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
Previous study demonstrated that single nucleotide polymorphism (SNP) in NUDT15 c.415C>T (encoding p.Arg139Cys) in exon 3 affects thiopurine-induced leukopenia in Asian patients with inflammatory bowel disease (IBD). In acute lymphoblastic leukemia (ALL), there are other variants of NUDT15 in exon 1 and exon 3. We demonstrated the variants of c.36_37insGGAGTC (encoding p.Val18_Val19insGlyVal) and c.52G > A (encoding p.Val18Ile) in exon 1 also affect the thiopurine-induced leukopenia. To present thiopurine-induced leukopenia and other side effects, checking both exons 1 and exon 3 of NUDT15 is definitely needed.
It is well known that leukopenia is one of the most important adverse effects of thiopurines. To distinguish the high risk group of the adverse effects is clinically very important. Thus we investigated other NUDT15 variants than NUDT15 c.415 C > T in exon 3.
The main of this paper is to investigate other NUDT15 variants than c.415 > T have an effect on hematological pictures including WBC count.
We enrolled 96 Japanese patients with IBD. Genotyping for NUDT15 and TPMT genes was performed using Custom TaqMan SNP genotyping assays or Sanger sequencing. The changes of white blood cell (WBC) count, mean corpuscular volume (MCV), platelet count, hemoglobin, CRP, amylase, albumin, AST, ALT and ESR were analyzed.
In 24 out of 96 patients (25.0%), genetic variants of exons 1 and 3 were identified. C.52G > A and c.36_37insGGAGTC in exon 1 was found in 3 cases each. All 3 cases of c.36_37insGGAGTC in exon 1 had heterozygote of p.Arg139Cys in exon 3. Eighteen patients showed p.Arg139Cys in exon 3 alone. WBC count gradually decreased after thiopurine was started in the mutant (n = 24). The WBC count of the mutant was statistically significantly lower at 6, 8, 10 and 16 wk (P = 0.0271, 0.0037, 0.0051 and 0.0185, respectively). We also analyzed WBC count in the cases with and without prednisolone. In the cases with prednisolone, WBC count tended to decrease more in the mutant cases and was significantly lower at 8 and 10 wk (P = 0.012 and 0.029, respectively). In the cases without prednisolone, WBC count was significantly lower at 2, 4, 8 and 14 wk in the mutant than the wild cases (P = 0.0196, 0.0182, 0.0237 and 0.0241, respectively). MCV increased after starting thiopurine in the mutant. MCV was significantly higher at 10 wk in the mutant than the wild cases (P = 0.0085). Platelet count, hemoglobin, CRP, amylase, albumin, AST, ALT, and ESR was not different between the wild and the mutant cases. TPMT mutation was not found in any of our Japanese patients.
We reported NUDT15 variant in exon 1 also affect thiopurine-induced leukopenia in patients with IBD. Before starting the treatment with thiopurines for patients with IBD, NUDT15 variant in exon 1 and 3 will be routinely performed for preventing adverse events of thiopurines in the near future.
There are other NUDT15 variants which are reported in patients with ALL and near future their role on IBD patients will be investigated.