HUMAN THIOPURINE METHYLTRANSFERASE PHARMACOGENETICS - GENE SEQUENCE POLYMORPHISMS

Thiopurine methyltransferase (TPMT) catalyzes the S-methylation of thi opurine drugs. TPMT activity is regulated by a common genetic polymorp hism that is associated with large individual variations in thiopurine toxicity and efficacy. We previously cloned the functional gene for h uman TPMT and reported a common variant allele for low enzyme activity , TPMT3A, that contains point mutations at cDNA nucleotides 460 and 7 19. In the present study, we set out to determine the number, types, a nd frequencies of TPMT variant alleles associated with low enzyme acti vity in clinical laboratory samples in the United States and to compar e those results with data obtained from two different ethnic groups. W e identified a total of six different variant alleles for low TPMT act ivity in the 283 clinical laboratory samples studied. The most common variant was 3A; the second most frequent variant allele, *3C, contain ed only the nucleotide 719 polymorphism; and four other variant allele s were detected. TPMT3A also appeared to be the most common variant a llele in a Norwegian white population sample, but it was not found in a population sample of Korean children. However, 3C was present in sa mples from the Korean children, as was a novel allele, 6. Characteriz ation of variant alleles for low TPMT enzyme activity will help make i t possible to assess the potential clinical utility of deoxyribonuclei c acid-based diagnostic tests for determining TPMT genotype.