This DGI pertains to the interaction between the thiopurine methyltransferase (TPMT) gene and the thiopurine drugs azathioprine, 6-mercaptopurine, and thioguanine. Thiopurines are used to suppress the normal activity of the body’s immune system. Thiopurines are used to treat acute lymphoblastic leukemia, autoimmune disorders, and organ transplant recipients. Extensive literature and FDA warning labels indicate that patients with specific genetic differences in the TPMT gene have an increased risk for myelotoxicity (bone marrow damage) with thiopurine use.
Information presented on this page is based on evidence provided by the Clinical Pharmacogenomics Implementation Consortium (CPIC®). One goal of CPIC is to provide peer-reviewed, updated, evidence-based, and freely accessible guidelines for implementing the use of pharmacogenomic tests into actionable prescribing decisions for patient care. CPIC guidelines follow standardized formats, include systematic grading of evidence and clinical recommendations, use standardized terminology, are peer-reviewed, and are published in a leading journal (in partnership with Clinical Pharmacology and Therapeutics) with simultaneous posting to cpicpgx.org, where they are regularly updated.
The TPMT gene is an enzyme that is involved in the metabolism of thiopurine drugs such as azathioprine, 6-mercaptopurine (6MP) and 6-thioguanine. There are different TPMT gene versions, or variants, and each has a different effect on how well thiopurines are metabolized in the body. Some variants result in normal function while others function only at an intermediate or low level. See chart below for a description of each phenotype and any implications for treatment.
Patient’s genetic information is reported as a diplotype and this corresponds to a phenotype (i.e. metabolizer status). To see an interpretation table assigning metabolizer status by genetic variant, click here to visit CPIC and scroll down to click and download “TPMT diplotype-Phenotype table”.
Genotyping for TPMT 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 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 races/ethnic groups, a table that defines genetic variants, and a table that provides a phenotype interpretation (i.e. metabolizer status).