Study: TPMT*8 allele in thiopurine metabolism
January 2025—The biochemical genetics and molecular technologies laboratories at Mayo Clinic in Rochester, Minn., reported in a recently published study that individuals with a TPMT*1/*8 diplotype displayed reduced thiopurine 6-mercaptopurine metabolism between that of normal metabolizers and intermediate metabolizers, suggesting that TPMT*8 is a reduced-function allele (Sterner RM, et al. J Mol Diagn. 2024;26[11]:988–994).
That allele is common among individuals of African or African American ancestry (approximately 2.3 percent minor allele frequency), the authors write, but is not included in genotyping recommendations owing to its uncertain function.
“This is important because a competing reaction converts 6-mercaptopurine to the active metabolites that are responsible for toxicity, and reduced TPMT activity is associated with thiopurine toxicity,” says Ann Moyer, MD, PhD, coauthor and consultant at Mayo Clinic in the Division of Laboratory Genetics and Genomics, Department of Laboratory Medicine and Pathology. Dr. Moyer is former chair of the CAP/ACMG Biochemical and Molecular Genetics Committee.
Dr. Moyer and coauthors write in their article that their study included the largest number of individuals carrying a TPMT*8 allele to date (n = 22). Recommendations for the management of patients with a *8 allele are out of their study’s scope, they say, but its recognition as a reduced-function allele “may have clinical implications.”
The Clinical Pharmacogenetics Implementation Consortium currently considers *8 as an uncertain function allele. “In contrast,” the authors write, “the Dutch Pharmacogenetics Working Group recommends that the TPMT*8 allele should be treated the same as TPMT*3A, *3B, or *3C null alleles, and patients homozygous or compound heterozygous for TPMT*8 should be considered as poor metabolizers.”
They add, “Larger clinical studies involving populations in which the *8 allele is prevalent (eg, individuals of African descent) that focus on thiopurine dosing and clinical adverse reactions among these patients may further clarify the clinical implications of this allele and guide recommendations on translation of reduced function alleles to phenotype.”
FDA grants breakthrough device designation to MeMed Severity
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