An international team of scientists, including researchers at UMC Utrecht, has identified nearly a dozen genes that contribute to calcium accumulation in our coronary arteries. Coronary artery calcification can lead to life-threatening coronary artery disease, a condition responsible for more than 542,000 deaths each year in Europe. Doctors may be able to target these genes with existing drugs – or possibly even nutritional supplements – to slow or stop the progression of the disease.
Even before people develop clinical coronary artery disease, doctors can identify calcium buildup in the walls of coronary arteries. They do this using noninvasive CT (computed tomography) scans. Such scans predict with a high degree of reliability future cardiovascular events such as heart attacks or strokes, the leading causes of mortality and morbidity worldwide. Calcium accumulation is also associated with other diseases of aging, such as dementia, cancer, chronic kidney disease and even hip fractures.
Despite the known role of genetics in calcium accumulation in coronary arteries, only a limited number of related genes were known until now. Lead author Maryam Ksavousi, MD, PhD (Erasmus Medical Center in Rotterdam) and her collaborators were thus keen to identify new genetic factors. The researchers analyzed previously collected genetic information from more than 35,000 people around the world. Thus, they conducted the largest meta-analysis of genome-wide association studies (GWAS) to date to better understand the determining genetic factors of coronary artery calcification.
“Coronary artery calcification is the accumulation of lifelong exposure to risk factors in the blood vessel,” Kavousi says. She is an epidemiologist investigating the role of arterial calcium measurements in primary prevention and risk stratification. ‘Our previous study, completed more than a decade ago, identified a handful of genes, so it was clear that larger and more diverse studies would be needed to expand our knowledge of the underlying pathways of coronary calcification. This will also improve our understanding of currently available risk assessment tools for patients at increased risk of coronary artery disease.
The scientists applied several statistical analysis methods to identify more than 40 candidate genes at 11 different locations on our chromosomes associated with coronary artery calcification. Eight of these genetic risk locations had not previously been associated with coronary artery calcification, and five of these had not previously been reported for coronary artery disease. Genes at these sites play an important role in determining the mineral content of our bones. Moreover, among other functions, they regulate important metabolic pathways in the formation of calcium deposits. ‘By sharing valuable genetic and phenotype datasets collected over many years, our team was able to discover new genes that may be harbingers of clinical coronary artery disease,’ said researcher Clint L. Miller, PhD, from the University of Virginia School of Medicine’s Center for Public Health Genomics. ‘This is a critical first step in identifying the biological mechanisms we can target to prevent coronary artery disease.’
One of the genes the team identified, ENPP1, is altered in rare forms of arterial calcification in children. ‘What’s really fantastic is that we were able to demonstrate direct cellular effects of these gene products on calcification. This gives us confidence that we are looking at the right targets for potential new therapies,’ said Rajeev Malhotra, of Massachusetts General Hospital and Harvard Medical School.
Now that the researchers have revealed the role of genes in coronary artery calcification, scientists can develop drugs (or identify existing drugs) that target the genes or encoded proteins to control the calcification process. Some of the promising new targets may even be sensitive to changes in diet or nutritional supplements, such as vitamin C or D, as the researchers mention in their article. ‘We have opened a door by uncovering these genes,’ said Sander W. van der Laan, of UMC Utrecht. ‘Now it is up to us and others to find the way to the clinical impact behind the door.’
The researchers have published their findings in the scientific journal Nature Genetics. ‘I think I can say on behalf of all of us that we are very happy that this work has finally been published,’ said Sander W. van der Laan of UMC Utrecht. ‘To me it really is a testament to team science: where it took a diverse group of scientists, each with their own specific skills and expertise, to crack the code.’
