Nomenclature for alleles of the thiopurine methyltransferase gene

Abstract

The drug-metabolizing enzyme thiopurine methyltransferase (TPMT) has become one of the best examples of pharmacogenomics to be translated into routine clinical practice. TPMT metabolizes the thiopurines 6-mercaptopurine, 6-thioguanine, and azathioprine, drugs that are widely used for treatment of acute leukemias, inflammatory bowel diseases, and other disorders of immune regulation. Since the discovery of genetic polymorphisms in the TPMT gene, many sequence variants that cause a decreased enzyme activity have been identified and characterized. Increasingly, to optimize dose, pretreatment determination of TPMT status before commencing thiopurine therapy is now routine in many countries. Novel TPMT sequence variants are currently numbered sequentially using PubMed as a source of information; however, this has caused some problems as exemplified by two instances in which authors’ articles appeared on PubMed at the same time, resulting in the same allele numbers given to different polymorphisms. Hence, there is an urgent need to establish an order and consensus to the numbering of known and novel TPMT sequence variants. To address this problem, a TPMT nomenclature committee was formed in 2010, to define the nomenclature and numbering of novel variants for the TPMT gene. A website (http://www.imh.liu.se/tpmtalleles) serves as a platform for this work. Researchers are encouraged to submit novel TPMT alleles to the committee for designation and reservation of unique allele numbers. The committee has decided to renumber two alleles: nucleotide position 106 (G > A) from TPMT*24 to TPMT*30 and position 611 (T > C, rs79901429) from TPMT*28 to TPMT*31. Nomenclature for all other known alleles remains unchanged.

Complete sequence-based screening of TPMT variants in the Korean population

“…TPMT activity is largely influenced by polymorphisms of the TPMT gene. To date, more than 35 variants in TPMT are known to be associated with reduced enzyme activity (http://www.imh.liu.se/tpmtalleles) [1].…”

“…Thiopurine S-methyltransferase (TPMT) is a cytoplasmic enzyme involved in the metabolism of thiopurine drugs [1]. As patients with impaired TPMT are at risk for myelosuppression related to thiopurine therapy [2], determination of TPMT activity is important to prevent myelosuppression.…”

Pharmacology and Optimization of Thiopurines and Methotrexate in Inflammatory Bowel Disease

“…In fact, thiopurine-related myelotoxicity can, at least partly, be predicted by TPMT genotyping [66,67]; however, other side effects, including fever, arthralgia, hepatitis, and pancreatitis, are independent of TPMT status in up to 70 % of patients [62,66]. To date, more than 35 variants of the TPMT gene have been associated with decreased enzymatic TPMT activity [68][69][70][71][72][73]. A trimodal distribution of TPMT activity levels has been described in a general population.…”

Pre-Screening TPMT Status of Liver Transplant Patients for Azathioprine Therapy–a Single Centre Experience From South India

“…Genetic variation in TPMT enzyme has been related to the occurrence of toxicity with thiopurine treatment. More than 27 mutations are now documented, but the clinical relevance of some of them remains unclear [16]. TPMT*3A, TPMT*3C, and TPMT*2 represent the most prevalent mutant alleles in Caucasians and Asians, resulting from genetic polymorphism; 6-11% of mutations account for 'intermediate' and 0.3% 'low' thiopurine methyltransferase activity [16].…”