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

• Published in: Frontiers in medicine Vol. 9; p. 880937
• Main Authors: 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
• Format: Journal Article
• Language: English
• Published: Frontiers Media S.A 05.08.2022
• Subjects: genetic polymorphism; inflammatory bowel disease; leukopenia; Medicine; NUDT15; thiopurines
• ISSN: 2296-858X; 2296-858X
• DOI: 10.3389/fmed.2022.880937

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