Thiopurine S-methyltransferase (TPMT) activity is better determined by biochemical assay versus genotyping in the Jewish population

Yair Kasirer, Rephael Mevorach, Paul Renbaum, Nurit Algur, Devora Soiferman, Rachel Beeri, Yelana Rachman, Reeval Segel, Dan Turner*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

8 Scopus citations

Abstract

Background: Thiopurine S-methyltransferase (TPMT) is a key enzyme that deactivates thiopurines, into their inactive metabolite, 6-methylmercaptopurine. Intermediate and low TPMT activity may lead to leukopenia following thiopurine treatment. The aim of this study was to determine TPMT activity and TPMT alleles (genotype-phenotype correlation) in Jews, aiming to develop an evidence-based pharmacogenetic assay for this population. Methods: TPMT activity was determined in 228 Jewish volunteers by high performance liquid chromatography. Common allelic variants in the Caucasian population [TPMT*2 (G238C), TPMT*3A (G460A and A719G), TPMT*3B (G460A) and TPMT*3C (A719G)] were tested. Phenotype-genotype correlation was examined and discordant cases were fully sequenced to identify novel genetic variants. Results: Mean TPMT activity was 15.4 ± 4 U/ml red blood cells (range 1-34). Intermediate activity was found in 33/228 (14 %) subjects and absent activity was found in one sample (0.4 %). Only eight individuals (3.5 % of the entire cohort and 24 % of those with intermediate/low activity) were identified as carriers of a TPMT genetic variant, all of whom had the TPMT*3A allele. Sequencing the entire TPMT coding region and splice junctions in the remainder of the discordant cases did not reveal any novel variants. Conclusion: Genotyping TPMT in Jews yields a much lower rate of variants than identified in the general Caucasian population. We conclude that a biochemical assay to determine TPMT enzymatic activity should be performed in Jews before starting thiopurine treatment in order to identify low activity subjects.

Original languageAmerican English
Pages (from-to)1207-1212
Number of pages6
JournalDigestive Diseases and Sciences
Volume59
Issue number6
DOIs
StatePublished - Jun 2014

Bibliographical note

Funding Information:
Acknowledgments This study was funded by internal academic grants from Shaare Zedek Medical Center and the Hebrew University of Jerusalem. There was no influence of the sponsors on the study design, implementation or analysis.

Keywords

  • Genotype
  • Jewish population
  • Phenotype
  • TPMT activity
  • Thiopurines

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