From the Journals
Heart disease risk soars in young adults with coronary calcium
Young adults with even small amounts of coronary calcium have a 5-fold higher risk of coronary heart disease and a 1.6-fold risk of death,...
in a large mendelian randomization study published online July 25 in JAMA.
Each 0.5-mg rise in genetically predicted serum calcium concentration increased the odds of coronary artery disease (CAD) and myocardial infarction by about 25%, reported Susanna C. Larsson, Ph.D., of Karolinska Institutet in Stockholm, Sweden, and her associates. It remains unclear whether short- or medium-term calcium supplementation also increases the risk of these outcomes, they added.
Observational studies have linked high serum calcium with cardiovascular disease, but such studies are subject to confounding, the researchers noted. Randomized trials indicate that calcium supplementation might contribute to MI, but the trials are not designed to quantify long-term risks. Therefore, the investigators evaluated a proxy for lifelong hypercalcemia – six single nucleotide polymorphisms (SNPs) that have been linked to high serum calcium, but not to other CAD risk factors such as type 2 diabetes, fasting glucose and insulin levels, body mass index, waist-to-hip ratio, major lipids, or hypertension (JAMA. 2017 Jul 25;318[4]:371-80. doi: 10.1001/jama.2017.8981).
To examine how these SNPs affect the risk of CAD and MI, the researchers analyzed summary statistics for 184,305 individuals from a meta-analysis of CAD genome-wide association studies (Nat Genet. 2015;47:1121-30), including 60,801 cases (of whom about 70% also had MI) and 123,504 controls.
Together, these six SNPs explained about 0.8% of variations in serum calcium levels. Each 0.5-mg/dL (about one standard deviation) increase in genetically predicted serum calcium level significantly increased the risk of CAD (odds ratio, 1.25; 95% confidence interval, 1.08-1.45; P = .003) and MI (OR, 1.24; 95% CI, 1.05-1.46; P = .009). The genetic variant rs1801725 exerted the greatest effect on serum calcium levels, the investigators noted. This SNP affects the CASR gene, which encodes a calcium-sensing receptor that “plays a key role in calcium homeostasis.” However, four of the other five variants also had odds ratios above 1.0, and three had odds ratios above 1.25. A sensitivity analysis that excluded the CASR variant generated an identical odds ratio, although the confidence interval was wider. Studies of other risk factors for CAD have yielded odds ratios between 1.3 (triglyceride levels) and 1.7 (LDL cholesterol levels), the researchers noted.
A link between calcium supplementation and MI remains debatable. However, supplementation can lead to hypercalcemia and greater formation of insoluble calciprotein particles, the investigators said. Coronary artery disease might result from downstream effects on vascular calcification, vascular cells, blood coagulation pathways, or gene expression, but such mechanisms need more study, they added.
This analysis included men and women from the United States, Canada, the United Kingdom, Germany, Sweden, Ireland, the Netherlands, Finland, Iceland, Italy, Estonia, Lebanon, China, Korea, India, Pakistan and Greece. Participants tended to be men in their 50s and 60s, but more than half of studies lacked data on age and sex. Nearly all participants were of white European ancestry.
Karolinska Institutet supported Dr. Larsson. The investigators reported having no relevant conflicts of interest.
