Researchers have discovered a previously unknown gene linked to calcium buildup in the coronary arteries, a harbinger of future heart disease. They found that existing drugs or nutritional supplements could target some of these genes, potentially providing new ways to prevent coronary artery disease.
Coronary artery disease is a leading cause of morbidity and mortality in developed countries. The main cause is atherosclerosis, the buildup of plaque on the walls of arteries. Coronary artery calcification (CAC) is the presence of calcium in the coronary arteries that supply blood to the heart muscle and is an early sign of coronary artery disease.
Although the heritability of coronary artery calcification is estimated to be 30% to 40%, only a few causative genes have been identified to date. So researchers at the University of Virginia Health once again looked at the genetic factors that influence coronary artery calcification.
"Coronary artery calcification reflects the accumulation of life-long exposure of blood vessels to risk factors," said Clint Miller, one of the study's corresponding authors. "While studies more than a decade ago identified a handful of genes, it became clear that larger and more diverse studies would be necessary to begin to identify the underlying pathways for coronary artery calcification."
The researchers conducted the largest meta-analysis of genome-wide association studies (GWAS) to date, looking at data from 26,909 individuals of European ancestry and 8,867 individuals of African ancestry. They found 43 CAC candidate genes at 11 different chromosomal locations. Eight of these locations were not previously associated with CAC, and five were not associated with coronary artery disease.
One of the genes found, ENPP1, is altered in a rare form of arterial calcification in infants. The researchers also identified genes involved in the adenosine signaling pathway, which is known to inhibit arterial calcification. To validate their findings, the researchers conducted genetic studies in human coronary artery tissue and smooth muscle cells, which demonstrated a direct genetic influence on calcification and related cellular processes.
The researchers also performed a druggability analysis on 11 risk sites to study the potential clinical use of CAC candidate genes. The study found that several CAC-related genes are targets of interactions with drugs or nutritional supplements, such as vitamins C and D, providing an opportunity to study how these compounds promote or inhibit CAC.
Further research is needed to determine how best to target these genes and their pathways, but the researchers say their findings could lead to improved risk prediction and early therapeutic intervention to prevent the development of coronary artery disease.
"This interdisciplinary collaboration reveals the power of meta-analysis in an understudied and clinically relevant measure," Miller said. "We look forward to continued progress in translating these preliminary findings into clinical applications and to identifying additional genes that will generalize risk prediction in more diverse populations."
The research was published in the journal Nature Genetics.