LAUSR

Pharmacogenetics is the study focusing on genetic variations that affect sensitivity to specific medications. Recent advances in this field have enabled us to provide individualized medicine based on genetic characteristics, and genomic variants conferring thiopurine metabolism are one of the representatives of precision medicine in clinical pharmacogenomics. 6-Mercaptopurine (6-MP), one of the thiopurines, is an essential drug in the treatment of lymphoid malignancy, used in the consolidation phase and maintenance therapy. Daily 6MP and weekly methotrexate is typical form of maintenance therapy. Interindividual differences in sensitivity to 6-MP are well recognized, and the dose of 6-MP is adjusted based on actual myelosuppression, to keep a target leukocyte count of 2,000–3,000/mm. Sensitivity to 6-MP is associated with race, and a possible genetic basis for this heterogeneity is supposed to exist. Previous studies identified TPMT as a causative gene for sensitivity to 6-MP, and the clinical utility of genetic testing for TPMT is recognized to minimize a risk of severe thiopurine-cytotoxicity. However, the minor allele frequency of TPMT variants in Asian is 2% or less, although the Asian population is known to be relatively sensitive to 6-MP. Recently, NUDT15 was identified as another determinant of sensitivity to 6-MP. A genome-wide association study found a significant association between NUDT15 c.415C >T and sensitivity to 6MP in leukemia patients, and following studies confirmed low enzymatic activity of NUDT15 with the variant. NUDT15 hydrolyzes 6-thio-(d)GTP and regulates the thiopurine metabolizing pathway, and dysfunction of NUDT15 leads to intolerance of thiopurines (Fig. 1). Patients with homozygous variants are extremely sensitive to 6-MP, and tolerable dose of 6-MP in maintenance therapy is as low as <10 mg/m (approximately 10% of standard dose). As well as 6-MP, azathioprine (AZA), another purine antimetabolites, is used in clinical practice for inflammatory bowel diseases and rheumatoid arthritis. Several studies show that patients with NUDT15 hypomorphic variants also show intolerance to AZA, with severe and prolonged myelosuppression and unexpected alopecia. Given clinical importance of NUDT15 genotyping, upfront gene testing of NUDT15 has been approved under health-insurance coverage in Japan since February 2019. According to a study by Pu et al., the Bai people, the second largest minority in Yunnan province of China, have a high frequency of the NUDT15 variants, accounting for ~2% of homozygous variants. As shown in Figure 1, the allele frequency of NUDT15 hypomorphic variants varies according to race, and the Asian and Hispanic populations have a higher frequency of NUDT15 whereas TPMT variants are high frequency in other races. We can select which of the two major genetic determinants should be genotyped not only to minimize severe toxicity due to high sensitivity to thiopurines but also to avoid unnecessary underdose resulting from a fear of intolerance.