Association of Genetic Variants Related to Serum Calcium Levels With Coronary Artery Disease and Myocardial Infarction

Abstract

Importance: Serum calcium has been associated with cardiovascular disease in observational studies and evidence from randomized clinical trials indicates that calcium supplementation, which raises serum calcium levels, may increase the risk of cardiovascular events, particularly myocardial infarction.

Objective: To evaluate the potential causal association between genetic variants related to elevated serum calcium levels and risk of coronary artery disease (CAD) and myocardial infarction using mendelian randomization.

Design, setting, and participants: The analyses were performed using summary statistics obtained for single-nucleotide polymorphisms (SNPs) identified from a genome-wide association meta-analysis of serum calcium levels (N = up to 61 079 individuals) and from the Coronary Artery Disease Genome-wide Replication and Meta-analysis Plus the Coronary Artery Disease Genetics (CardiogramplusC4D) consortium's 1000 genomes-based genome-wide association meta-analysis (N = up to 184 305 individuals) that included cases (individuals with CAD and myocardial infarction) and noncases, with baseline data collected from 1948 and populations derived from across the globe. The association of each SNP with CAD and myocardial infarction was weighted by its association with serum calcium, and estimates were combined using an inverse-variance weighted meta-analysis.

Exposures: Genetic risk score based on genetic variants related to elevated serum calcium levels.

Main outcomes and measures: Co-primary outcomes were the odds of CAD and myocardial infarction.

Results: Among the mendelian randomized analytic sample of 184 305 individuals (60 801 CAD cases [approximately 70% with myocardial infarction] and 123 504 noncases), the 6 SNPs related to serum calcium levels and without pleiotropic associations with potential confounders were estimated to explain about 0.8% of the variation in serum calcium levels. In the inverse-variance weighted meta-analysis (combining the estimates of the 6 SNPs), the odds ratios per 0.5-mg/dL increase (about 1 SD) in genetically predicted serum calcium levels were 1.25 (95% CI, 1.08-1.45; P = .003) for CAD and 1.24 (95% CI, 1.05-1.46; P = .009) for myocardial infarction.

Conclusions and relevance: A genetic predisposition to higher serum calcium levels was associated with increased risk of CAD and myocardial infarction. Whether the risk of CAD associated with lifelong genetic exposure to increased serum calcium levels can be translated to a risk associated with short-term to medium-term calcium supplementation is unknown.

Figure 1.. Schematic Diagram of the Mendelian Randomization Assumptions Underpinning a Mendelian Randomization Analysis of the Association Between Serum Calcium Levels and Coronary Artery Disease

SNPs indicate single-nucleotide polymorphisms. The dashed lines represent potential causal associations between variables that would represent violations of the mendelian randomization assumptions. For a formal treatment of the assumptions, see Greenland.

Figure 2.. Data Sources and Analysis Plan Using Mendelian Randomization

BMI indicates body mass index; DIAGRAM, Diabetes Genetics Replication and Meta-analysis; GIANT, Genetic Investigation of Anthropometric Traits; GLGC, Global Lipids Genetics Consortium; ICBP, International Consortium of Blood Pressure; MAGIC, Meta-Analyses of Glucose and Insulin-related traits Consortium; SNPs, single-nucleotide polymorphisms. ^aFor sample sizes of each study, see Methods. ^bAny SNP with pleiotropic effects (ie, associated with more than 1 risk factor) violates the Mendelian randomization assumptions. One SNP (rs780094 in the GCKR gene region) had pleiotropic associations with cardiometabolic risk factors and was excluded, leaving 6 calcium-related SNPs for inclusion in the mendelian randomization analyses. ^cThe estimates for the association of each SNP with coronary artery disease were combined using the inverse-variance weighted method, with summary statistics for coronary artery disease obtained from the CardiogramplusC4D consortium.

Figure 3.. Mendelian Randomization Estimates of the Association Between Genetically Predicted Serum Calcium Levels and Coronary Artery Disease

OR indicates odds ratio; SNP, single-nucleotide polymorphisms. Data markers indicate the OR for the association of each calcium-associated SNP with coronary artery disease. Size of the data marker is inversely proportional to variance of the estimate. Error bars indicate 95% CIs.