Nudix Hydroxylase 15 Mutations Strongly Predict Thiopurine-Induced Leukopenia Across Different Asian Ethnicities: Implications for Screening in a Diverse Population

<jats:sec><jats:title>Background and Aims</jats:title>
<jats:p>Thiopurines, which are immunosuppressive drugs for maintaining remission for inflammatory bowel disease, are known to cause myelotoxicity in patients with Nudix Hydroxylase 15 (<jats:italic>NUDT15</jats:italic>) genetic variants in some Asian countries with monoethnic populations. We aimed to investigate the association of <jats:italic>NUDT15</jats:italic> variants with leukopenia in a multiethnic population in Southeast Asia.</jats:p></jats:sec>
<jats:sec><jats:title>Methods</jats:title>
<jats:p>Patients with a confirmed diagnosis of inflammatory bowel disease were recruited. We collected demographic and clinical characteristics and whole blood counts before and after initiating thiopurines. Thiopurine S-methyltransferase (<jats:italic>TPMT</jats:italic>) and <jats:italic>NUDT15</jats:italic> genotypes were analyzed with the single nucleotide polymorphisms (SNPs) genotyping assay. Leukopenia was defined as a white blood cell (WBC) count &lt; 3,000/μl.</jats:p></jats:sec>
<jats:sec><jats:title>Results</jats:title>
<jats:p>In this study, 19 (18.6%) of the 102 patients who had adequate thiopurine therapy experienced leukopenia, 11 patients (57.9%) had <jats:italic>NUDT15</jats:italic> c.415C &gt; T variants, 2 patients (10.5%) had <jats:italic>NUDT15</jats:italic> c.52G &gt; A variants while one (5.3%) had a <jats:italic>TPMT</jats:italic> variation. Individually, <jats:italic>NUDT15</jats:italic> c.415C &gt; T had a sensitivity and specificity of 57.9% and 94.0% (odds ratio [<jats:italic>OR</jats:italic>] = 21.45, 95% <jats:italic>CI</jats:italic> 5.94–77.41, <jats:italic>p</jats:italic> &lt; 0.001), respectively, for predicting thiopurine-induced leukopenia, while <jats:italic>NUDT15</jats:italic> c.52G &gt; A was only observed in patients with leukopenia. As compared with patients with wild-type <jats:italic>NUDT15</jats:italic>, both <jats:italic>NUDT15</jats:italic> variations had a combined sensitivity and specificity of 68.4% and 94%, respectively (<jats:italic>OR</jats:italic> = 33.80, 95% <jats:italic>CI</jats:italic> 8.99–127.05, <jats:italic>p</jats:italic> &lt; 0.001), for predicting thiopurine-induced leukopenia as well as a shorter onset to leukopenia (median onset [months] 2.0 vs. 5.5; <jats:italic>p</jats:italic> = 0.045). Sub-group analysis showed that both <jats:italic>NUDT15</jats:italic> variations were strongly associated with leukopenia among the Chinese and Indians but not among the Malays.</jats:p></jats:sec>
<jats:sec><jats:title>Conclusion</jats:title>
<jats:p><jats:italic>Nudix Hydroxylase 15</jats:italic> variants strongly predicted thiopurine-induced leukopenia across a multiethnic Southeast Asian population, particularly among the Chinese and Indians.</jats:p></jats:sec>