TPMT and NUDT15

Last Literature Review: December 2023 Last Update:

Use to assess genetic variants contributing to risk for severe myelosuppression with standard dosing of thiopurine drugs in individuals for whom thiopurine therapy is being considered or who have had an adverse reaction to thiopurine therapy. This test can be performed irrespective of whether thiopurine therapy is currently being administered.

TPMT and NUDT15 are also available as standalone tests:

Thiopurine drug therapy is used to treat autoimmune diseases, inflammatory bowel disease, acute lymphoblastic leukemia, and to prevent rejection after solid organ transplant.  The inactivation of thiopurine drugs is catalyzed in part by thiopurine methyltransferase (TPMT) and nudix hydrolase 15 (NUDT15). , ,  Variants in the TPMT and/or NUDT15 genes are associated with an accumulation of cytotoxic metabolites leading to increased risk of drug-related toxicity with standard doses of thiopurine drugs, ,  and the effects on thiopurine catabolism can be additive.

This Test Fact Sheet focuses on genetic testing for TPMT and NUDT15 variants, which can be performed before or during thiopurine therapy. The enzyme activity phenotype of TPMT can be measured directly before drug administration. After the initiation of therapy, concentrations of thiopurines and metabolites can be measured to optimize thiopurine therapy dosing. For more information about these tests, refer to the Thiopurine Methyltransferase, RBC and Thiopurine Metabolites in Red Blood Cells Test Fact Sheets.

For more information on pharmacogenetic testing, refer to the ARUP Consult Germline Pharmacogenetics - PGx topic.

Disease Overview

Thiopurine drugs include azathioprine, mercaptopurine, and thioguanine. ,  These are inactive prodrugs that must be metabolized to 6-thioguanine nucleotides (6-TGNs) to function. ,  The primary metabolic route for inactivation of thiopurine drugs is catalyzed by TPMT.  TPMT can be inhibited by common drugs, including NSAIDs, diuretics, and ulcerative colitis treatments such as mesalamine.

When TPMT activity is low, more 6-mercaptopurine (6-MP) may be converted into active (cytotoxic) 6-TGN, which accumulates in the body.  Excess 6-TGN in bone marrow (BM) inhibits purine synthesis, which in turn inhibits cell proliferation and contributes to excessive myelosuppression.  Specific TPMT variants (seen with higher frequency among individuals of African and European descent) have been associated with TPMT deficiency of varying severity. ,  In individuals with no or very low TPMT activity, severe myelosuppression occurs with conventional thiopurine doses. ,  Thirty to sixty percent of individuals with intermediate TPMT activity experience moderate to severe myelosuppression with conventional thiopurine doses. , 

NUDT15 catalyzes the conversion of cytotoxic 6-TG triphosphate metabolites to the less toxic 6-TG monophosphate.  NUDT15 variants (seen with higher frequency among individuals of Asian and Hispanic descent) reduce enzyme activity and contribute to excessive myelosuppression. , 

Thiopurine dosing should rely on disease-specific guidelines and the degree of myelosuppression. 

Genetics

Genes

TPMT, NUDT15

Inheritance

TPMT: Autosomal codominant 

NUDT15: Autosomal codominant

Test Interpretation

Variants Tested

Gene (Transcript)AllelesPredicted Allele Function
TPMT (NM_000367)TPMT*2: rs1800462, c.238G>C No function
TPMT*3A: rs1800460, c.460G>A; rs1142345, c.719A>GNo function
TPMT*3B: rs1800460, c.460G>ANo function
TPMT*3C: rs1142345, c.719A>GNo function
TPMT*4: rs1800584, c.626-1G>ANo function
TPMT*11: rs72552738, c.395G>ANo function
TPMT*29: rs267607275, c.2T>CNo function
TPMT*42: rs759836180, c.95dupAPossible no function
NUDT15 (NM_018283)NUDT15*2 or *3: rs116855232, c.415C>TNo function
NUDT15*4: rs147390019, c.416G>AUncertain function
NUDT15*14: rs777311140, c.80-81insCGGGPossible no function

Allele frequencies and phenotype predictions are available at PharmVar  or PharmGKB. 

Sensitivity/Specificity

Analytic sensitivity/specificity: 99%

Results

Metabolizer status is reported separately for each gene analyzed.

Metabolizer StatusInterpretation
IntermediatePossible susceptibility to dose-related toxicity from standard doses of thiopurine drugs
Possible intermediateSusceptibility to dose-related toxicity from standard doses of thiopurine drugs
PoorProbable susceptibility to dose-related toxicity from standard doses of thiopurine drugs
NormalStandard doses of thiopurine drugs are likely appropriate
IndeterminateGenotype cannot help determine susceptibility to dose-related toxicity when using thiopurines

Limitations

  • Only targeted TPMT and NUDT15 variants will be detected by this test.
  • Diagnostic errors can occur due to rare sequence variations.
  • Genotyping in individuals who have received an allogeneic stem cell or bone marrow transplant will reflect donor status and is not recommended.
  • Because the complex TPMT*3A allele contains the variants found in the *3B and *3C alleles, genotyping cannot distinguish the *1/*3A genotype (intermediate TPMT activity) from the rare *3B/*3C genotype (no or low TPMT activity); the *1/*3A genotype is assumed when both *3B and *3C are detected.
  • Thiopurine drug metabolism and risk for adverse reactions to thiopurines may be affected by genetic and nongenetic factors that are not evaluated by this test.
  • This test does not assess for TPMT allele variants associated with ultrahigh enzyme activity.
  • Genotyping does not replace the need for therapeutic drug monitoring and clinical observation.