Clinical Pharmacology Department, William Harvey Research Institute (W.J.Y., H.R.W., J.R., S.v.D., A.T., P.B.M.), Barts and the London School of Medicine and Dentistry, Queen Mary University of London.
Barts Heart Centre, St Bartholomew's Hospital, Barts Health NHS trust (W.J.Y., M.O., P.D.L.).
Circ Genom Precis Med. 2021 Jun;14(3):e003231. doi: 10.1161/CIRCGEN.120.003231. Epub 2021 Apr 22.
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).
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.
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.
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.
心室去极化和复极化的 ECG 标志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，一般人群中血清钙浓度较低与 QT 和 JT 间期延长相关。在这里，我们使用孟德尔随机化（MR）研究血清钙是否是 ECG 测量变化的因果危险因素。
来自 UK Biobank 的超过 300,000 名欧洲血统参与者的新进行的血清钙全基因组关联研究中的独立导联变异用作工具变量。在不参与血清钙全基因组关联研究的 76,226 名参与者中，使用逆加权法进行两样本 MR 分析，以近似血清钙对 QT、JT 和 QRS 间期的因果效应。进行了 MR-Egger、加权中位数估计和 MR 多效性残差和异常值的敏感性分析，以测试是否存在水平多效性。
205 个独立的钙相关导联变异用作 MR 的工具变量。血清钙降低 0.1mmol/L 与 QT 延长（3.01ms[95%CI，2.03 至 3.99]）和 JT 延长（2.89ms[1.91 至 3.87]）相关。QRS 持续时间（仅二次分析）观察到弱关联。所有敏感性分析的结果均一致。
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，血清钙浓度可能稳定且慢性。因此，钙浓度的调节可能直接影响心血管疾病的风险。
