在患有慢性淋巴细胞白血病的患者中,与易布鲁替尼相关的心血管副作用的遗传预测因素
Issam S Hamadeh1, Jai N Patel1, Ryan Jacobs2
1Department of Cancer Pharmacology and Pharmacogenomics, Atrium Health Levine Cancer Institute, Charlotte, North Carolina.
在Ibrutinib治疗的慢性淋巴细胞白血病 (CLL) 患者中,GATA4和KCNQ1的遗传变异与心血管副作用 (CVSE) 有关. 药物遗传测试可以个性化治疗并减轻风险.
科学领域:
- 药物基因组学 药物基因组学
- 在瘤学瘤学.
- 心脏病学 心脏病学
背景情况:
- 患有慢性淋巴细胞白血病 (CLL) 的患者接受ibrutinib治疗,面临心血管副作用 (CVSE) 的风险.
- 导致这些CVSE的潜在遗传因素在很大程度上是未知的.
- 研究布鲁顿氨酸激酶 (BTK) 信号通路中的遗传多态性对于理解与ibrutinib相关的CVSE至关重要.
研究的目的:
- 为了确定与患有慢性淋巴细胞白血病 (CLL) 接受ibrutinib治疗的患者心血管副作用 (CVSE) 的发展相关的遗传多态性.
- 探索布鲁顿氨酸激酶 (BTK) 信号通路在调解ibrutinib诱导的CVSE中的作用.
- 建立一个潜在的遗传风险评分来预测CLL患者的CVSE.
主要方法:
- 一项回顾性/前性观察性药物遗传学研究,涉及50名用ibrutinib治疗的CLL患者.
- 使用下一代测序,从口腔拭子中分离DNA,对40个单核酸多态基因 (SNPs) 进行基因定型,包括GATA4,SGK1,KCNQ1,KCNA4,NPPA和SCN5A等基因.
- 单变量和多变量逻辑回归分析以确定遗传因素和CVSE发病率之间的关联.
主要成果:
- 10名患者 (20%) 患有CVSE,主要是心房动和高血压.
- 特定的基因型,包括GATA4 rs804280 AA,KCNQ1 rs163182 GG和KCNQ1 rs2237895 AA,显示与易布鲁替尼相关的CVSE无变异关联.
- 通过至少两种特定基因型的存在来定义的高遗传风险得分与患有CVSE的几率增加了11.5倍 (P = 0.019).
结论:
- 在GLL患者中,GATA4和KCNQ1的遗传变异可能是IBRUTINIB相关心血管副作用的重要决定因素.
- 治疗前对这些多态的药物遗传测试可以帮助个性化治疗策略.
- 未来需要进行更大规模的研究来验证这些发现,并实施早期风险减轻策略,以治疗ibrutinib的CLL患者.
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