慢性淋巴细胞白血病（CLL）患者使用伊布替尼治疗可能会出现心血管副作用（CVSEs）。CVSEs的分子决定因素尚未完全阐明。我们对布氏酪氨酸激酶（BTK）信号通路中的遗传多态性进行了研究，以探究其与伊布替尼相关的CVSEs的关联。我们对50名新诊断或复发的CLL患者进行了回顾性/前瞻性的药物基因组学观察研究，这些患者连续至少6个月每天使用起始剂量为420 mg的伊布替尼。10名患者（20%）中出现了CVSEs，主要为心房颤动和高血压，其中4人停止了治疗。我们从所有50名患者的颊粘膜拭子中提取了DNA，并使用定制的下一代测序面板对GATA4、SGK1、KCNQ1、KCNQ1、NPPA和SCN5A的40个单核苷酸多态性进行了基因分型。我们进行了单变量和多变量的 logistic 回归分析，以确定与ibrutinib相关的CVSEs发生率相关的遗传和临床因素。GATA4 rs804280 AA（P = 0.043）、KCNQ1 rs163182 GG（P = 0.036）和KCNQ1 rs2237895 AA（P = .023）基因型在单变量分析中与ibrutinib相关的CVSEs相关。根据多元分析，高遗传风险评分，即至少具有这些基因型之一的存在，与CVSEs的患病率增加了11.5倍（P = 0.019；95% CI，1.79-119.73）。我们的发现提示了CLL中ibrutinib相关的CVSEs可能存在的遗传决定因素。如果在更大的研究中验证，针对GATA4和KCNQ1多态性的治疗前药物基因测试可能成为个体化CLL治疗选择或早期风险缓解策略的有用临床工具。

Patients with chronic lymphocytic leukemia (CLL) treated with ibrutinib are at risk of developing cardiovascular side effects (CVSEs). The molecular determinants of CVSEs have not been fully elucidated. We interrogated genetic polymorphisms in the Bruton Tyrosine Kinase (BTK) signaling pathway for their association with ibrutinib-related CVSEs.We conducted a retrospective/prospective observational pharmacogenetic study of 50 patients with newly diagnosed or relapsed CLL who received ibrutinib at a starting daily dose of 420 mg for at least six months. CVSEs, primarily atrial fibrillation and hypertension, occurred in ten patients (20%), of whom four discontinued therapy. DNA was isolated from buccal swabs of all 50 patients and genotyped for 40 single nucleotide polymorphisms in GATA4, SGK1, KCNQ1, KCNA4, NPPA, and SCN5A using a customized next generation sequencing panel. Univariate and multivariate logistic regression analysis were performed to determine genetic and clinical factors associated with the incidence of ibrutinib-related CVSEs.GATA4 rs804280 AA (P =.043), KCNQ1 rs163182 GG (P =.036) and KCNQ1 rs2237895 AA (P =.023) genotypes were univariately associated with ibrutinib-related CVSEs. Based on multivariate analysis, a high genetic risk score, defined as the presence of at least two of these genotypes, was associated with 11.5-fold increased odds of CVSEs (P =.019; 95% CI, 1.79-119.73).Our findings suggest possible genetic determinants of ibrutinib-related CVSEs in CLL. If replicated in a larger study, pre-treatment pharmacogenetic testing for GATA4 and KCNQ1 polymorphisms may be a useful clinical tool for personalizing treatment selection for CLL and/or instituting early risk-mitigation strategies.