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Pharmacogenetic Risk Factors for Thiopurine-Induced Leukopenia in Patients with Inflammatory Bowel Disease
Eun Kyung Boo1, Jongwook Yu2, Sohyung Oh2
1Seoul National University Biomedical Informatics (SNUBI), Department of Biomedical Sciences, Seoul National University College of Medicine, Seoul, Korea.
Purpose:
Thiopurines remain an effective treatment for maintaining remission in inflammatory bowel disease (IBD), yet their use is often limited by thiopurine-induced leukopenia (TIL), a potentially life-threatening adverse effect. We aimed to investigate pharmacogenetic associations with TIL in patients with IBD.
Materials And Methods:
We retrospectively analyzed 218 thiopurine-treated patients from two independent IBD cohorts with whole-exome sequencing. Pharmacogenetic subgroups were defined using Clinical Pharmacogenetics Implementation Consortium star allele-based molecular phenotypes or genotype-based classifications. Genetic associations with TIL, defined as white blood cell count ≤3000/µL, were analyzed using Andersen-Gill models adjusted for clinical covariates.
Results:
NUDT15 intermediate metabolizers [hazard ratio (HR) 5.21, p<0.001], poor metabolizers (HR 6.42, p<0.001), and IL6 heterozygotes (HR 4.35, p<0.001) showed reproducible, independent associations with increased TIL risk. Incorporating IL6 into the traditional TPMT/NUDT15 model significantly improved sensitivity (p=0.0156) and negative predictive value (p=0.046).
Conclusion:
Our findings confirm the central role of NUDT15 in TIL susceptibility and identify IL6 as a novel, independent contributor in Korean patients with IBD. Incorporating IL6 into existing pre-emptive pharmacogenetic testing may support safer thiopurine therapy.
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