Genetic Polymorphism of Thiopurine S-Methyltransferase in the Russian Population.

Thiopurine S-methyltransferase (TPMT) is a key enzyme in the catabolism of 6-mercaptopurine (6MP), a key component of therapy for childhood acute lymphoblastic and promyelocytic leukemias and lymphoblastic non-Hodgkin lymphoma. TPMT mutations reduce TPMT enzymatic activity; therefore, TPMT-deficient patients develop severe hematopoietic toxicity when treated with standard doses of 6MP (50–75 mg/m²/day). The frequency of TPMT alleles has not previously been evaluated in the Russian Federation. We determined the allele frequency and the pattern of mutant TPMT alleles in Russian children with hematologic malignancies (leukemia/lymphoma) and other diseases, and in healthy adults, in different areas of the Russian Federation. A microchip was designed to detect the main mutant alleles of human TPMT (TPMT*2, *3A, *3B, *3D, *7, and *8) and was used to assay 982 samples. Only 3 inactivating mutations of the TPMT gene were identified: 45 subjects (4.6%) had TPMT genotype *1/*3A, 8 (0.8%) had *1/*3C, and 2 (0.2%) had *1/*2. No homozygous genotypes and no mutant *3B, *3D, *7, or *8 alleles were found. The estimated frequency of the wild-type allele was 97.1% (95% CI, 93.8%–100%) and that of variant alleles was 2.9% (95% CI, 0%–6%). Most individuals with the *1/*3A genotype were of Slavic background, and genotype *1/*3C was found in a buryat (Mongolian race) and in residents of the North Caucasian and the Urals regions. These findings indicate ethnic differences in the frequency of nonfunctional TPMT alleles. The overall frequency of mutant TPMT genotypes in the Russian Federation is 5.6%, which is similar to that observed in the white populations of the United States and Europe.