European journal of clinical pharmacology · 2026
Pharmacogenomic screening strategy and indicative screening efficiency for antithyroid drug-induced agranulocytosis in the Southern Han Chinese.
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Ma Li, Ke Sujie, Huang Peiji, Chen Yao, Lin Qian, Lin Menghua, He Guanlian, Zou Laiyu, Chen Xiaoling, Liu Xiaoying, Liu Libin, Wang Lijing
Аннотация
PURPOSE: Antithyroid drug-induced agranulocytosis (ATDIA) is a life-threatening adverse drug reaction with strong population-specific genetic predispositions. This study aimed to develop a pharmacogenomic risk-stratification model and to evaluate the indicative screening efficiency of targeted pretherapeutic screening in the mainland Southern Han Chinese population.
METHODS: This retrospective case-control study enrolled 171 patients with Graves' disease: 36 with ATDIA, 59 with antithyroid drug-induced neutropenia (ATDIN), and 76 ATD-tolerant controls. High-throughput genotyping of HLA-B, HLA-DRB1, and 32 candidate single nucleotide polymorphisms (SNPs) was performed. Genetic associations, predictive modeling with 1,000-resample bootstrap internal validation, and indicative economic impact estimations were evaluated.
RESULTS: HLA-B*38:02 (OR = 48.667, 95% CI = 12.660-187.088) and HLA-DRB1*08:03 (OR = 11.698, 95% CI = 4.452-30.737) were strongly associated with ATDIA, but not with ATDIN. Six independent SNPs remained significantly associated with ATDIA. A multifactorial predictive model incorporating HLA-B*38:02, HLA-DRB1*08:03, and rs1811197 showed preliminary predictive potential (AUC = 0.909). Bootstrap internal validation supported the stability of the overall predictive performance (empirical P < 0.05). Indicative screening efficiency estimation yielded a number needed to screen (NNS) of 252 to prevent one case of ATDIA.
CONCLUSION: ATDIA and ATDIN possess distinct genetic mechanisms. Pretherapeutic screening using this population-specific, multi-locus model may offer a preliminary but promising pharmacovigilance strategy for preventing life-threatening ATDIA.
TRIAL REGISTRATION: Chinese Clinical Trial Registry (ChiCTR1900028690, registered on 31 December 2019).
METHODS: This retrospective case-control study enrolled 171 patients with Graves' disease: 36 with ATDIA, 59 with antithyroid drug-induced neutropenia (ATDIN), and 76 ATD-tolerant controls. High-throughput genotyping of HLA-B, HLA-DRB1, and 32 candidate single nucleotide polymorphisms (SNPs) was performed. Genetic associations, predictive modeling with 1,000-resample bootstrap internal validation, and indicative economic impact estimations were evaluated.
RESULTS: HLA-B*38:02 (OR = 48.667, 95% CI = 12.660-187.088) and HLA-DRB1*08:03 (OR = 11.698, 95% CI = 4.452-30.737) were strongly associated with ATDIA, but not with ATDIN. Six independent SNPs remained significantly associated with ATDIA. A multifactorial predictive model incorporating HLA-B*38:02, HLA-DRB1*08:03, and rs1811197 showed preliminary predictive potential (AUC = 0.909). Bootstrap internal validation supported the stability of the overall predictive performance (empirical P < 0.05). Indicative screening efficiency estimation yielded a number needed to screen (NNS) of 252 to prevent one case of ATDIA.
CONCLUSION: ATDIA and ATDIN possess distinct genetic mechanisms. Pretherapeutic screening using this population-specific, multi-locus model may offer a preliminary but promising pharmacovigilance strategy for preventing life-threatening ATDIA.
TRIAL REGISTRATION: Chinese Clinical Trial Registry (ChiCTR1900028690, registered on 31 December 2019).