Department of Epidemiology, Erasmus MC, University Medical Center, Rotterdam, The Netherlands.
Department of Internal Medicine, Catharina Hospital, Eindhoven, The Netherlands.
Br J Clin Pharmacol. 2024 Sep;90(9):2159-2165. doi: 10.1111/bcp.16130. Epub 2024 May 31.
Common genetic variations in the nitric oxide synthase-1 adaptor protein (NOS1AP) gene are associated with QT-interval prolongation. In a previous study, we observed an association between the rs10494366 variant of this gene and an increased QT-interval shortening in digoxin users. As QT-interval shortening is a risk factor for sudden cardiac death (SCD), in this study, we investigated whether the association between digoxin use and risk of SCD differs in participants with different NOS1AP rs10494366 genotypes.
We included 11 377 individuals from the prospective population-based cohort of the Rotterdam Study. We used Cox proportional hazard regression analysis with digoxin as time-dependent exposure to estimate the associations between current digoxin use and the risk of SCD among different rs10494366 genotype groups in the adjusted models. We also studied whether such an association was dose-dependent, comparing high dosage (≥ 0.250 mg), moderate dosage (0.125 mg ≤ dose< 0.250 mg) and low dosage (< 0.125 mg) digoxin users with non-users.
The median baseline age of the total study population was 62 (interquartile range [IQR] 58-71) years. The cumulative incidence of SCD was 4.1% (469 cases), and among them, 74 (15.7%) individuals were current digoxin users at the time of death, during a median follow-up of 11.5 (IQR 6.5-17) years. Current digoxin users had an increased risk of SCD (multivariable adjusted model hazard ratio [HR]: 3.07; 95% confidence interval [CI]: 2.38-3.98), with no significant differences between the three genotype groups. The adjusted HRs were 4.03 [95% CI: 1.98-8.21] in the minor homozygous GG, 3.46 [95% CI: 2.37-5.04] in the heterozygous TG and 2.56 [95%CI: 1.70-3.86] in the homozygous TT genotype groups. Compared to low- and moderate-dose, high-dose digoxin users with GG genotype had the highest risk of SCD (HR: 5.61 [95% CI: 1.34-23.47]).
Current use of digoxin is associated with a significantly increased risk of SCD. The NOS1AP gene rs10494366 variant did not modify the digoxin-associated risk of SCD in a population of European ancestry.
一氧化氮合酶-1 衔接蛋白（NOS1AP）基因中的常见遗传变异与 QT 间期延长有关。在之前的一项研究中，我们观察到该基因的 rs10494366 变体与地高辛使用者 QT 间期缩短增加之间存在关联。由于 QT 间期缩短是心源性猝死（SCD）的危险因素，因此在本研究中，我们研究了地高辛使用与 SCD 风险之间的关联是否因 NOS1AP rs10494366 基因型不同而不同。
我们纳入了前瞻性基于人群的鹿特丹研究的 11377 名参与者。我们使用 Cox 比例风险回归分析，以地高辛作为时间依赖性暴露，在调整模型中估计不同 rs10494366 基因型组中当前地高辛使用与 SCD 风险之间的关联。我们还研究了这种关联是否存在剂量依赖性，比较了高剂量（≥0.250mg）、中剂量（0.125mg≤剂量<0.250mg）和低剂量（<0.125mg）地高辛使用者与非使用者之间的差异。
总研究人群的中位基线年龄为 62（四分位距[IQR]58-71）岁。SCD 的累积发生率为 4.1%（469 例），其中 74 例（15.7%）在死亡时正在使用地高辛，中位随访时间为 11.5（IQR 6.5-17）年。当前使用地高辛的患者 SCD 风险增加（多变量调整模型的危险比[HR]：3.07；95%置信区间[CI]：2.38-3.98），但在三个基因型组之间没有显著差异。在 GG 纯合子的 HR 为 4.03（95%CI：1.98-8.21），在 TG 杂合子的 HR 为 3.46（95%CI：2.37-5.04），在 TT 纯合子的 HR 为 2.56（95%CI：1.70-3.86）。与低剂量和中剂量相比，GG 基因型的高剂量地高辛使用者 SCD 风险最高（HR：5.61 [95%CI：1.34-23.47]）。
当前使用地高辛与 SCD 风险显著增加相关。NOS1AP 基因 rs10494366 变体在欧洲血统人群中并未改变地高辛相关 SCD 的风险。
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