Genotype and Phenotype Correlation of the TPMT∗8 Allele in Thiopurine Metabolism.

Autor:	Sterner RM; Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota., Hall PL; Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota., Matern D; Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota., Black JL; Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota., Moyer AM; Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota. Electronic address: moyer.ann@mayo.edu.
Jazyk:	angličtina
Zdroj:	The Journal of molecular diagnostics : JMD [J Mol Diagn] 2024 Nov; Vol. 26 (11), pp. 988-994. Date of Electronic Publication: 2024 Aug 31.
DOI:	10.1016/j.jmoldx.2024.07.005
Abstrakt:	Thiopurine 6-mercaptopurine (6-MP) is metabolized by thiopurine methyl transferase (TPMT). TPMT genetic variation results in some individuals having reduced or absent TPMT enzyme activity. If these individuals take a full thiopurine dose, life-threatening adverse events can occur. Testing identifies patients with reduced or absent TPMT activity and is recommended before initiation of therapy. The TPMT∗8 allele, defined by c.644G>A (p.Arg215His), is common among individuals of African ancestry (approximately 2.3% minor allele frequency) but is not included in genotyping recommendations due to its uncertain function. Here, a clinical TPMT enzyme activity assay was used to assess TPMT activity in red blood cells from 982 patients, including those with ∗1/∗8 (n = 22), ∗3A/∗8 (n = 1), and ∗3C/∗8 (n = 1) TPMT diplotypes. The average production of 6-methylmercaptopurine (primary TPMT product measured clinically) was 3.08 ± 0.16 nmol/mL per hour for ∗1/∗8 individuals, compared with 3.77 ± 0.03 nmol/mL per hour for normal metabolizers (P = 0.0001) and 2.39 ± 0.06 nmol 6-methylmercaptopurine/mL per hour for intermediate metabolizers (P < 0.0001). Individuals with a TPMT∗1/∗8 diplotype displayed reduced 6-MP metabolism between that of normal metabolizers and intermediate metabolizers, suggesting that TPMT∗8 is a reduced function allele. Competing Interests: Disclosure Statement A.M.M. is a member of the College of American Pathologists/American College of Medical Genetics and Genomics Biochemical and Molecular Genetics Committee and Pharmacogenetics Workgroup, the Association for Molecular Pathology Pharmacogenomics Working Group, and the ClinPGx Scientific Advisory Board. (Copyright © 2024 Association for Molecular Pathology and American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.)
Databáze:	MEDLINE
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