BACKGROUND & AIM:
Inter-individual variation seen in the thiopurine metabolism is attributed to the genetic variant in Thiopurine methyltransferase (TPMT) gene leading to myelosuppression. In Asians, the thiopurine-induced toxicity is not completely explained by TPMT variants. Literature indicates that a newer genetic variant in nucleoside diphosphate-linked moiety X-type motif 15 (NUDT15) gene is associated with thiopurine intolerance. We aimed to determine the risk allele frequency of NUDT15 genetic variant and it's association with thiopurine-induced toxicity in Indian patients.

METHODS:
In this pilot study, 69 patients on thiopurine therapy were analyzed. The frequencies of thiopurine-induced leukopenia were recorded. NUDT15 (C415T) and TPMT (*2, *3A, *3B & *3C) genotyping were performed using Amplification-refractory mutation system-polymerase chain reaction and Restriction fragment length polymorphism technique. Results validated by DNA sequencing.

RESULTS:
The NUDT15 CC, CT and TT genotypes were found to be 86.9%, 11.5% and 1.5% respectively, whereas TPMT genetic variants were absent. Of 60 patients without NUDT15 variant, none developed leukopenia, whereas of 9 patients with NUDT15 variant, 6 developed leukopenia. (p value <0.0001). The mean thiopurine dose of 1.01 mg/kg/day and 0.73 mg/kg/day for patients with wild and mutant NUDT15 alleles respectively was statistically significant (p < 0.01). The sensitivity and specificity for NUDT15 variant were 100% and 95.2% respectively.

CONCLUSIONS:
The NUDT15 risk allele frequency was 7.2%. 6/69 (8.7%) patients developed leukopenia and harbored NUDT15 variant, thus showing a strong association for thiopurine-induced toxicity. Hence NUDT15 genotyping may be considered before thiopurine therapy in Indian patients.