Inosine Triphosphate Pyrophosphatase and NUDT15 are Good Predictors of Clinical Outcomes in Thiopurine-Treated Chinese Patients with Inflammatory Bowel Disease

Ther Drug Monit. 2022 Jun 1;44(3):391-395. doi: 10.1097/FTD.0000000000000965.

Abstract

Background: Although the relationship between NUDT15 and thiopurine-induced leukopenia has been proven in previous studies, no prominent factors explaining interindividual variations in its active metabolite, 6-thioguanine nucleotide (6-TGN), and clinical efficacy have been identified. In this study, the correlation between genotypes (thiopurine S-methyltransferase, NUDT15, and ITPA polymorphisms), 6-TGN concentrations, and clinical outcomes (efficacy and side effects) in patients with inflammatory bowel disease were investigated.

Methods: In total, 160 patients with inflammatory bowel disease were included, and the 3 genotyped genes and 6-TGN levels were measured by high-performance liquid chromatography. Statistical analyses and calculations were performed to determine their relationships.

Results: ITPA genotypes and 6-TGN concentration were both associated with the clinical effectiveness of azathioprine (P = 0.036 and P = 4.6 × 10-7), with a significant correlation also detected between them (P = 0.042). Patients with ITPA variant alleles exhibited higher 6-TGN levels than those with the wild-type allele. In addition, the relationship between NUDT15 and leukopenia and neutropenia was confirmed (P = 1.79 × 10-7 and 0.002).

Conclusions: In summary, it is recommended that both ITPA and NUDT15 genotyping should be performed before azathioprine initiation. Moreover, the 6-TGN concentration should be routinely monitored during the later period of treatment.

MeSH terms

  • Azathioprine / therapeutic use
  • Biomarkers / metabolism
  • China
  • Guanine Nucleotides / genetics
  • Guanine Nucleotides / metabolism
  • Humans
  • Inflammatory Bowel Diseases* / drug therapy
  • Inflammatory Bowel Diseases* / genetics
  • Inflammatory Bowel Diseases* / metabolism
  • Leukopenia / chemically induced
  • Leukopenia / drug therapy
  • Leukopenia / genetics
  • Methyltransferases / genetics
  • Methyltransferases / metabolism
  • Prognosis
  • Pyrophosphatases* / genetics
  • Pyrophosphatases* / metabolism
  • Thionucleotides / genetics
  • Thionucleotides / metabolism

Substances

  • Biomarkers
  • Guanine Nucleotides
  • Thionucleotides
  • 6-thioguanylic acid
  • Methyltransferases
  • NUDT15 protein, human
  • Pyrophosphatases
  • ITPA protein, human
  • Azathioprine