title: Nucleoside diphosphate-linked moiety X-type motif 15 C415T variant as a predictor for thiopurine-induced toxicity in Indian patients.
abstract: OBJECTIVE
  Interindividual variation seen in the thiopurine metabolism is attributed to the genetic variant in thiopurine methyltransferase (TPMT) gene leading to myelosuppression. In Asians, the thiopurine-induced toxicity is not completely explained by TPMT variants. Literature indicates that a newer genetic variant in nucleoside diphosphate-linked moiety X-type motif 15 (NUDT15) gene is associated with thiopurine intolerance. We aimed to determine the risk allele frequency of NUDT15 genetic variant and its association with thiopurine-induced toxicity in Indian patients.
  
  
  METHODS
  In this pilot study, 69 patients on thiopurine therapy were analyzed. The frequencies of thiopurine-induced leukopenia were recorded. NUDT15 (C415T) and TPMT (*2, *3A, *3B, and *3C) genotyping was performed using amplification refractory mutation system-polymerase chain reaction and restriction fragment length polymorphism technique. Results were validated by DNA sequencing.
  
  
  RESULTS
  The NUDT15 CC, CT, and TT genotypes were found to be 86.9%, 11.5%, and 1.5%, respectively, whereas TPMT genetic variants were absent. Of 60 patients without NUDT15 variant, none developed leukopenia, whereas of nine patients with NUDT15 variant, six developed leukopenia (P-value < 0.0001). The mean thiopurine dose of 1.01 and 0.73 mg/kg/day for patients with wild and mutant NUDT15 alleles, respectively, was statistically significant (P < 0.01). The sensitivity and specificity for NUDT15 variant were 100% and 95.2%, respectively.
  
  
  CONCLUSIONS
  The NUDT15 risk allele frequency was 7.2%. There are 6/69 (8.7%) patients who developed leukopenia and harbored NUDT15 variant, thus showing a strong association for thiopurine-induced toxicity. Hence, NUDT15 genotyping may be considered before thiopurine therapy in Indian patients.
authors.affiliation: Department of Research Laboratories, P. D. Hinduja National Hospital and Medical Research Centre, Mumbai, India.
authors.forename: Swarup A V
authors.initials: SA
authors.lastname: Shah
authors.affiliation: Department of Research Laboratories, P. D. Hinduja National Hospital and Medical Research Centre, Mumbai, India.
authors.forename: Minal
authors.initials: M
authors.lastname: Paradkar
authors.affiliation: Department of Gastroenterology, P. D. Hinduja National Hospital and Medical Research Centre, Mumbai, India.
authors.forename: Devendra
authors.initials: D
authors.lastname: Desai
authors.affiliation: Department of Biochemistry, P. D. Hinduja National Hospital and Medical Research Centre, Mumbai, India.
authors.forename: Tester F
authors.initials: TF
authors.lastname: Ashavaid
mesh_terms: D000368:Aged; D044466:Asian People; D001379:Azathioprine / Q000009:adverse effects / Q000378:metabolism / Q000633:toxicity*; D005260:Female; D005787:Gene Frequency; D056726:Genetic Association Studies; D014644:Genetic Variation; D005838:Genotype; D006801:Humans; D007194:India; D007970:Leukopenia / Q000139:chemically induced*; D008297:Male; D015122:Mercaptopurine / Q000009:adverse effects / Q000378:metabolism / Q000633:toxicity*; D008780:Methyltransferases / Q000235:genetics / Q000502:physiology; D008875:Middle Aged; D011755:Pyrophosphatases / Q000235:genetics*; D012306:Risk; D000096964:Nudix Hydrolases
chemical_list: D001379:Azathioprine; D015122:Mercaptopurine; D008780:Methyltransferases; D011755:Pyrophosphatases; C022745:thiopurine methyltransferase; C543721:NUDT15 protein, human; D000096964:Nudix Hydrolases
keywords: Indians; NUDT15; genetic screening; thiopurine toxicity