NUDT15 polymorphisms are better than thiopurine S‐methyltransferase as predictor of risk for thiopurine‐induced leukopenia in Chinese patients with Crohn's disease

Summary Background Thiopurine‐induced leukopenia is the most common dangerous adverse event in Asians. NUDT 15 R139C was recently proposed to be a promising biomarker for leukopenia with thiopurine therapy in Asians, but this has not been replicated in the Chinese population. Aim To investigate the influence of NUDT 15 R139C, thiopurine S‐methyltransferase ( TPMT ), 6‐ TGN and 6‐ MMPR on thiopurine‐induced leukopenia in Chinese patients with Crohn's disease. Methods Clinical and epidemiological characteristics were reviewed from medical records. NUDT 15 R139C and TPMT were genotyped. 6‐ TGN /6‐ MMPR concentrations were measured with high‐performance liquid chromatography ( HPLC ). Results A total of 253 patients were included, 65 (25.7%) of whom experienced leukopenia. The median follow‐up with thiopurine treatment was 38.0 weeks (range, 1–192 weeks). NUDT 15 R139C was strongly associated with the incidence of leukopenia (70.2% mutation vs. 12.8% wild type; P =8.61×10 −19 ; odds ratio, 10.80; 95% CI , 5.89–19.83). However, TPMT genotype was not found to be correlated with the incidence of leukopenia ( P = 0.44). In subgroup of NUDT 15 wild type, there was significant difference of 6 TGN concentration between patients with and without leukopenia (413.0 (174.2–831.4) vs. 279.7 (77.3–666.9) pmol/8 × 10 8 RBC , P = 0.0055). In contrast, no association was found in patients with NUDT 15 R139C variant alleles ( P = 0.26). 6‐ MMPR was not correlated with leukopenia ( P = 0.84). Conclusions In Chinese patients, it is strongly recommended to detect NUDT 15 genotype rather than TPMT before initiating thiopurine drugs. 6 TGN concentration should be routinely monitored in CD patients with NUDT 15 wild type. As for CT genotype, starting at low dose and careful monitoring for leukopenia and 6 TGN levels is recommended.