Combined Detection of NUDT15 Variants Could Highly Predict Thiopurine-induced Leukopenia in Chinese Patients with Inflammatory Bowel Disease

NUDT15 c.415CT was a novel genetic marker confirmed in our center for thiopurine-induced leukopenia in Chinese inflammatory bowel disease (IBD). For validation, a large cohort study is needed. Meanwhile, the newly discovered NUDT15 coding variants (c.36_37insGGAGTC and c.52 GA) have not been studied in patients with IBD. We aimed to further confirm the influence of 3 NUDT15 variants (c.415CT, c.36_37insGGAGTC, and c.52GA) on thiopurine-induced leukopenia in Chinese patients with IBD.Patients prescribed on thiopurines for at least 2 weeks were recruited from 4 tertiary hospitals. Clinical data were collected. NUDT15 genotypes were determined with polymerase chain reaction-RFLP and sequencing. The interactions between variants and leukopenia were analyzed.A total of 732 patients were included, 177 (24.3%) of whom developed leukopenia. There were strong associations of NUDT15 c.415CT, c.36_37insGGAGTC, and c.52GA with thiopurine-induced leukopenia (P = 1.81 × 10, P = 4.74 × 10 and P = 0.04, respectively), whereas there was no relevance for thiopurine S-methyltransferase genotypes (P = 0.25). The predictive sensitivity of NUDT15 c.415CT was 49.2%, whereas it increased to 55.4% when combined analysis with c.36_37insGGAGTC and c.52GA. Notably, not only the homozygotes with NUDT15 c.415CT but also the heterozygotes both carrying c.415CT and c.52GA developed early leukopenia. The median dosage for NUDT15 c.415CT carriers was significantly lower than that for wild-type (P0.001).We confirmed that NUDT15 c.415CT, c.36_37insGGAGTC, and c.52GA variants were risk factors for thiopurine-induced leukopenia. Combined detection of the 3 variants could increase the predictive sensitivity of thiopurine-induced leukopenia and help to distinguish early leukopenia in heterozygote of c.415CT in Chinese patients with IBD. Treatment monitoring by NUDT15 variants may be promising in individualized therapy.