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Purpose <p>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.</p> Methods <p>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 <i>HLA-B</i>, <i>HLA-DRB1</i>, 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.</p> Results <p><i>HLA-B*38:02</i> (OR = 48.667, 95% CI = 12.660–187.088) and <i>HLA-DRB1*08:03</i> (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 <i>HLA-B*38:02</i>, <i>HLA-DRB1*08:03</i>, and rs1811197 showed preliminary predictive potential (AUC = 0.909). Bootstrap internal validation supported the stability of the overall predictive performance (empirical <i>P</i> &lt; 0.05). Indicative screening efficiency estimation yielded a number needed to screen (NNS) of 252 to prevent one case of ATDIA.</p> Conclusion <p>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.</p> Trial registration <p>Chinese Clinical Trial Registry (ChiCTR1900028690, registered on 31 December 2019).</p>

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Pharmacogenomic screening strategy and indicative screening efficiency for antithyroid drug-induced agranulocytosis in the Southern Han Chinese

  • 期刊论文

  • 发表日期：

    2026年7月11日

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  • Li Ma,
  • Sujie Ke,
  • Peiji Huang,
  • Yao Chen,
  • Qian Lin,
  • Menghua Lin,
  • Guanlian He,
  • Laiyu Zou,
  • Xiaoling Chen,
  • Xiaoying Liu,
  • Libin Liu,
  • Lijing Wang

摘要

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).