Gene Expression and Thiopurine Metabolite Profiling in Inflammatory Bowel Disease – Novel Clues to Drug Targets and Disease MechanismsReportar como inadecuado




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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.



Autor: Sofie Haglund , Sven Almer, Curt Peterson, Jan Söderman

Fuente: http://plos.srce.hr/



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