NUDT15 codon 139 is the best pharmacogenetic marker for predicting thiopurine-induced severe adverse events in Japanese patients with inflammatory bowel disease: a multicenter study

J Gastroenterol. 2018 Sep;53(9):1065-1078. doi: 10.1007/s00535-018-1486-7. Epub 2018 Jun 19.


Background: Despite NUDT15 variants showing significant association with thiopurine-induced adverse events (AEs) in Asians, it remains unclear which variants of NUDT15 or whether additional genetic variants should be tested to predict AEs. To clarify the best pharmacogenetic test to be used clinically, we performed association studies of NUDT15 variants and haplotypes with AEs, genome-wide association study (GWAS) to discover additional variants, and ROC analysis to select the model to predict severe AEs.

Methods: Overall, 2630 patients with inflammatory bowel disease (IBD) were enrolled and genotyped for NUDT15 codon 139; 1291 patients were treated with thiopurines. diplotypes were analyzed in 970 patients, and GWASs of AEs were performed with 1221 patients using population-optimized genotyping array and imputation.

Results: We confirmed the association of NUDT15 p.Arg139Cys with leukopenia and alopecia (p = 2.20E-63, 1.32E-69, OR = 6.59, 12.1, respectively), and found a novel association with digestive symptoms (p = 6.39E-04, OR = 1.89). Time to leukopenia was significantly shorter, and when leukopenia was diagnosed, thiopurine doses were significantly lower in Arg/Cys and Cys/Cys than in Arg/Arg. In GWASs, no additional variants were found to be associated with thiopurine-induced AEs. Despite strong correlation of leukopenia frequency with estimated enzyme activities based on the diplotypes (r2 = 0.926, p = 0.0087), there were no significant differences in the AUCs of diplotypes from those of codon 139 to predict severe AEs (AUC = 0.916, 0.921, for acute severe leukopenia, AUC = 0.990, 0.991, for severe alopecia, respectively).

Conclusions: Genotyping of NUDT15 codon 139 was sufficient to predict acute severe leukopenia and alopecia in Japanese patients with IBD.

Keywords: GWAS; Inflammatory bowel disease; NUDT15; Pharmacogenetics; Thiopurine.

Publication types

  • Multicenter Study

MeSH terms

  • Alopecia / chemically induced
  • Antibodies, Monoclonal / adverse effects
  • Antibodies, Monoclonal / therapeutic use
  • Azathioprine / adverse effects*
  • Azathioprine / therapeutic use*
  • Biomarkers, Pharmacological*
  • Genetic Predisposition to Disease
  • Genome-Wide Association Study
  • Genomic Structural Variation
  • Haplotypes
  • Humans
  • Immunosuppressive Agents / adverse effects*
  • Immunosuppressive Agents / therapeutic use*
  • Inflammatory Bowel Diseases / drug therapy*
  • Japan
  • Leukopenia / chemically induced
  • Logistic Models
  • Mercaptopurine / adverse effects*
  • Mercaptopurine / therapeutic use*
  • Mesalamine / adverse effects
  • Mesalamine / therapeutic use
  • Pharmacogenetics
  • Pyrophosphatases / genetics*
  • ROC Curve
  • Retrospective Studies
  • Risk
  • Sulfasalazine / adverse effects
  • Sulfasalazine / therapeutic use


  • Antibodies, Monoclonal
  • Biomarkers, Pharmacological
  • Immunosuppressive Agents
  • Sulfasalazine
  • Mesalamine
  • Mercaptopurine
  • NUDT15 protein, human
  • Pyrophosphatases
  • Azathioprine