Practice Update: Cardiology

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Association of Genetic Variants Related to
Serum Calcium Levels With Coronary Artery
Disease and Myocardial Infarction
JAMA: The Journal of the American Medical Association
Take-home message
• This study evaluated single-nucleotide polymorphisms associated with serum
calcium levels to determine risk for CAD and MI related to these genetic markers.
The results revealed that an increase in serum calcium levels due to genetic
variations over a lifetime were associated with an increased risk of CAD and MI.
• While a genetic predisposition to elevated serum calcium levels poses an increased
CAD risk, the study was unable to make an association between calcium supple-
mentation and increased CAD or MI risk.
Abstract
IMPORTANCESerum 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 analy-
ses were performed using summary statistics
obtained for single-nucleotide polymorphisms
(SNPs) identified from a genome-wide associa-
tion 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 associa-
tion meta-analysis (N=up to 184 305 individuals)
that included cases (individuals with CAD and
myocardial infarction) and noncases, with base-
line 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 cal-
cium, 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 out-
comes were the odds of CAD and myocardial
infarction.
RESULTS Among the mendelian randomized ana-
lytic sample of 184 305 individuals (60 801 CAD
cases [approximately 70%with myocardial infarc-
tion] 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
weightedmeta-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 predis-
position 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 medi-
um-term calcium supplementation is unknown.
Association of genetic variants related to
serum calcium levels with coronary artery dis-
ease and myocardial infarction. JAMA 2017
Jul 25;318(4)371-380, SC Larsson, S Burgess, K
Michaëlsson.
COMMENT
By Paul D Thompson MD
Is there a bone to pick with calcium supplementation?
Twenty percent of American adults take
calcium (Ca) supplements, but is this
good for the heart? Ca supplementation
in cross-sectional studies has been asso-
ciated with an increased risk of coronary
artery disease (CAD), especially myocar-
dial infarction (MI). Randomized clinical
trials are the best strategy to determine
the risk and benefits of a potentially ther-
apeutic intervention. A meta-analysis of
nine randomized controlled trials of Ca
supplementation with or without vita-
min D suggested a 24% increase in CAD
risk with Ca, but these results have been
questioned, and meta-analyses have their
own limitations. So, in the absence of a
widely accepted clinical trial–based con-
clusion, perhaps the next best approach
is a “mendelian randomization” study.
Mendelian randomization studies eval-
uate the effect of an intervention, in this
case increases in blood Ca, by examining
what happens to individual with genetic
variants that increase Ca levels.
Larsson and colleagues used this
approach to examine the association of
CAD with six genes regulating serum Ca.
They found that having genes associated
with a predicted 0.5% increase in blood
Ca was associated with a 25% increase
in CAD risk (95% CI, 8%–45%) and a 24%
increase in MI risk (CI, 5%–46%). Several
possible mediating mechanisms exist. Ca
could increase coronary calcium, alter
the coagulation cascade where Ca has
prominent roles, or alter the arterial wall
calcium-sensing receptor thereby alter-
ing downstream gene expression.
These results are provocative and add to
the concern raised by the cross-sectional
and prospective studies of Ca supple-
mentation. Patients and clinicians need to
balance these concerns with other con-
cerns such as the risk of osteoporosis.
Right now, there is only smoke around
the Ca supplementation concerns, but,
where there is smoke, there is usually fire.
Dr Thompson is Physician
Co-Director of the Hartford
Healthcare Cardiovascular
Institute, Hartford, and
Professor of Medicine,
University of Connecticut,
Storrs, Connecticut.
EDITOR’S PICKS 9
VOL. 2 • NO. 2 • 2017