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Clinical Chemistry and Laboratory Medicine (CCLM)

Published in Association with the European Federation of Clinical Chemistry and Laboratory Medicine (EFLM)

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Ed. by Gillery, Philippe / Lackner, Karl J. / Lippi, Giuseppe / Melichar, Bohuslav / Payne, Deborah A. / Schlattmann, Peter / Tate, Jillian R.

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Thiopurine S-methyltransferase (TPMT) pharmacogenetics: three new mutations and haplotype analysis in the Estonian population

Riin Tamm1 / Kersti Oselin2 / Kristi Kallassalu3 / Reedik Magi4 / Kaili Anier5 / Maido Remm6 / Andres Metspalu7

1Institute of Molecular and Cell Biology, University of Tartu, Tartu, Estonia

2Department of Pharmacology, University of Tartu, Tartu, Estonia

3Institute of Molecular and Cell Biology, University of Tartu, Tartu, Estonia and Estonian Biocentre, Tartu, Estonia

4Institute of Molecular and Cell Biology, University of Tartu, Tartu, Estonia

5Department of Pharmacology, University of Tartu, Tartu, Estonia

6Institute of Molecular and Cell Biology, University of Tartu, Tartu, Estonia

7Institute of Molecular and Cell Biology, University of Tartu, Tartu, Estonia, Estonian Biocentre, Tartu, Estonia and Estonian Genome Project of University of Tartu, Tartu, Estonia

Corresponding author: Riin Tamm, Department of Biotechnology, Institute of Molecular and Cell Biology, University of Tartu, 23 Riia Street, 51010, Tartu, Estonia Phone: +372-737-5881, Fax: +372-742-0286,

Citation Information: Clinical Chemistry and Laboratory Medicine. Volume 46, Issue 7, Pages 974–979, ISSN (Online) 1437-4331, ISSN (Print) 1434-6621, DOI: 10.1515/CCLM.2008.187, May 2008

Publication History

Published Online:


Background: Thiopurine methyltransferase (TPMT) is a cytoplasmic enzyme involved in the metabolism of thiopurine drugs. To date, at least 25 single nucleotide polymorphisms have been reported in the TPMT gene, 23 of these are associated with reduced enzyme activity.

Methods: The aim of the present study was to sequence the whole coding region of TPMT (exons 3–10) to identify known and novel TPMT sequence variants amongst healthy Estonians. Erythrocyte TPMT activity was also measured to carry out a genotype-phenotype comparison.

Results: A total of 21 subjects were heterozygous for known TPMT alleles (*2, *3A, *3C, *9, *12). Several other previously described intronic and exon polymorphisms were identified. Three novel mutations were detected −30T>A in exon 3, 10A>G in intron 3, and 145A>G in intron 10. Association analysis revealed four markers (114T>A, 94T>A, 460G>A, 719A>G) whose frequencies were significantly different in intermediate (enzyme activity ≤60 ng/mL/h) methylators compared to normal (enzyme activity 61–139 ng/mL/h) and high (enzyme activity ≥140 ng/mL/h) methylators (p<0.001). Haplotype analysis found one haplotype to be associated with intermediate TPMT activity.

Conclusions: Our results point to several markers that predict reduced enzyme activity. None of the identified markers were associated with high enzyme activity.

Clin Chem Lab Med 2008;46:974–9.

Keywords: enzyme activity; haplotype analysis; pharmacogenetics; thiopurine methyltransferase (TPMT)

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