New genes identified that contribute to coronary artery disease

An international collaboration of scientists, which includes a researcher from the University of Virginia, has identified nearly a dozen genes associated with the accumulation of calcium in our coronary arteries. This buildup is a major factor contributing to life-threatening coronary artery disease, responsible for up to 25% of deaths in the United States. There’s hope that doctors could potentially target these genes using existing medications or even nutritional supplements to slow down or stop the progression of the disease.

Clint L. Miller, a researcher from the UVA School of Medicine’s Center for Public Health Genomics, explained, “By pooling valuable genotype and phenotype data gathered over many years, our team has uncovered novel genes that could serve as early indicators of clinical coronary artery disease. This marks a crucial initial step in identifying the biological mechanisms we can focus on for primary prevention of coronary artery disease.”

The research findings have been published in the journal Nature Genetics.

Coronary artery calcification

Before clinical atherosclerotic coronary artery disease manifests, doctors can employ non-invasive computed tomography scans to detect calcium buildup within coronary artery walls. This reliable indicator of subclinical coronary atherosclerosis strongly predicts future cardiovascular events, including heart attacks and strokes, which are leading global causes of death. Moreover, this calcium accumulation is associated with various age-related ailments, such as dementia, cancer, chronic kidney disease, and even hip fractures.

Despite our understanding of genetics’ role in coronary calcium buildup, only a limited number of contributing genes had been identified. Thus, researcher Clint L. Miller and his collaborators were eager to uncover new genetic factors influencing the risk of coronary calcium buildup.

Their approach involved analyzing data from over 35,000 individuals of European and African descent worldwide. This marked the most extensive “meta-analysis” conducted to date for understanding the genetic basis of coronary artery calcification.

Miller explained, “Coronary artery calcification reflects the cumulative impact of risk factors on blood vessels over a lifetime. While previous studies had identified a few genes more than a decade ago, it was evident that larger and more diverse studies were needed to uncover the pathways driving coronary artery calcification.”

By employing various statistical analysis methods, the researchers identified over 40 candidate genes at 11 different locations on our chromosomes linked to coronary artery calcification. Notably, eight of these locations had no prior connection to coronary calcification, and five were previously unreported for coronary artery disease. Genes at these locations play vital roles in determining bone mineral content and regulating key metabolic pathways involved in calcium deposit formation.

One of the genes uncovered, ENPP1, is known to be altered in rare instances of arterial calcification in infants. Additionally, the researchers identified genes associated with the adenosine signaling pathway, which is known to suppress arterial calcification.

To validate their findings, the scientists conducted gene queries and experimental studies on human coronary artery tissues and smooth muscle cells, demonstrating direct effects on calcification and related cellular processes.

Now that these genes’ roles in coronary artery calcification are known, scientists can explore the development of drugs, including potential use of existing ones, to target these genes or encoded proteins, thereby modulating the calcification process. Some promising targets may even be amenable to dietary adjustments or nutrient supplementation, such as vitamins C or D.

While further research is needed to determine the best strategies for targeting these genes and affected pathways, these discoveries hold the potential to revolutionize risk assessment for patients or enable early interventions to halt the progression of coronary artery disease. This could represent a significant advancement in addressing a disease responsible for over 17 million deaths annually worldwide.

“This interdisciplinary collaboration underscores the potency of meta-analyses for an understudied yet clinically significant measure,” stated Miller, who is affiliated with UVA’s departments of Biochemistry and Molecular Genetics and Public Health Sciences. “We anticipate ongoing progress in translating these initial findings into clinical applications and identifying additional genes applicable to risk prediction across more diverse populations.”

Source: University of Virginia

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