5]. Both metabolite groups contribute to the immunomodulatory effects in different ways [4,6,7,8,9]. Up to 30% of IBD-patients discontinue thiopurine therapy due to adverse events or refractoriness [1,10,11]. The methyl thioinosine monophosphate (meTIMP)/6-thioguanine nucleotide (6-TGN) concentration ratio has been associated with drug efficacy. We explored the molecular basis of differences in metabolite profiles and in relation to disease activity
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