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 <or=60 ng/mL/h) methylators compared to normal (enzyme activity 61-139 ng/mL/h) and high (enzyme activity >or=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.