Influence of NUDT15 variants on hematological pictures of patients with inflammatory bowel disease treated with thiopurines

Abstract

AIMThe single nucleotide polymorphism (SNP) c.415C>T in exon 3 of NUDT15 affects thiopurine-induced leukopenia in Asian patients with Crohn’s disease. Meanwhile, three additional genetic variants of NUDT15 were reported in patients with acute lymphoblastic leukemia. We evaluated the effects of these additional genetic variants of NUDT15 in patients with inflammatory bowel disease (IBD) treated with thiopurines.METHODSNinety-six Japanese patients with IBD were enrolled. Genotyping for the NUDT15 and TPMT genes was performed using Custom TaqMan SNP genotyping assays or Sanger sequencing. The changes in white blood cell (WBC) count, mean corpuscular volume (MCV), platelet count, hemoglobin, CRP, amylase, albumin, AST, ALT, and ESR were evaluated.RESULTSGenetic variants of exon 1 and exon 3 of NUDT15 were identified in 24 of 96 patients (25.0%). C.52G > A and c.36_37insGGAGTC in exon 1 were found in three patients each. All three patients with c.36_37insGGAGTC in exon 1 were heterozygotes of p.Arg139Cys in exon 3. Eighteen patients had p.Arg139Cys in exon 3 alone. The WBC count gradually decreased after initiation of thiopurine treatment in the mutated cases (n = 24), and was significantly lower at 6, 8, 10, and 16 wk (P = 0.0271, 0.0037, 0.0051, and 0.0185, respectively). The WBC counts were also evaluated in patients with and without prednisolone treatment. In the patients with prednisolone treatment, the WBC count tended to show a greater decrease in the mutated cases, with significant differences at 8 and 10 wk (P = 0.012 and 0.029, respectively). In the patients without prednisolone treatment, the WBC count was significantly lower at 2, 4, 8, and 14 wk in mutated cases (P = 0.0196, 0.0182, 0.0237 and 0.0241, respectively). MCV increased after starting thiopurine treatment in the mutated cases, and was significantly higher at 10 wk (P = 0.0085). Platelet count, hemoglobin, CRP, amylase, albumin, AST, ALT and ESR did not differ significantly between the wild-type and mutated cases. TPMT mutations were not found in any of the patients.CONCLUSIONMutations in exon 1 of NUDT15 also affect thiopurine-induced leukopenia in patients with IBD. To discuss thiopurine-induced leukopenia in more detail, investigation of SNPs in both exon 1 and exon 3 of NUDT15 is needed.

Long‐term effect of NUDT15 R139C on hematologic indices in inflammatory bowel disease patients treated with thiopurine

“…Our study also showed that the MCV at each time point was significantly higher in the C/T group than in the C/C group, indicating that the red blood cells of patients heterozygous for the NUDT15 R139C variant are more sensitive than those of patients homozygous for the wild‐type allele. This result is consistent with a previous study reporting that MCV values at 10 weeks after initiating thiopurine were significantly higher in patients with the heterozygous variant alleles of NUDT15 than in those without . Several studies suggest that thiopurine‐mediated inhibition of DNA synthesis in bone marrow precursor cells leads to megaloblastic erythropoiesis .…”

“…Kojima et al . observed that compared with patients with the variant, the WBC count became significantly lower at 6 weeks and remained lower through the remainder of the 16‐week study period in those with the variant . Although the WBC count beyond 16 weeks was not determined in their study, their WBC results up to this point are consistent with ours.…”

“…Conversely, Kojima et al . addressed that platelet count did not differ significantly between wild type and mutated type of NUDT15 during 16 weeks of thiopurine administration . Further studies are necessary to figure out this point.…”

“…Our study is the first study to demonstrate the long‐term kinetics of WBC count in patients heterozygous for the NUDT15 R139C variant. Previous studies demonstrated a strong association between the NUDT15 R139C genotype and early thiopurine‐induced leukopenia in Asian IBD patients . Kojima et al .…”

“…Previous studies demonstrated a strong association between the NUDT15 R139C genotype and early thiopurine-induced leukopenia in Asian IBD patients. 12,15,16,22,23 Kojima et al observed that compared with patients with the variant, the WBC count became significantly lower at 6 weeks and remained lower through the remainder of the 16-week study period in those with the variant. 23 Although the WBC count beyond 16 weeks was not determined in their study, their WBC results up to this point are consistent with ours.…”