Published online Jan 28, 2018. doi: 10.3748/wjg.v24.i4.511
Peer-review started: October 17, 2017
First decision: November 8, 2017
Revised: December 2, 2017
Accepted: December 5, 2017
Article in press: December 4, 2017
Published online: January 28, 2018
Processing time: 101 Days and 11.2 Hours
The 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.
Ninety-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.
Genetic 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.
Mutations 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.
Core tip: Single nucleotide polymorphism (SNP) in NUDT15 c.415C>T in exon 3 affects thiopurine-induced leukopenia in Asian Crohn’s disease patients. Meanwhile, there is a report of additional three genetic variants of NUDT15 in patients with acute lymphoblastic leukemia. We evaluated the effect of these additional genetic variants of NUDT15 on inflammatory bowel disease (IBD) treated with thiopurines. The increase rate of mean corpuscular volume was higher in the variants than the wild, Mutations of NUDT15 in exon 1 also affects thiopurine-induced leukopenia in patients with IBD. To discuss thiopurine-induced leukopenia, investigating SNPs both exons 1 and exon 3 of NUDT15 is needed.