title: Further evidence that a variant of the gene NUDT15 may be an important predictor of azathioprine-induced toxicity in Chinese subjects: a case report.
abstract: OBJECTIVE
  Thiopurine methyltransferase (TPMT) enzyme is an important component in the metabolism of azathioprine (AZA). Its mutation may lead to AZA-induced toxicity. The dysfunctional genetic variant TPMT *3C is of low frequency among Asians. Moreover, AZA-induced toxicity still occurs in some patients with normal TPMT activity. This suggests that additional factors, including other genetic variants, may contribute to such toxicity. Recent studies described a strong association between a variant of the NUDT15, a gene that mediates the hydrolysis of some nucleoside diphosphate derivatives, and thiopurine-related myelosuppression in Asians. We report the first case of a Chinese patient with AZA-induced severe toxicity with no clinically significant TPMT variant but with the NUDT15 c.415C>T allele.
  
  
  METHODS
  A 40-year-old Chinese patient with PBC-AIH overlap syndrome had been receiving for one month, azathioprine (50 mg/day) and methylprednisolone (24 mg/day) based on his TPMT*3C wild-type genotype. The patient developed serious myelosuppression and hair loss. AZA was stopped, and the patient was given liver-protective drugs and supportive treatment. TPMT and NUDT15 gene sequencing suggests that NUDT15 c.415C>T mutation was the likely cause of the adverse reaction.
  
  
  CONCLUSIONS
  NUDT15 c.415C>T may be another predictor of AZA-induced leukocytopenia. If further well-controlled studies validate this association with sufficient predictive power, NUDT15 and TPMT genotyping before starting AZA treatment may become appropriate.
authors.affiliation: Department of Pharmacy, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China.
authors.forename: Z
authors.initials: Z
authors.lastname: Ailing
authors.affiliation: Department of Pharmacy, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China.
authors.forename: Y
authors.initials: Y
authors.lastname: Jing
authors.affiliation: Department of Pharmacy, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China.
authors.forename: L
authors.initials: L
authors.lastname: Jingli
authors.affiliation: Department of Gastroenterology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China.
authors.forename: X
authors.initials: X
authors.lastname: Yun
authors.affiliation: Department of Pharmacy, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China.
authors.forename: Z
authors.initials: Z
authors.lastname: Xiaojian
mesh_terms: D000328:Adult; D044466:Asian People / Q000235:genetics*; D001379:Azathioprine / Q000009:adverse effects*; D064420:Drug-Related Side Effects and Adverse Reactions / Q000235:genetics*; D005838:Genotype; D006801:Humans; D008297:Male; D011110:Polymorphism, Genetic / Q000235:genetics*; D011755:Pyrophosphatases / Q000235:genetics*; D000096964:Nudix Hydrolases
chemical_list: D001379:Azathioprine; D011755:Pyrophosphatases; C543721:NUDT15 protein, human; D000096964:Nudix Hydrolases
keywords: NUDT15 c.415C>T; azathioprine; hair loss; myelosuppression; thiopurine methyltransferase