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Genetically Determined Serum Calcium Levels and Markers of Ventricular Repolarization: A Mendelian Randomization
William J Young1,2, Helen R Warren1,3, Dennis O Mook-Kanamori4,5
1Clinical 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.
Insights
Lower serum calcium levels are causally linked to prolonged ventricular repolarization, specifically longer QT and JT intervals. This finding suggests that modulating calcium may impact cardiovascular disease risk.
Area of Science:
- Cardiovascular Genetics
- Electrophysiology
- Metabolic Health
Background:
- Electrocardiogram (ECG) markers of ventricular depolarization and repolarization are linked to arrhythmia and sudden cardiac death risk.
- Previous research suggests lower serum calcium is associated with prolonged QT and JT intervals in the general population.
Purpose of the Study:
- To investigate the causal effect of serum calcium on ECG measures using Mendelian randomization (MR).
Main Methods:
- Utilized independent lead variants from a large genome-wide association study for serum calcium (>300,000 participants).
- Performed two-sample MR analyses on 76,226 participants to assess the causal effect of serum calcium on QT, JT, and QRS intervals.
- Conducted sensitivity analyses (MR-Egger, weighted-median, MR-PRESSO) to evaluate pleiotropy.
Main Results:
- A decrease of 0.1 mmol/L in serum calcium was associated with significantly longer QT intervals (3.01 ms) and JT intervals (2.89 ms).
- A weak association was noted for QRS duration.
- Sensitivity analyses confirmed the robustness of the findings.
Conclusions:
- Serum calcium levels have a causal effect on ventricular repolarization in a European-ancestry population.
- Modulating serum calcium concentrations may directly influence cardiovascular disease risk.
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.