NUDT15 polymorphisms are better than thiopurine S-methyltransferase as predictor of risk for thiopurine-induced leukopenia in Chinese patients with Crohn's disease.
Thiopurine-induced leukopenia is the most common dangerous adverse event in Asians. NUDT15 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.



To investigate the influence of NUDT15 R139C, thiopurine S-methyltransferase (TPMT), 6-TGN and 6-MMPR on thiopurine-induced leukopenia in Chinese patients with Crohn's disease.



Clinical and epidemiological characteristics were reviewed from medical records. NUDT15 R139C and TPMT were genotyped. 6-TGN/6-MMPR concentrations were measured with high-performance liquid chromatography (HPLC).



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). NUDT15 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 NUDT15 wild type, there was significant difference of 6TGN concentration between patients with and without leukopenia (413.0 (174.2-831.4) vs. 279.7 (77.3-666.9) pmol/8 × 108RBC, P = 0.0055). In contrast, no association was found in patients with NUDT15 R139C variant alleles (P = 0.26). 6-MMPR was not correlated with leukopenia (P = 0.84).



In Chinese patients, it is strongly recommended to detect NUDT15 genotype rather than TPMT before initiating thiopurine drugs. 6TGN concentration should be routinely monitored in CD patients with NUDT15 wild type. As for CT genotype, starting at low dose and careful monitoring for leukopenia and 6TGN levels is recommended.
Institute of Clinical Pharmacology, School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou, China.
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X
Zhu
Institute of Clinical Pharmacology, School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou, China. xueding99@163.com.
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XD
Wang
Department of Gastroenterology, the Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, China.
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K
Chao
Department of Gastroenterology, the Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, China.
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M
Zhi
Institute of Clinical Pharmacology, School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou, China.
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H
Zheng
School of Public Health, Guangzhou Medical University, Guangzhou, China.
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HL
Ruan
Institute of Clinical Pharmacology, School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou, China.
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S
Xin
Department of Gastroenterology, the Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, China.
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N
Ding
Department of Gastroenterology, the Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, China.
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PJ
Hu
Institute of Clinical Pharmacology, School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou, China.
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M
Huang
Department of Gastroenterology, the Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, China. helengao818@163.com.
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X
Gao
D000293:Adolescent; D000328:Adult; D044466:Asian People / Q000235:genetics*; D003424:Crohn Disease / Q000097:blood / Q000188:drug therapy / Q000235:genetics*; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D007970:Leukopenia / Q000097:blood / Q000139:chemically induced / Q000235:genetics*; D008297:Male; D008780:Methyltransferases / Q000097:blood / Q000235:genetics*; D008875:Middle Aged; D011110:Polymorphism, Genetic / Q000235:genetics*; D011237:Predictive Value of Tests; D011755:Pyrophosphatases / Q000235:genetics*; D012307:Risk Factors; D055815:Young Adult; D000096964:Nudix Hydrolases
D008780:Methyltransferases; D011755:Pyrophosphatases; C022745:thiopurine methyltransferase; C543721:NUDT15 protein, human; D000096964:Nudix Hydrolases