AUTHOR=Khoo Xin-Hui , Wong Shin Yee , Ibrahim Nik Razima Wan , Ng Ruey Terng , Chew Kee Seang , Lee Way Seah , Wong Zhi Qin , Raja Ali Raja Affend , Shahrani Shahreedhan , Leow Alex Hwong-Ruey , Hilmi Ida Normiha 

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

JOURNAL=Frontiers in Medicine

VOLUME=9

YEAR=2022

URL=https://www.frontiersin.org/journals/medicine/articles/10.3389/fmed.2022.880937

DOI=10.3389/fmed.2022.880937

ISSN=2296-858X

ABSTRACT=<sec><title>Background and Aims</title><p>Thiopurines, which are immunosuppressive drugs for maintaining remission for inflammatory bowel disease, are known to cause myelotoxicity in patients with Nudix Hydroxylase 15 (<italic>NUDT15</italic>) genetic variants in some Asian countries with monoethnic populations. We aimed to investigate the association of <italic>NUDT15</italic> variants with leukopenia in a multiethnic population in Southeast Asia.</p></sec><sec><title>Methods</title><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 (<italic>TPMT</italic>) and <italic>NUDT15</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.</p></sec><sec><title>Results</title><p>In this study, 19 (18.6%) of the 102 patients who had adequate thiopurine therapy experienced leukopenia, 11 patients (57.9%) had <italic>NUDT15</italic> c.415C &gt; T variants, 2 patients (10.5%) had <italic>NUDT15</italic> c.52G &gt; A variants while one (5.3%) had a <italic>TPMT</italic> variation. Individually, <italic>NUDT15</italic> c.415C &gt; T had a sensitivity and specificity of 57.9% and 94.0% (odds ratio [<italic>OR</italic>] = 21.45, 95% <italic>CI</italic> 5.94–77.41, <italic>p</italic> &lt; 0.001), respectively, for predicting thiopurine-induced leukopenia, while <italic>NUDT15</italic> c.52G &gt; A was only observed in patients with leukopenia. As compared with patients with wild-type <italic>NUDT15</italic>, both <italic>NUDT15</italic> variations had a combined sensitivity and specificity of 68.4% and 94%, respectively (<italic>OR</italic> = 33.80, 95% <italic>CI</italic> 8.99–127.05, <italic>p</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; <italic>p</italic> = 0.045). Sub-group analysis showed that both <italic>NUDT15</italic> variations were strongly associated with leukopenia among the Chinese and Indians but not among the Malays.</p></sec><sec><title>Conclusion</title><p><italic>Nudix Hydroxylase 15</italic> variants strongly predicted thiopurine-induced leukopenia across a multiethnic Southeast Asian population, particularly among the Chinese and Indians.</p></sec>