The study, published in JAMA, is a collaboration between the Karolinska Institute, Stockholm, Cambridge University and Uppsala University.
The researchers used a technique called mendelian randomisation (MR) to identify six genetic variations linked to blood levels of calcium. Risks of CAD and heart attack were found to be increased in those with higher blood calcium levels.
Specifically, for every increase of 0.5 millgrams per decilitre (mg/dL) increase in serum calcium content, the risks of heart attack and CAD were heightened by around 25%.
“A genetic predisposition to higher serum calcium levels was associated with increased risk of CAD and myocardial infarction,” commented Dr. Susanna Larsson, Associate Professor of Epidemiology at the Karolinska Institute.
The finding is important because it builds on previous observational studies which had associated higher blood calcium levels with increased risk of heart attack and CAD.
“Because of the widespread use of calcium supplements, any association between raised serum calcium and CAD risk by a high calcium intake could have clinical and public health implications,” wrote Larsson.
Additionally, some randomised controlled trials (RCTs) had reported that calcium supplementation slightly increased heart attack risk and led to excessive blood calcium levels (hypercalcaemia), with consequent calcification of the arteries.
Although the study established the genetic risk of long-term exposure to high calcium levels, the researchers could not draw conclusions about whether short- to medium-term calcium supplementation increased risks similarly.
“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,” they concluded.
Mendelian Randomisation
Larrson and colleagues explained the advantages of the trial design:“This method, known as mendelian randomisation, avoids some of the limitations of observational studies (because genetic information should be free from confounding) and is not affected by disease status, thereby avoiding reverse causation bias.”
The possibility of confounding is one reason why observational studies cannot be used to determine causal mechanisms. The other drawback is the inability to ascertain the direction of cause and effect – raising the possibility of reverse causation.
By eliminating these two limitations, MR trials can strengthen the evidence for causal conclusions to be established, thus preparing the groundwork for RCTS to provide final confirmation.
MR has been used to establish a number of causal relationships in previous research involving numerous outcomes; and is gaining wider acceptance. Nevertheless, MR still faces methodological challenges that limit the circumstances in which it can confirm causality.
In this study, the technique was useful in identifying a genetic causal link between lifelong high blood calcium exposure and CAD and heart attack. However, it did not enable a causal relationship to be determined between calcium supplementation and CAD / heart attack risk. Nevertheless, study findings may strengthen the justification for further RCTs into this outcome.
Source: JAMA
Volume 318, Issue 4, pages 371-380
“Association of Genetic Variants Related to Serum Calcium Levels With Coronary Artery Disease and Myocardial Infarction”
Authors: Susanna C Larsson, Stephen Burgess, Karl Michaëlsson