Thiopurine S-methyltransferase testing for averting drug toxicity: a meta-analysis of diagnostic test accuracy

Zur, Richard M.; Roy, L.; Itô, Shinya; Beyene, Joseph; Carew, Christopher; Ungar, Wendy J.

doi:10.1038/tpj.2016.37

Cited by 16 publications

(8 citation statements)

References 60 publications

(61 reference statements)

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“…Sensitivity and specificity of phenotyping for deficient patients are 75.9% and 98.9%, respectively, and for TPMT*2 and TPMT*3 genotypes 90.4% and 100.0%, respectively. In cases with deficient or intermediate activity, phenotype sensitivity and specificity are 91.3% and 92.6%, respectively, and for TPMT*2 and TPMT*3 88.9% and 99.2%, respectively [145]. TPMT testing shows that approximately 90% of patients receiving thiopurines are wild-type and that nearly 30% of patients may benefit with TPMT testing and consequent dosing modification to reduce the incidence of myelosuppression [146].…”

Section: Bevacizumab and Paclitaxelmentioning

confidence: 99%

Genophenotypic Factors and Pharmacogenomics in Adverse Drug Reactions

Cacabelos

Naidoo

Corzo

et al. 2021

IJMS

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Adverse drug reactions (ADRs) rank as one of the top 10 leading causes of death and illness in developed countries. ADRs show differential features depending upon genotype, age, sex, race, pathology, drug category, route of administration, and drug–drug interactions. Pharmacogenomics (PGx) provides the physician effective clues for optimizing drug efficacy and safety in major problems of health such as cardiovascular disease and associated disorders, cancer and brain disorders. Important aspects to be considered are also the impact of immunopharmacogenomics in cutaneous ADRs as well as the influence of genomic factors associated with COVID-19 and vaccination strategies. Major limitations for the routine use of PGx procedures for ADRs prevention are the lack of education and training in physicians and pharmacists, poor characterization of drug-related PGx, unspecific biomarkers of drug efficacy and toxicity, cost-effectiveness, administrative problems in health organizations, and insufficient regulation for the generalized use of PGx in the clinical setting. The implementation of PGx requires: (i) education of physicians and all other parties involved in the use and benefits of PGx; (ii) prospective studies to demonstrate the benefits of PGx genotyping; (iii) standardization of PGx procedures and development of clinical guidelines; (iv) NGS and microarrays to cover genes with high PGx potential; and (v) new regulations for PGx-related drug development and PGx drug labelling.

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Section: Bevacizumab and Paclitaxelmentioning

confidence: 99%

Genophenotypic Factors and Pharmacogenomics in Adverse Drug Reactions

Cacabelos

Naidoo

Corzo

et al. 2021

IJMS

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“…6-Thioguanine levels have been associated with thiopurine efficacy, while 6-MMP levels ARE associated with drug-related toxicity (190)(191)(192). Testing for TPMT activity has therefore been suggested to predict thiopurine toxicity, including bone marrow suppression (191,193,194), although with conflicting findings (195,196). The costeffectiveness of TPMT testing (197,198) needs to be re-evaluated (199)(200)(201)(202).…”

Section: Thiopurinesmentioning

confidence: 99%

Safety of treatments for inflammatory bowel disease: Clinical practice guidelines of the Italian Group for the Study of Inflammatory Bowel Disease (IG-IBD)

Biancone

Annese

Ardizzone

et al. 2017

Digestive and Liver Disease

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Inflammatory bowel diseases are chronic conditions of unknown etiology, showing a growing incidence and prevalence in several countries, including Italy. Although the etiology of Crohn's disease and ulcerative colitis is unknown, due to the current knowledge regarding their pathogenesis, effective treatment strategies have been developed. Several guidelines are available regarding the efficacy and safety of available drug treatments for inflammatory bowel diseases. Nevertheless, national guidelines provide additional information adapted to local feasibility, costs and legal issues related to the use of the same drugs. These observations prompted the Italian Group for the Study of Inflammatory Bowel Disease (IG-IBD) to establish Italian guidelines on the safety of currently available treatments for Crohn's disease and ulcerative colitis. These guidelines discuss the use of aminosalicylates, systemic and low bioavailability corticosteroids, antibiotics (metronidazole, ciprofloxacin, rifaximin), thiopurines, methotrexate, cyclosporine A, TNFα antagonists, vedolizumab, and combination therapies. These guidelines are based on current knowledge derived from evidence-based medicine coupled with clinical experience of a national working group.

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“…Notably, TWAS also identified TPMT as a high confidence gene associated with IEAA and PhenoAge. TPMT ’s product, thiopurine S-methyltransferase (TPMT), metabolizes thiopurine immunosuppressants 46 . Little data is available on the endogenous function of TPMT; its role in metabolizing immunosuppressants and our PheWAS findings linking SNPs near TPMT to immune-related disorders like post-dysenteric arthropathy and Guillain-Barre syndrome suggest it may enhance immune activity, while our GO analysis suggested that it may be involved in metabolism, mitochondrial function, and cellular response to oxidative stress.…”

Section: Discussionmentioning

confidence: 99%

Multi-omic underpinnings of epigenetic aging and human longevity

et al. 2023

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Biological aging is accompanied by increasing morbidity, mortality, and healthcare costs; however, its molecular mechanisms are poorly understood. Here, we use multi-omic methods to integrate genomic, transcriptomic, and metabolomic data and identify biological associations with four measures of epigenetic age acceleration and a human longevity phenotype comprising healthspan, lifespan, and exceptional longevity (multivariate longevity). Using transcriptomic imputation, fine-mapping, and conditional analysis, we identify 22 high confidence associations with epigenetic age acceleration and seven with multivariate longevity. FLOT1, KPNA4, and TMX2 are novel, high confidence genes associated with epigenetic age acceleration. In parallel, cis-instrument Mendelian randomization of the druggable genome associates TPMT and NHLRC1 with epigenetic aging, supporting transcriptomic imputation findings. Metabolomics Mendelian randomization identifies a negative effect of non-high-density lipoprotein cholesterol and associated lipoproteins on multivariate longevity, but not epigenetic age acceleration. Finally, cell-type enrichment analysis implicates immune cells and precursors in epigenetic age acceleration and, more modestly, multivariate longevity. Follow-up Mendelian randomization of immune cell traits suggests lymphocyte subpopulations and lymphocytic surface molecules affect multivariate longevity and epigenetic age acceleration. Our results highlight druggable targets and biological pathways involved in aging and facilitate multi-omic comparisons of epigenetic clocks and human longevity.

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Thiopurine S-methyltransferase testing for averting drug toxicity: a meta-analysis of diagnostic test accuracy

Cited by 16 publications

References 60 publications

Genophenotypic Factors and Pharmacogenomics in Adverse Drug Reactions

Genophenotypic Factors and Pharmacogenomics in Adverse Drug Reactions

Safety of treatments for inflammatory bowel disease: Clinical practice guidelines of the Italian Group for the Study of Inflammatory Bowel Disease (IG-IBD)

Multi-omic underpinnings of epigenetic aging and human longevity

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