Thiopurine methyltransferase (TPMT) pharmacogenetics: Polymorphism characterization

The TPMT genetic polymorphism is responsible for large individual differences in thiopurine therapeutic efficacy and toxicity. The "wild type" allele, TPMT*1, and three variant low activity alleles have been described previously. Allele *2 has a G238C mutation (Ala80Pro). The most common low activity variant allele in Caucasians, *3A, has G460A and A719G transitions (Ala154Thr and Tyr240Cys); while the variant allele, *4, contains a G to A transition at the intron 9-exon 10 splice junction. In the present study, 4 of 6 "intermediate activity" Norwegian samples were heterozygous for *1/*3A, while 2 were heterozygous at nucleotide 719 only (*7/*3C). Four of 10 Korean samples with "lower" TPMT activity were also heterozygous, * 1/*3C. We also genotyped 27 "intermediate" activity clinical samples from Mayo. The most common variant allele, *3A, had a frequency of 58%, and 5 other variant alleles were identified. Ten of 16 "very low" TPMT samples were homozygous for *3A. DNA-based tests for TPMT might prove clinically useful in some situations.