一个基于纳米孔测序的药物基因组面板,以个性化结核病药物剂量
Renu Verma1,2,3, Kesia Esther da Silva1, Neesha Rockwood4,5,6
1Division of Infectious Diseases and Geographic Medicine, Stanford University School of Medicine, California, USA.
medRxiv : the preprint server for health sciences
|September 21, 2023
概括
一个新的纳米孔测序面板准确地识别了影响结核病药物代谢的遗传变异. 这使得个性化剂量策略能够改善治疗结果,并减少活跃结核病患者的不良药物反应.
科学领域:
- 药物基因组学 药物基因组学
- 分子诊断学 分子诊断
- 传染性疾病 传染性疾病
背景情况:
- 标准化抗结核病 (TB) 药物剂量产生可变的血药物水平,导致不良反应,延迟反应和复发.
- 遗传突变对结核病药物代谢中个体间的药物动力学变异有显著的贡献.
- 缺乏药物基因组 (PGx) 测定阻碍了个性化的抗结核病药物剂量.
研究的目的:
- 开发一个纳米孔测序面板,用于检测结核病药物代谢中的遗传变异.
- 验证该小组在活跃结核病患者中的表现.
- 根据个人的遗传特征,实现个性化的结核病治疗剂量.
主要方法:
- 开发了一个纳米孔测序面板,针对5个关键药物代谢基因 (异化,利芬,线化,贝达奎林) 的15个单核酸多态 (SNPs).
- 使用1000基因组项目DNA样本 (n=48) 对Illumina测序进行验证.
- 来自南非活跃结核病患者 (n=100) 的DNA测序,以及与异化 (INH) 和利法 (RIF) 药理学参数相关的基因型.
主要成果:
- 该PGx小组证明了100%的一致性与Illumina测序用于变种识别.
- 在临床队列中的99.8%的目标中,实现了高安普利康覆盖率 (>100x).
- 在异化乙化剂状态和异化清除 (p<0.0001) 之间发现了显著的关联.
- 同卵性AADAC rs1803155 G>A替代与利法清除率降低17.3% (p=0.0015) 有关.
结论:
- 使用低成本,便携式纳米孔仪器的向测序可以有效地检测影响结核病药物代谢的多形态.
- 这种方法可以为结核病治疗和预防提供个性化剂量.
- 开发的PGx小组对改善结核病治疗的有效性和安全性充满希望.
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