Background:ECG markers of ventricular depolarization and repolarization are associated with an increased risk of arrhythmia and sudden cardiac death. Our prior work indicated lower serum calcium concentrations are associated with longer QT and JT intervals in the general population. Here, we investigate whether serum calcium is a causal risk factor for changes in ECG measures using Mendelian randomization (MR).Methods:Independent lead variants from a newly performed genome-wide association study for serum calcium in >300 000 European-ancestry participants from UK Biobank were used as instrumental variables. Two-sample MR analyses were performed to approximate the causal effect of serum calcium on QT, JT, and QRS intervals using an inverse-weighted method in 76 226 participants not contributing to the serum calcium genome-wide association study. Sensitivity analyses including MR-Egger, weighted-median estimator, and MR pleiotropy residual sum and outlier were performed to test for the presence of horizontal pleiotropy.Results:Two hundred five independent lead calcium-associated variants were used as instrumental variables for MR. A decrease of 0.1 mmol/L serum calcium was associated with longer QT (3.01 ms [95% CI, 2.03 to 3.99]) and JT (2.89 ms [1.91 to 3.87]) intervals. A weak association was observed for QRS duration (secondary analyses only). Results were concordant in all sensitivity analyses.Conclusions:These analyses support a causal effect of serum calcium levels on ventricular repolarization, in a middle-aged population of European-ancestry where serum calcium concentrations are likely stable and chronic. Modulation of calcium concentration may, therefore, directly influence cardiovascular disease risk.

中文翻译：

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基因决定的血清钙水平和心室复极标志物：英国生物银行的孟德尔随机研究

背景：心室除极和复极的心电图标记物与心律失常和心源性猝死的风险增加相关。我们之前的研究表明，一般人群中较低的血清钙浓度与较长的 QT 和 JT 间期相关。在这里，我们使用孟德尔随机化 (MR) 方法研究血清钙是否是心电图测量变化的因果危险因素。方法：来自一项新进行的血清钙全基因组关联研究的独立先导变异，研究对象为超过 300 000 名欧洲血统参与者。英国生物银行被用作工具变量。对未参与血清钙全基因组关联研究的 76 226 名参与者进行了两样本 MR 分析，以使用反加权方法来估计血清钙对 QT、JT 和 QRS 间期的因果影响。进行敏感性分析，包括 MR-Egger、加权中值估计量、MR 多效性残差和和离群值，以测试水平多效性的存在。结果：使用 205 个独立的铅钙相关变异作为 MR 的工具变量。血清钙降低 0.1 mmol/L 与较长的 QT（3.01 ms [95% CI，2.03 - 3.99]）和 JT（2.89 ms [1.91 - 3.87]）间隔相关。观察到 QRS 持续时间的弱关联（仅二次分析）。所有敏感性分析的结果都是一致的。结论：这些分析支持血清钙水平对心室复极的因果影响，在欧洲血统的中年人群中，其血清钙浓度可能是稳定且长期的。因此，钙浓度的调节可能直接影响心血管疾病的风险。