Impact of Genetic Polymorphisms on 6-Thioguanine Nucleotide Levels and Toxicity in Pediatric Patients with IBD Treated with Azathioprine

Lee, Mina; Kang, Ben; Choi, So Yoon; Kim, Mi Jin; Woo, Sook Young; Kim, Jong-Won; Choe, Yon Ho; Lee, Soo-Youn

doi:10.1097/mib.0000000000000570

Cited by 36 publications

(58 citation statements)

References 56 publications

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“…The ABCC5 gene is polymorphic 58 and variants have been associated with altered risk for toxicity to a variety of drugs including methotrexate, 59 irinotecan 60 and azathioprine. 61 These variants are thought to either modulate transporter affinity for the drug or drug metabolite or alter expression of the transporter itself. Therefore, decreased expression of ABCC5 observed in the present study could possibly lead to increased intracellular accumulation of SMX and its metabolites, contributing to increased cytotoxicity in vitro and possibly increased immunogenic drug adduct formation in vivo.…”

Section: Discussionmentioning

confidence: 99%

RNA expression profiling in sulfamethoxazole‐treated patients with a range of in vitro lymphocyte cytotoxicity phenotypes

Reinhart

Rose

Panyard

et al. 2018

Pharmacology Res & Perspec

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The lymphocyte toxicity assay (LTA) is a proposed surrogate marker of sulfonamide antibiotic hypersensitivity. In the LTA, peripheral blood mononuclear cells (PBMCs) undergo apoptosis more readily in hypersensitive versus tolerant patients when exposed to drug‐hydroxylamine metabolites in vitro. The purpose of this study was to identify key gene transcripts associated with increased cytotoxicity from sulfamethoxazole‐hydroxylamine in human PBMCs in the LTA. The LTA was performed on PBMCs of 10 patients hypersensitive to trimethoprim‐sulfamethoxazole (HS) and 10 drug‐tolerant controls (TOL), using two cytotoxicity assays: YO‐PRO (n = 20) and MTT (n = 12). mRNA expression profiles of PBMCs, enriched for CD8+ T cells, were compared between HS and TOL patients. Transcript expression was interrogated for correlation with % cytotoxicity from YO‐PRO and MTT assays. Correlated transcripts of interest were validated by qPCR. LTA results were not significantly different between HS and TOL patients, and no transcripts were found to be differentially expressed between the two groups. 96 transcripts were correlated with cytotoxicity by YO‐PRO (r = ±.63‐.75, FDR 0.188). Transcripts were selected for validation based on mechanistic plausibility and three were significantly over‐expressed by qPCR in high cytotoxicity patients: multi‐specific organic anion transporter C (ABCC5), mitoferrin‐1 (SLC25A37), and Porimin (TMEM123). These data identify novel transcripts that could contribute to sulfonamide‐hydroxylamine induced cytotoxicity. These include SLC25A37, encoding a mitochondrial iron transporter, ABCC5, encoding an arylamine drug transporter, and TMEM123, encoding a transmembrane protein that mediates cell death.

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Section: Discussionmentioning

confidence: 99%

RNA expression profiling in sulfamethoxazole‐treated patients with a range of in vitro lymphocyte cytotoxicity phenotypes

Reinhart

Rose

Panyard

et al. 2018

Pharmacology Res & Perspec

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“…Despite an abundance of observational studies examining the relationship between molecular markers and adverse events related to immunomodulator use in IBD, evidence regarding biomarkers as predictors of treatment efficacy are scarce (Table S5 and Figure ) . Homozygous carriers for IL23R‐G9T were more likely to respond to azathioprine therapy .…”

Section: Resultsmentioning

confidence: 99%

Systematic review: predictive biomarkers of therapeutic response in inflammatory bowel disease—personalised medicine in its infancy

Stevens

Matheeuwsen

Lönnkvist

et al. 2018

Aliment Pharmacol Ther

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Summary Background Inflammatory bowel disease (IBD) is characterised by substantial heterogeneity in treatment response. With an expanding number of therapeutic agents, identifying optimal treatment at the patient level remains a major challenge. Aim To systematically review the available literature on predictive biomarkers of therapeutic response in IBD. Methods An electronic literature search was performed on 30 January 2018 using MEDLINE, EMBASE and the Cochrane Library. Retrospective, prospective, uncontrolled and controlled studies reporting on biomarkers predicting therapeutic response in paediatric and adult IBD populations were eligible for inclusion. The methodological quality of the included studies was assessed using the QUIPS tool. Due to anticipated heterogeneity and limited data, a qualitative, rather than quantitative, assessment was planned. Results Of the 10 638 citations identified, 92 articles met the inclusion criteria. Several potential DNA, mRNA and protein markers were evaluated as predictive biomarkers. Most studies focused on predicting response to anti‐TNF agents. Substantial between‐study heterogeneity was identified with respect to both the biomarkers studied and the definition of response. None of the included studies received a low risk of bias rating for all six domains. Currently, none of the biomarkers is sufficiently predictive for clinical use. Conclusions The search for predictive biomarkers is still in its infancy and current evidence is limited. Future research efforts should take into account the high patient heterogeneity within prospective trials with objective response assessment. Predictive models will most likely comprise a combination of several molecular markers from integrated omics‐levels and clinical characteristics.

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“…ADK (rs10824095), SLC29A1 (rs747199) and TYMS (rs34743033) have been associated with neutropenia. Moreover, ABCC1 (rs2074087), IMPDH1 (rs2278294) and IMPDH2 (rs11706052) were found to have a significant impact on lymphopenia . No association between the variants ITPA (ITPA C94A) and TPMT (TPMT*3) and the occurrence of AZA‐related adverse events have been observed in pediatric IBD patients .…”

Section: Current Knowledge About Pharmacogenetics Of Adsmentioning

confidence: 99%

“…(rs2074087), IMPDH1 (rs2278294) and IMPDH2 (rs11706052) were found to have a significant impact on lymphopenia. 186 No association between the variants ITPA (ITPA C94A) and TPMT (TPMT*3) and the occurrence of AZA-related adverse events have been observed in pediatric IBD patients. 187 The genes involved and SNPs related to response to therapy and associated with toxicity are shown in Table 3.…”

Section: 165-167mentioning

confidence: 99%

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Pharmacogenetics: A strategy for personalized medicine for autoimmune diseases

2018

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For many years, a considerable number of patients with autoimmune diseases (ADs) have suffered from a lack of drug response and drug-related toxicity. Despite the emergence of new therapeutic options such as biological agents, patients continue to struggle with these problems. Unfortunately, new challenges, including the paradoxical effects of biological drugs, have complicated the situation. In recent decades, efforts have been made to predict drug response as well as drug-related side effects. Thanks to the many advances in genetics, evaluation of markers to predict drug response/toxicity before the initiation of treatment may be an avenue toward personalizing treatments. Implementing pharmacogenetics and pharmacogenomics in the clinic could improve clinical care; however, obstacles remain to effective personalized medicine for ADs. The present study attempted to clarify the concept of pharmacogenetics/pharmacogenomics for ADs. After an overview on the pathogenesis of the most common types of treatments, this paper focuses on pharmacogenetic studies related to the selected ADs. Bridging the gap between pharmacogenetics and personalized medicine is also discussed. Moreover, the advantages, disadvantages and recommendations related to making personalized medicine practical for ADs have been addressed.

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Impact of Genetic Polymorphisms on 6-Thioguanine Nucleotide Levels and Toxicity in Pediatric Patients with IBD Treated with Azathioprine

Cited by 36 publications

References 56 publications

RNA expression profiling in sulfamethoxazole‐treated patients with a range of in vitro lymphocyte cytotoxicity phenotypes

RNA expression profiling in sulfamethoxazole‐treated patients with a range of in vitro lymphocyte cytotoxicity phenotypes

Systematic review: predictive biomarkers of therapeutic response in inflammatory bowel disease—personalised medicine in its infancy

Pharmacogenetics: A strategy for personalized medicine for autoimmune diseases

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