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Thiopurine methyltransferase (TPMT) variants

Pharmacogenetic Biomarker

Thiopurine methyltransferase (TPMT) variants

Selected Variants (Mutant Allele, Enzyme Activity)

TPMT*2 (238G>C, ↓);

TPMT*3A (460G>A and 719A>G, ↓↓);

TPMT*3B (460G>A, ↓);

TPMT*3C (719A>G, ↓)

Allele Frequency

About 10–12% of whites and blacks have reduced enzyme activity because they are heterozygous for one of the mutant alleles. About 1 in 300 whites is homozygous for a mutant allele.


Azathioprine (AZA), 6-mercaptopurine (6-MP)

Clinical Relevance

AZA is a prodrug that is metabolized to 6-MP, which is then further metabolized to active 6-thioguanine (6-TG) and inactive 6-methylmercaptopurine (6-MMP) by hypoxanthine phosphoribosyltransferase and TPMT, respectively. Variation in the TPMT gene can result in functional inactivation of the enzyme and an increased risk of life-threatening 6-TG–associated myelosuppression. TPMT genotyping before instituting AZA or 6-MP can help prevent toxicity by identifying individuals with low or absent TPMT enzyme activity. Patients with homozygous or compound heterozygous mutant alleles (“poor metabolizers”) should not be given AZA or 6-MP, whereas heterozygotes with a single mutant allele should be treated with lower doses.

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McPhee, Stephen J., et al. "Thiopurine Methyltransferase (TPMT) Variants." Guide to Diagnostic Tests, 7th ed., McGraw-Hill Education, 2017. Medicine Central, im.unboundmedicine.com/medicine/view/GDT/619294/all/Thiopurine_methyltransferase__TPMT__variants.
McPhee SJ, Lu CM, Nicoll D. Thiopurine methyltransferase (TPMT) variants. Guide to Diagnostic Tests. 7th ed. McGraw-Hill Education; 2017. https://im.unboundmedicine.com/medicine/view/GDT/619294/all/Thiopurine_methyltransferase__TPMT__variants. Accessed April 19, 2019.
McPhee, S. J., Lu, C. M., & Nicoll, D. (2017). Thiopurine methyltransferase (TPMT) variants. In Guide to Diagnostic Tests. Available from https://im.unboundmedicine.com/medicine/view/GDT/619294/all/Thiopurine_methyltransferase__TPMT__variants
McPhee SJ, Lu CM, Nicoll D. Thiopurine Methyltransferase (TPMT) Variants [Internet]. In: Guide to Diagnostic Tests. McGraw-Hill Education; 2017. [cited 2019 April 19]. Available from: https://im.unboundmedicine.com/medicine/view/GDT/619294/all/Thiopurine_methyltransferase__TPMT__variants.
* Article titles in AMA citation format should be in sentence-case
TY - ELEC T1 - Thiopurine methyltransferase (TPMT) variants ID - 619294 A1 - McPhee,Stephen J, AU - Lu,Chuanyi Mark, AU - Nicoll,Diana, BT - Guide to Diagnostic Tests UR - https://im.unboundmedicine.com/medicine/view/GDT/619294/all/Thiopurine_methyltransferase__TPMT__variants PB - McGraw-Hill Education ET - 7 DB - Medicine Central DP - Unbound Medicine ER -