Gene Description

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Gene Description

TPMT

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

Click here for the full CPIC guideline for thiopurine dosing based on TPMT and NUDT15 genotypes.

References
  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]