Practice Update: Cardiology

EDITOR’S PICKS 9

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

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. www.practiceupdate.com/c/56387

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

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.

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.

VOL. 2 • NO. 2 • 2017