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

• Published in: The American journal of gastroenterology Vol. 95; no. 9; pp. 2313 - 2317
• Main Authors: Corominas, Hèctor, Domènech, Montserrat, González, Dolors, Diaz, César, Roca, Martín, García-González, Maria Asunción, Peña, Salvador, Baiget, Montserrat
• Format: Journal Article Conference Proceeding
• Language: English
• Published: Oxford . 01-09-2000; Blackwell Publishing; Wolters Kluwer Health Medical Research, Lippincott Williams & Wilkins
• Subjects: Biological and medical sciences; Gastroenterology; Gastroenterology. Liver. Pancreas. Abdomen; Medical sciences; Other diseases. Semiology; Stomach. Duodenum. Small intestine. Colon. Rectum. Anus; Europe; Human; Purine nucleoside; Enzyme; Transferases; Deficiency; Metabolic diseases; Cytotoxicity; Tioguanine; Enzymopathy; Epidemiology; Inflammatory disease; Incidence; Methyltransferases; Digestive diseases; Intestinal disease; Thiopurine S-methyltransferase; Azathioprine; Mercaptopurine; Polymorphism; Ulcerative colitis
• ISSN: 0002-9270; 1572-0241
• DOI: 10.1111/j.1572-0241.2000.02256.x

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 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 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.