Genetically Determined Serum Calcium Levels and Markers of Ventricular Repolarization: A Mendelian Randomization Study in the UK Biobank.
action potential
calcium
cardiovascular diseases
electrocardiography
electrolyte
Journal
Circulation. Genomic and precision medicine
ISSN: 2574-8300
Titre abrégé: Circ Genom Precis Med
Pays: United States
ID NLM: 101714113
Informations de publication
Date de publication:
06 2021
06 2021
Historique:
pubmed:
23
4
2021
medline:
15
2
2022
entrez:
22
4
2021
Statut:
ppublish
Résumé
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.
Sections du résumé
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.
Identifiants
pubmed: 33887147
doi: 10.1161/CIRCGEN.120.003231
pmc: PMC8208093
mid: EMS124343
doi:
Substances chimiques
Calcium
SY7Q814VUP
Types de publication
Clinical Trial
Journal Article
Multicenter Study
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
e003231Subventions
Organisme : Medical Research Council
ID : MC_PC_17228
Pays : United Kingdom
Organisme : British Heart Foundation
ID : FS/16/30/32162
Pays : United Kingdom
Organisme : Medical Research Council
ID : MR/N025083/1
Pays : United Kingdom
Organisme : Medical Research Council
ID : MR/R017468/1
Pays : United Kingdom
Organisme : Medical Research Council
ID : MC_QA137853
Pays : United Kingdom
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