Previously unidentified genes linked to coronary artery disease
Researchers have identified previously unknown genes linked to calcium buildup in the coronary arteries, a predictor of future heart disease. They found that some of these genes can be targeted by existing drugs or nutritional supplements, potentially providing new avenues for preventing coronary artery disease.
Coronary artery disease is the leading cause of morbidity and mortality in developed countries. It’s primarily caused by atherosclerosis, plaque buildup on the artery walls. Coronary artery calcification (CAC), the presence of calcium in the coronary arteries, which supply blood to the heart muscle, can be an early sign of coronary artery disease.
Despite the heritability of CAC, which is estimated to be 30% to 40%, only a handful of contributing genes have so far been identified. So, researchers at University of Virginia (UVA) Health took another look at the genetic factors that influence coronary calcium buildup.
“Coronary artery calcification reflects the vessel’s accumulation of lifetime exposure to risk factors,” said Clint Miller, one of the study’s corresponding authors. “While previous studies from over a decade ago identified a handful of genes, it was clear that larger and more diverse studies would be necessary to begin to identify the pathways underlying coronary artery calcification.”
The researchers undertook the largest genome-wide association study (GWAS) meta-analysis to date, examining data from 26,909 individuals of European ancestry and 8,867 individuals of African ancestry. They identified 43 candidate genes for CAC at 11 different chromosomal locations. Eight locations had not previously been associated with CAC, and five had not been reported for coronary artery disease.
One of the genes identified, ENPP1, is altered in rare forms of arterial calcification in infants. And the researchers identified genes involved in the adenosine signaling pathway, which is known to suppress arterial calcification. To validate their findings, they conducted gene studies in human coronary artery tissues and smooth muscle cells and demonstrated direct effects on calcification and related cellular processes.
The researchers also performed a druggability analysis on the 11 risk loci to investigate the potential clinical utility of CAC candidate genes. Several CAC-associated genes were found to be targets of drug or nutrient supplement interactions, such as vitamins C and D, revealing opportunities to study how these compounds may promote or inhibit CAC.
Further studies are needed to determine how best to target these genes and their pathways, but the researchers say their discoveries could lead to improved risk prediction and early treatment interventions that prevent the progression of coronary artery disease.
“This interdisciplinary collaboration reveals the power of meta-analysis for an understudied and clinically relevant measurement,” Miller said. “We look forward to continued progress in translating these preliminary findings to the clinic, and also to identifying additional genes that could generalize risk prediction across more diverse populations.”
The study was published in the journal Nature Genetics.
Source: UVA Health