Allelic variants of the thiopurine S-methyltranferase deficiency in patients with ulcerative colitis and in healthy controls

OBJECTIVE: Thiopurine S-methyltransferase (TPMT) is a cytosolic enzyme that catalyzes the inactivation of mercaptopurine, azathioprine, and thioguanin e. The genetic polymorphisms in the TPMT gene that regulate TPMT activity a re inherited as an autosomal recessive trait and patients with genetically determined low levels of TPMT activity develop severe myelosupression when treated with standard doses of the above-mentioned drugs. We have analyzed the frequencies of the allelic variants of the TPMT gene in a white Europea n population of healthy blood donors from Spain and The Netherlands, and in a group of patients suffering from ulcerative colitis (UC) with a similar genetic background. METHODS: Two hundred and thirteen unrelated healthy individuals (HC) and 14 6 UC patients were typed for the polymorphic sites at positions 460 (G --> A) and 719 (A --> G) of the TPMT gene using specific polymerase chain react ion-restriction fragment-length polymorphism (PCR-RFLP) methods. RESULTS: There were no significant differences between the allele frequenci es observed in the group of UC patients and those of the control group (10% of cases were heterozygous carriers of a TPMT mutant allele). The most fre quent mutant allele in both UC and HC groups was TPMT3A (A(460) --> G(719)) (60% of carriers). TPMT3B (A(460) --> A(719)) and TPMT3C (G(460) --> G(719 )) alleles were more often found in our study than in previously reported s tudies, reflecting the different genetic backgrounds of the European popula tions analyzed. CONCLUSIONS: Genotyping methods provide a simple and reliable screening to identify patients with a high risk of developing severe bone marrow toxicit y if treated with thiopurine drugs. In UC patients, TPMT genotype should be determined before the initiation of azathioprine therapy. (Am J Gastroente rol 2000;95:2313-2317. (C) 2000 by Am. Cell. of Gastroenterology).