P755 NUDT15 polymorphism is associated with thiopurine-related leukopenia independently of 6-thioguanine nucleotide levels in Korean paediatric inflammatory bowel disease patients

Kang B.^*1, Choi J.Y.¹, Lee K.¹, Lee S.-Y.², Ahn S.H.³, Lee H.J.⁴, Choe Y.H.¹

¹Samsung Medical Center, Sungkyunkwan University School of Medicine, Department of Pediatrics, Seoul, South Korea ²Samsung Medical Center, Sungkyunkwan University School of Medicine, Department of Laboratory Medicine and Genetics, Seoul, South Korea ³Samsung Medical Center, Biostatistics and Clinical Epidemiology Center, Seoul, South Korea ⁴Samsung Changwon Hospital, Sungkyunkwan University School of Medicine, Department of Pediatrics, Changwon, South Korea

Background

Polymorphisms in the NUDT15 gene are associated with thiopurine-related myelosuppression in patients with inflammatory bowel disease (IBD). We aimed to investigate factors associated with leukopenia including NUDT15 polymorphisms in Korean paediatric IBD patients during treatment with thiopurines.

Methods

This retrospective study was conducted in 167 paediatric IBD patients who had performed NUDT15 genotyping and had been treated with azathiopurine (AZA) from January 2006 to August 2016 at the Department of Pediatrics, Samsung Medical Center. Subjects were divided into 3 groups according to NUDT15 activity based on NUDT15 diplotypic groups; normal activity (wild type), intermediate activity (heterozygous at a single variant with one prototype allele) and low activity (with both variant allele). The lowest white blood cell count during AZA treatment as well as 6-thioguanine nucleotide (6-TGN) levels, AZA dosage, concomitant drug usage, TPMT polymorphism status, and other clinicodemographic factors were investigated.

Results

NUDT15 groups of normal, intermediate, and low activity consisted of 71% (119/167), 27% (45/167), and 2% (3/167) of the enrolled subjects, respectively. Leukopenia was observed in 16% (19/119), 44% (20/45), and 100% (3/3) of the normal, intermediate, and low activity groups (p<0.001), and early leukopenia (within 8 weeks from AZA initiation) in 1% (1/119), 2% (1/45), and 100% (3/3) of each group, respectively (p<0.001).

Figure 1. Composition of subjects and leukopenia occurrence according to NUDT15 activity.

Among patients with leukopenia, 6-TGN levels were significantly lower in patients with low activity compared to intermediate activity (median 91.8 vs. 365.6, p=0.025) and to normal activity (median 91.8 vs. 308.3 pmol/8×10⁸ RBC, p=0.024).

Figure 2. 6-TGN levels according to NUDT15 activity in patients with leukopenia.

According to multivariable logistic regression, NUDT15 polymorphism was the only factor associated with leukopenia (odds ratio=4.719, 95% confidence interval=1.986–11.214, p<0.001). Among patients with NUDT15 variants, no significant difference was observed in 6-TGN levels between patients with and without leukopenia (median 343.9 vs. 273.1 pmol/8×10⁸ RBC, p=0.088).

Conclusion

NUDT15 polymorphism is the major factor associated with thiopurine-related leukopenia in Korean paediatric IBD patients under AZA treatment, which is independent of 6-TGN levels. Genetic evaluation of the NUDT15 gene is required in order to prevent leukopenia during AZA treatment.

Posted in: Poster presentations: Genetics (2017)