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P154 Complete sequence-based NUDT15 and TPMT variants for predicting thiopurine-induced leukopenia in patients with Crohn's disease

Kim T.J., Kim E.R., Hong S.N., Chang D.K., Kim Y.-H.

Samsung Medical Center, Seoul, South Korea

Background

Thiopurine-induced leukopenia is a life-threatening complication in Asians. Other than previously known thiopurine S-methyltransferase (TPMT) mutation, the NUDT15 genetic variant was recently identified to have a strong association with thiopurine-induced leukopenia. We investigated the association of NUDT15, TPMT, metabolites of thiopurines on leukopenia in patients with Crohn's disease (CD).

Methods

We investigated the data of 168 adult patients with CD undergoing thiopurine treatment. Clinical evaluation and laboratory examinations were performed every 1–3 months. We carried out a complete sequencing analysis for evaluating NUDT15 and TPMT variants and measured thiopurine metabolites levels.

Results

Of 168 patients, 34 patients (20.2%) had NUDT15 variant alleles. NUDT15 heterozygous variants were found in 28 patients (16.7%) and NUDT15 homozygous variants were found in 6 patients (3.6%). Among the 168 patients, 35 (20.8%) patients experienced leukopenia during first year of thiopurine treatment. NUDT15 variant types were strongly associated with developing leukopenia [10.9% wild type as reference; 48.5% heterozygous variant genotype; 100% homozygous variant genotype, odds ratio (OR) 3.44 (95% CI, 1.21–9.78)].

Table 1. The risk of leukopenia according to NUDT15 and TPMT genotype

Number of participantsNumber of early leukopenia (0–8 weeks)Number of leukopenia (0–48 weeks)Early leukopenia (0–8 weeks), OR (95% CI)Leukopenia (0–48 weeks), OR (95% CI)
NUDT15
Wild1291 (0.8%)14 (10.9%)1.00 (reference)1.00 (reference)
Heterozygous variant338 (24.2%)15 (48.5%)26 (2.81–241.10)3.44 (1.21–9.78)
Homozygous variant66 (100%)6 (100%)
TPMT
Wild16114 (8.7%)34 (21.1%)1.00 (reference)1.00 (reference)
Variant71 (14.3%)1 (14.3%)1.89 (0.21–9.98)0.58 (0.07–4.96)

However, TPMT genotype was not associated with developing leukopenia (OR 0.58, 95% CI 0.07–4.96). Patients with NUDT15 homozygous variant genotype developed severe early leukopenia with average 88.2% (range, 84–94%) reduction from baseline WBC count at 4 weeks.

Figure 1. WBC count as a percentage of baseline at 4 weeks after thiopurines treatment.

In subgroup of NUDT15 variant type, there was no significant difference of 6-TGN levels between patients with and without leukopenia [298.5 (205–407) vs. 280.8 (174–327) pmol/8×108 RBC, p=0.344].

Table 2. Thiopurine metabolites levels and thiopurine-induced leukopenia in NUDT15 variant genotype subgroup

NUDT15 variant type (n=22)p-value
Leukopenia (n=12)Normal (n=10)
6-TGN (pmol/8×108 RBC)298.5 (205–407)280.8 (174–327)0.344
6-MMPN (pmol/8×108 RBC)625 (352–780)406.7 (212–745)0.124

Conclusion

This is the first complete sequence-based analysis for NUDT15 variants in Asian populations. Our findings suggest that NUDT15 genotype should be detected rather than TPMT before initiating thiopurines. Thiopurines treatment should not be recommended to patients with NUDT15 homozygous variant genotype due to severe early leukopenia.