Genetic Predisposition to Elevated Serum Calcium Linked to CAD, MI

Neil Osterweil

July 26, 2017

STOCKHOLM, SWEDEN — Individuals with a genetic tendency to have higher serum levels of calcium than the general population are at increased risk for both coronary artery disease (CAD) and MI, a new study suggests[1].

The findings are from a Mendelian randomization study of more than 180,000 cases and controls.

"Our study examined whether genetic variants that are associated with higher calcium levels in the blood are related to increased risk of coronary artery disease and myocardial infarction," lead investigator Dr Susanna Larson (Karolinska Institute, Stockholm) told | Medscape Cardiology.

By using genetic variants as "proxies" for lifelong elevated serum calcium levels, Larson said, their study reduced potential confounding that may have biased the results from previous observational studies based on measured serum calcium from other risk factors.

"Our finding indicates that lifelong high levels of calcium in the bloodstream may be causally associated with increased risk of coronary artery disease and myocardial infarction. Thus, having excess calcium in the bloodstream for a long time may be harmful," she said in an email.

It's less clear, however, whether short- or medium-term calcium supplementation have similar effects on coronary artery disease risk, Larsson added.

The study is published in the July 25, 2017 issue of the Journal of the American Medical Association.

Marriage of Genetics and Epidemiology

Mendelian randomization is a mash-up of genetics and traditional epidemiology that uses genes with known functions as instrumental variables to examine whether potentially modifiable characteristics could have causal effects.

Larsson et al used the techniques to probe the potential causal association between elevated serum calcium and CAD/MI.

They obtained information on known calcium-related single-nucleotide polymorphisms (SNPs) from a genomewide association meta-analysis including data on serum calcium levels on up to 61,709 individuals and from the Coronary Artery Disease Genome-wide Replication and Meta-analysis Plus the Coronary Artery Disease Genetics (CardiogramplusC4D) consortium's genomewide association meta-analysis containing data from 1000 genomes on up to 184,306 individuals.

The latter data set included baseline data from 1948 populations from around the world on both 60,801 patients with CAD (cases, approximately 70% of whom had MIs) and 123,504 others without cardiovascular disease or events (noncases).

They found that among the cases and noncases, six SNPs that are related to serum calcium levels but are not pleiotropically associated with other genetic traits that might be potential confounders (eg, cholesterol levels) explained approximately 0.8% of variance in serum calcium levels.

The investigators then conducted an inverse-variance weighted meta-analysis technique combining the estimates of the six SNPs and determined that for every 0.5-mg/dL increase in genetically predicted serum calcium levels—about one standard deviation—the odds ratio (OR) for CAD was 1.25 (P=0.003) and the OR for MI was 1.24 (P=0.009).

Larsson and colleagues noted that the risk increase with serum calcium is on a par with that previously reported for triglyceride levels (OR 1.28) and weaker than that seen in genetic-association studies of LDL cholesterol (OR 1.68), systolic and diastolic blood pressure (OR 1.49), or body-mass index (OR 1.40).

They acknowledged that the study was limited by overrepresentation in the sample of a genetic variant in the gene CASR, a partial overlap between the calcium meta-analysis and case/noncase CAD sample, lack of information on the sex or age of individuals, and absence of a replication data set containing a large number of CAD cases.

A Bigger Role for Calcium?

"I thought this study was really interesting," commented Dr Deepak Bhatt (Brigham and Women's Hospital, Boston) in an interview with / Medscape Cardiology.

"First of all, Mendelian randomization is a powerful technique: it has been shown successfully to corroborate that LDL cholesterol is a risk factor, that's it not just a risk marker. You can look at a population and say high LDL levels predict risk, but Mendelian randomization allows us to go further and say it's not just a marker of risk, it's actually along the causal pathway."

The findings of Larsson's group are intriguing, Bhatt said "because the study suggests that calcium levels might actually be on the causal pathway to atherosclerosis," rather than a serum bystander that gets ensnared by developing atherosclerotic plaques.

The study results are informative but won't change clinical practice, said Bhatt's colleague, Dr Jorge Plutzky (Brigham and Women's Hospital), in an interview.

"In this particular kind of approach, there are many different variables of potential issues between the data they have and why patients ended up with maybe some increased cardiovascular risk," Plutzky said.

"It's intriguing and supports the idea that calcium might be related to cardiovascular risk, but it does not have any immediate short-term implications. I'm not going to be seeing a patient in clinic and thinking 'Oh gosh, your calcium levels are too high, increasing your cardiovascular risk.' It's more of a scientific argument that calcium may have a relationship with cardiovascular disease," he said.

The study was supported by a Junior Researcher Award grant to Larsson from the Strategic Research Area in Epidemiology at Karolinska Institutet. Larsson and coauthors, Bhatt, and Plutzky reported having no relevant financial relationships.

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