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Genetic Predisposition to High Blood Calcium Linked to Increased Heart Disease Risk

NEW YORK (GenomeWeb) – A genetic predisposition to higher blood calcium levels is also linked to an increased risk of heart disease and heart attack, according to a new study.

Observational studies have noted an association between blood calcium levels and heart disease risk, leading Uppsala University's Karl Michaëlsson and his colleagues to wonder how calcium supplementation might affect disease risk. Using genetic predisposition to increased calcium levels as a proxy, they used a Mendelian randomization approach to examine the link between calcium and heart disease and heart attack risk in about 184,000 individuals. As they reported today in the Journal of the American Medical Association, they found an increased risk of disease among people genetically predisposed to higher blood calcium levels.

"A genetic predisposition to higher serum calcium levels was associated with increased risk of [coronary artery disease] and myocardial infarction," Michaëlsson and his colleagues wrote in their paper.

The researchers drew upon publicly available data from a genome-wide association study of 39,400 people that linked seven SNPs to serum calcium levels. Those SNPs were replicated in a further 21,679 individuals and in a combined meta-analysis of the discovery and replication cohorts. This cohort included nearly 61,000 CAD cases, 70 percent of which had had a myocardial infarction.

The GWAS further assessed the pleotropic associations of these SNPs with traits like body-mass index, systolic and diastolic blood pressure, and type 2 diabetes using data from a suite of studies, including the Global Lipids Genetics Consortium and the Genetic Investigation of Anthropometric Traits. One SNP, they noted, was linked with some of these measures and left out of the follow-up Mendelian randomization analyses to avoid confounding interactions.

The six remaining SNPs explain about 0.8 percent of the variation in serum calcium levels, the researchers noted.

For their Mendelian randomization analysis, they extracted summary statistics from the CardiogramplusC4D cohort, which included 60,801 coronary artery disease cases and 123,504 controls, mostly of European ancestry. They noted that the cohort relied on a broad definition of coronary artery disease that included acute coronary syndrome, chronic stable angina, and coronary artery stenosis. About 70 percent of the cases included myocardial infarction. They then matched each SNP to coronary artery disease and heart attack, and weighted them by their association with serum calcium.

Through an inverse-variance weighed meta-analysis that combined these SNPs, the researchers estimated an odds ratio of 1.25 for coronary artery disease for every genetically predicted 0.5 milligram per deciliter increase in serum calcium levels.

Similarly, they estimated an odds ratio of 1.24 for heart attack for every genetically predicted 0.5 milligram per deciliter increase in serum calcium. The researchers noted the results largely held after they removed the most heavily weighted SNP —located in the CASR gene — from their analysis.

This, they said, supports the findings of previous observational studies, though they noted that it primarily included individuals of European ancestry and lacked some data on age and sex.

"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," the authors added. 

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