Gene Description

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Gene Description


Thiopurine Methyltransferase (TPMT) is a negative regulator of thiopurines activities. There are three types of thiopurines used clinically: azathioprine (a prodrug of mercaptopurine), mercaptopurine, and thioguanine. Patients with loss-of-function TPMT alleles are at higher risk for life-threatening myelosuppression than individual with wild-type alleles due to overexposure to active drug.1,2 Nudix hydrolase (NUDT)15 is another important regulator of thiopurines. Variants in NUDT15 are associated with thiopurine-induced myelosuppression in patients with acute lymphoblastic leukemia (ALL) and those with inflammatory bowel diseases (IBD). NUDT15 poor metabolizer alleles are particularly prevalent in Asian and Hispanic ethnicities.3,4 A recent study shows variants in NUDT15 are associated with increased risk of thiopurine-induced myelosuppression among patients of European ancestry with IBD.5 The recently updated Clinical Pharmacogenetics Implementation Consortium (CPIC) guideline recommends genotyping both TPMT and NUDT15 for thiopurines dosing.6


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Learn more about the NT (NUDT15 and TPMT) test


How TPMT and NUDT15 variants affect individuals’ response to thiopurines?

  1. Wang L, et al. Very Important Pharmacogene Summary: Thiopurine S-Methyltransferase. Pharmacogenet Genom. 
  2. Relling MV, et al. Mercaptopurine Therapy Intolerance and Heterozygosity at the Thiopurine S -Methyltransferase Gene Locus. J Natl Cancer Inst. 1999;9 (23):2001-8.
  3. Moriyama T, et al. NUDT15 Polymorphisms Alter Thiopurine Metabolism and Hematopoietic Toxicity. Nat Genet. 2016;48(4):367-73.
  4. Kakuta Y, et al. Pharmacogenetics of thiopurines for inflammatory bowel disease in East Asia: prospects for clinical application of NUDT15 genotyping. J Gastroenterol. 2018;53 (2):172-80.
  5. Walker GJ, et al. Association of Genetic Variants in NUDT15 with Thiopurine-induced Myelosuppression in Patients with Inflammatory Bowel Disease. JAMA. 2019;26;321(8):773-85.
  6. Relling MV, et al. Clinical Pharmacogenetics Implementation Consortium Guideline for Thiopurine Dosing Based on TPMT and NUDT15 Genotypes: 2018 Update. Clin Pharmacol Ther. 2018 [Epub ahead of print]