This drug gene interaction (DGI) pertains to the interaction between the thiopurine methyltransferase (TPMT) gene, the nudix hydrolase (NUDT15) gene, and the thiopurine drugs (azathioprine, mercaptopurine, and thioguanine). Thiopurines are used to treat acute lymphoblastic leukemia, autoimmune disorders, and prevent tissue rejection after organ transplantation. Extensive literature and FDA warning labels indicate that patients carrying specific genetic differences in the TPMT and NUDT15 genes have an increased risk for myelotoxicity (bone marrow suppression) with standard thiopurine dosing.
Information presented on this page is based on evidence provided by the Clinical Pharmacogenomics Implementation Consortium (CPIC). CPIC provides peer-reviewed, updated, evidence-based, and freely accessible guidelines for implementing pharmacogenomic results into actionable prescribing decisions for providers. CPIC guidelines include standardized terminology and a systematic grading of evidence and clinical recommendations published in a leading journal (Clinical Pharmacology and Therapeutics).
The TPMT and NUDT15 genes encode enzymes that are involved in the metabolism of thiopurine drugs. There are different (variant) forms of the TPMT and NUDT15 gene, or alleles, and differences affect how well thiopurines are metabolized in the body. Some alleles encode normal functioning enzymes while others encode low or absent functioning enzymes. Each of us carry two alleles of these genes. Assessing both alleles give a better picture of the functional status or phenotype of how thiopurines are metabolized. See the chart below for a description of each phenotype and any implications for treatment.
TPMT and NUDT15 metabolizer status
ONE normal function allele and ONE uncertain function allele
Greatly increased risk of thiopurine-related leukopenia, neutropenia, and myelosuppression.
Possible intermediate metabolizer
Increased risk of thiopurine-related leukopenia, neutropenia, and myelosuppression.
Normal risk of thiopurine-related leukopenia, neutropenia, and myelosuppression.
*Leukopenia, neutropenia, and myelosuppression are blood and bone marrow problems like low white blood cell counts, anemia, or low platelet counts which can happen with this class of drugs. The patient’s reported genotype corresponds to a phenotype (i.e. metabolizer status). To see an interpretation table assigning metabolizer status by genotype, click here to visit CPIC and scroll down to download the “TPMT diplotype-phenotype table” or “NUDT15 diplotype-phenotype table”.
Thiopurines (azathioprine, mercaptopurine, and thioguanine) are medications used to manage several different conditions, and genes can affect how well the drugs work. CPIC updates guidelines on how to best use these genetic results to support patient care and has published its current recommendations here.
Normal starting doses vary by phenotype and treatment regimens. Frequencies of TPMT and NUDT15 variants differ depending on ancestry. If starting dose is already below normal recommended dose, dose reduction might not be applicable.
Genotyping for TPMT and NUDT15 was performed within a certified DNA laboratory at Vanderbilt University Medical Center that is in full compliance with all guidelines established by the government as regulated by the Centers for Medicare & Medicaid Services under the Clinical Laboratory Improvement Act of 1988. This validated clinical laboratory developed test is carried out with strict adherence to protocols outlined by the College of American Pathology. The performance of the assay is closely monitored, and the accuracy of the results is determined to be > 99%.
Clinical Pharmacogenetics Implementation Consortium (CPIC) Guideline for Thiopurine Dosing Based on TPMT and NUDT15 Genotypes: 2018 Updates
This link will take you to the main page on the CPIC website relating to TPMT, NUDT15, and thiopurines. On the site, you will find links to the main guideline publication and all supplementary information including a table that reports variant frequencies across different ancestries, a table that defines genetic variants, and a table that provides a phenotype interpretation (i.e. metabolizer status).