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

Abstract

Thiopurine S-methyltransferase (TPMT) is a cytosolic enzyme that catalyzes the inactivation of mercaptopurine, azathioprine, and thioguanine. The genetic polymorphisms in the TPMT gene that regulate TPMT activity are inherited as an autosomal recessive trait and patients with genetically determined low levels of TPMT activity develop severe myelosuppression 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 European 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. Two hundred and thirteen unrelated healthy individuals (HC) and 146 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 reaction-restriction fragment-length polymorphism (PCR-RFLP) methods. There were no significant differences between the allele frequencies 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 frequent mutant allele in both UC and HC groups was TPMT3A (A460-->G719) (60% of carriers). TPMT3B (A460-->A719) and TPMT3C (G460-->G719) alleles were more often found in our study than in previously reported studies, reflecting the different genetic backgrounds of the European populations analyzed. Genotyping methods provide a simple and reliable screening to identify patients with a high risk of developing severe bone marrow toxicity if treated with thiopurine drugs. In UC patients, TPMT genotype should be determined before the initiation of azathioprine therapy.