Coronary artery disease is responsible for up to 1 in 4 deaths in the United States.
An international team of scientists has identified more than a dozen genes that contribute to potentially life-threatening calcium buildup in coronary arteries. coronary artery disease, a disease that causes up to one in four deaths in the United States. Doctors may be able to target these genes with existing drugs, or even nutritional supplements, to slow or stop the progression of the disease.
“By sharing valuable genotypic and phenotypic datasets collected over many years, our team was able to discover new genes that may be predictive of clinical coronary artery disease. ,” said Dr. Clint L. Miller, a researcher at the University of Virginia School of Medicine’s Public Center. Health genomics. “This is an important first step in identifying biological mechanisms that can be targeted for primary prevention of coronary artery disease.”
coronary artery calcification
Even before clinical atherosclerotic coronary artery disease develops, doctors can use non-invasive computed tomography (CT) scans to detect calcium buildup within the walls of coronary arteries. This reliable measure of subclinical coronary atherosclerosis strongly predicts future cardiovascular events such as heart attack and stroke, the leading cause of death worldwide. This calcium buildup is also linked to other age-related illnesses, such as dementia, cancer, chronic kidney disease, and even hip fractures.
Although the role of genetics in coronary artery calcium accumulation is known, only a few genes involved have been identified. So Miller and his collaborators were keen to identify new genetic factors that influence the risk of calcium buildup in the coronary arteries.
They did this by analyzing data collected from more than 35,000 people of European and African descent around the world. This was the largest meta-analysis ever conducted to understand the genetic basis of coronary artery calcification.
“Calcification in the coronary arteries reflects the lifetime exposure of blood vessels to risk factors,” Miller said. “While previous studies over a decade ago identified a small number of genes, it is clear that larger and more diverse studies are needed to begin to identify the pathways underlying coronary artery calcification. was.”
By combining several statistical analysis methods, the scientists identified more than 40 candidate genes at 11 different locations on the chromosome associated with coronary artery calcification. Eight of these locations had never previously been associated with coronary artery calcification, while five locations had not yet been reported for coronary artery disease. Genes at these locations play important roles in determining bone mineral content and regulating important metabolic pathways such as the formation of calcium deposits.
One of the genes that scientists have identified is ENPP1, is variable in a rare form of arterial calcification in infants. The researchers also identified genes in the adenosine signaling pathway, which are known to suppress arterial calcification.
To validate their findings, the scientists conducted genetic queries and experimental studies in human coronary artery tissue and smooth muscle cells, demonstrating direct effects on calcification and related cellular processes.
Now that researchers have uncovered the role of genes in coronary artery calcification, scientists will work to develop drugs (or identify existing drugs) that can target the genes or encoded proteins to modulate the calcification process. be able to. Some promising new targets may even be amenable to dietary changes or nutritional supplements such as vitamins C and D.
Additional research is needed to determine the best way to target these genes and the pathways affected, but Miller believes the new findings could help improve risk stratification and improve coronary artery disease. They say that early intervention may be in place to prevent the disease from progressing before it becomes established. This could revolutionize the treatment of a disease that kills more than 17 million people a year worldwide.
“This interdisciplinary collaboration highlights the power of meta-analysis for understudied clinically relevant measurements,” said Miller, of UVA’s Department of Biochemistry, Department of Molecular Genetics, and School of Public Health Sciences. . “We look forward to continuing progress in translating these preliminary findings into the clinic and identifying additional genes that can generalize risk prediction across more diverse populations.”
Publication of survey results
The researchers published their findings in a scientific journal natural genetics. The research team’s writing group consisted of Maryam Kavousi, Maxime M. Bos, Hanna J. Barnes, Christian L. Lino Cardenas, Doris Wong, Haojie Lu, Chani J. Hodonsky, Lennart PL Landsmeer, Lawrence F. Bielak, and Patricia A. It has been. Peyser, Rajeev Malhotra, Sundar W. van der Laan, Miller. A complete list of team members and their disclosures is included in this document. Miller said he has received support from biopharmaceutical company AstraZeneca on an unrelated project.
This research was supported by National Institutes of Health (NIH) grants R01HL105756, R01HL148239, R01HL164577, R01HL142809, R01HL159514, F31HL156463, R01HL125863, R01HL146860, K01HL164687, R01HL163972, P30DK063491, R01DK114183. A complete list of funding sources is available in this paper.
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