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Thiopurine S-methyltransferase (TPMT) Activity Is Better Determined by Biochemical Assay Versus Genotyping in the Jewish Population

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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.

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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.

Conflict of interest

None.

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Authors and Affiliations

  1. Pediatric Gastroenterology and Nutrition Unit, Shaare Zedek Medical Center, The Hebrew University, P.O. B 3235, 91031, Jerusalem, Israel

    Yair Kasirer, Yelana Rachman & Dan Turner

  2. Shaare Zedek Medical Center, The Hebrew University, Jerusalem, Israel

    Reeval Segel & Dan Turner

  3. Biochemistry Laboratory, Shaare Zedek Medical Center, Jerusalem, Israel

    Rephael Mevorach & Nurit Algur

  4. Medical Genetics Institute, Shaare Zedek Medical Center, Jerusalem, Israel

    Paul Renbaum, Devora Soiferman, Rachel Beeri & Reeval Segel

Authors
  1. Yair Kasirer
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  4. Nurit Algur
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  6. Rachel Beeri
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  9. Dan Turner
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Corresponding author

Correspondence to Dan Turner.

Additional information

Yair Kasirer, Rephael Mevorach, Reeval Segel and Dan Turner contributed equally to this work.

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Kasirer, Y., Mevorach, R., Renbaum, P. et al. Thiopurine S-methyltransferase (TPMT) Activity Is Better Determined by Biochemical Assay Versus Genotyping in the Jewish Population. Dig Dis Sci 59, 1207–1212 (2014). https://doi.org/10.1007/s10620-013-3008-z

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  • DOI: https://doi.org/10.1007/s10620-013-3008-z

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