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. 2024;25(16-18):679-688.
doi: 10.1080/14622416.2025.2463866. Epub 2025 Feb 16.

TPMT and NUDT15 genotyping, TPMT enzyme activity and metabolite determination for thiopurines therapy: a reference laboratory experience

Sherin Shaaban  1   2 , Brandon S Walker  2 , Yuan Ji  1   2 , Kamisha Johnson-Davis  1   2
Affiliations

TPMT and NUDT15 genotyping, TPMT enzyme activity and metabolite determination for thiopurines therapy: a reference laboratory experience

Sherin Shaaban et al. Pharmacogenomics. 2024.

Abstract

Aim: To share the experience of a US national reference laboratory, offering genotyping for TPMT and NUDT15, TPMT enzyme phenotyping and detection of thiopurine metabolites.

Methods: Retrospective review of archived datasets related to thiopurines drug therapy including patients' data that underwent TPMT and NUDT15 genotyping, and smaller data sets where genotyping was performed with TPMT enzyme levels (phenotyping) +/- therapeutic drug monitoring (TDM).

Results: Thirteen percent of patients had variants in one or both genes tested. Testing for NUDT15 revealed 3.9% additional patients requiring thiopurines dosing recommendations. A correlation between TPMT enzyme activity and TPMT polymorphisms (odds ratio OD = 71.41, p-value <0.001) and between older age and higher enzyme levels (OD = 0.98, p-value = 0.002) was identified. No correlation between sex and TPMT enzyme levels, nor between TPMT genotyping and the level of thiopurine metabolites was found.

Conclusion: Adding NUDT15 to TPMT genotyping, identified additional 3.9% patients to benefit from thiopurine dose modifications. A significant correlation between genetic variants in TPMT and TPMT enzyme levels and between age and enzyme levels was established, while no correlation was identified between sex and enzyme levels nor between TPMT variation and thiopurine metabolites. Providers rely more significantly on genotyping only approach, rather than genotyping and phenotyping.

Keywords: NUDT15; Pharmacogenomics; TPMT; drug monitoring; genotyping; phenotyping; thiopurines.

Plain language summary

The current study aimed at sharing the experience of a US national laboratory, offering three kinds of testing relevant to patients receiving thiopurine drugs. The testing included detecting variants in two genes (TPMT and NUDT15) in addition to measurements of TPMT enzyme levels and detection of thiopurine metabolites in patients’ blood samples. The study analyzed archived datasets of patients that underwent such tests. 13% of examined patients had variants in either one or both genes tested (TPMT and NUDT15) and required modifications to the standard recommended dosing of thiopurines to avoid severe toxicity and side effects. This study found that adding NUDT15 variant testing to TPMT testing, identified additional patients that could benefit from thiopurine dose modifications. Additionally, the study identified a significant relationship between TPMT enzyme levels and TPMT variants (a patient having a variant that caused loss of function, would have lower levels of TPMT enzyme). Another relation between age and enzyme levels was also detected (older patients were found to have higher enzyme levels). This study could not identify effect of sex on TPMT enzyme levels, nor establish a relationship between TPMT variants and the level of thiopurine drugs metabolites. Investigating providers’ attitudes through order choices, revealed that providers rely more significantly on detecting variants in genes affecting TPMT enzyme rather than testing for both gene variants and enzyme levels which is believed to give providers a more comprehensive knowledge about patient’s response to thiopurines. Because of the toxicity of thiopurines, it is important to be able to assess whether patients, due to their genetic make-up, can be more susceptible to side effects or toxicity upon receiving thiopurines. Testing for variants in TPMT and NUDT15 and measuring TPMT enzyme levels can help providers with proper dosing of thiopurines.

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Conflict of interest statement

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

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