Scripps researchers unlock heart disease key

9p21.3 haplotype identified as a major player in cardiovascular disease risk

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LA JOLLA, Calif.—Cardiovascular disease kills more Americans than any other cause, and is responsible for the most deaths worldwide for both men and women of all races. Also known as coronary artery disease (CAD), it is a common and complex chronic disease with traditional and genetic risk factors. The traditional risk factors of CAD include age, gender, obesity, abnormalities in blood lipids, diabetes, hypertension and smoking. However, scientists have long known that there was a genetic component to CAD as well, with 40 to 60 percent of CAD risk being heritable according to epidemiological, twin and family studies, suggesting a genetic explanation. In fact, evidence pointed to a mysterious DNA marker that strongly increases the risk for life-threatening cardiovascular issues—such as heart attacks, aneurysms or strokes—no matter what diet, exercise or medical regimen one followed.
The team at The Scripps Research Institute, along with colleagues at the University of California, San Diego, published a paper in December’s issue of Cell reporting exciting findings that suggest that new precision treatments may evolve to protect blood vessel walls and minimize the mortality of CAD. Their research shows that a large block of DNA known as the 9p21.3 cardiovascular risk haplotype causes abnormalities in vascular smooth muscular cells, the cells in blood vessel walls that normally allow them to expand and contract. These cells also can dysfunction and contribute to plaques that clog blood vessels, leading to heart attacks and stroke.
“We’ve known for more than a decade that the 9p21.3 haplotype was the most influential genetic risk for cardiovascular disease cases, accounting for an astonishingly large 10 to 15 percent of cases in the United States per year. But, until now we’ve been in the dark about what it might be doing to cause this,” says Kristin Baldwin, a professor at Scripps Research and senior author on the new paper. “Now, with strong evidence suggesting the 9p21.3 haplotype undermines the stability and function of vascular muscle cells, we may have a opened a new route to interventions that could impact many millions of people worldwide.”
While previous studies had identified the 9p21.3 haplotype as perhaps the most impactful known genetic cause of cardiovascular disease worldwide, it remained to be explained exactly how it functioned in people’s bodies. Efforts to explain the methodology were hampered by the fact that this particular haplotype is unique to humans, without a corresponding genetic area in mice or other lab animals. Another challenge is that this region doesn’t harbor any traditional protein coding genes, making it hard to predict what it might do.
“We call such regions ‘gene deserts,’ and in the past, they were neglected in research because people thought it was ‘junk’ DNA,” explained Ali Torkamani, co-author on the paper and an associate professor at Scripps Research and director of genome informatics at Scripps Research Translational Institute. “With rapid advances in genome sequencing and analysis, we are finding that these regions frequently play critical roles in the emergence of disease.”
Baldwin and her team collected blood from people who had either the high-risk or low-risk versions of the haplotype and reprogrammed it into induced pluripotent stem cells. Using specialized molecular scissors, called TALE nucleases, they could precisely remove the risk-promoting or benign versions of this DNA from affected and unaffected donor cells, and then created vascular smooth muscle cells from the edited stem cells. They found that abnormalities in cells from high-risk subjects affected more than 3,000 genes—accounting for nearly 10 percent of the human gene catalog.
Computer-based examinations of these genes indicated that those cells might be deficient when fighting disease, proving to be far weaker than the low-risk cells, contracting with much less force and less able to cling to their surroundings than low-risk vascular muscle cells. In further exploration, they were surprised to find that those high-risk genes impacted more than a third of the genes related to CAD, suggesting that the 9p21.3 haplotype could potentially even control this network of genes.
What they eventually found was that ANRIL, a potential key master regulator, presented in higher levels in the high-risk cells. When the specific ANRIL RNAs were added to healthy cells they developed key signatures of disease, suggesting that ANRIL RNAs may be master conductors of the switch between healthy and disease-promoting cell states in vascular muscle cells.
“This study demonstrates the power of genome editing of pluripotent stem cells for studying human genetic risk for disease, especially when risks are in uniquely human regions or gene deserts,” remarked Valentina Lo Sardo, a staff scientist at Scripps Research and first author on the Cell paper. “Our findings not only provide insight into how the high-risk 9p21.3 haplotype undermines vascular health, but also offer a new avenue to study and target gene regulatory networks widely involved in coronary artery disease.”   
Dr. Eric Topol, a co-author on the paper, cardiologist and executive vice president of Scripps Research, added “It’s remarkable that one region of our genome could have such a significant impact on both the functional and genetic characteristics of these blood vessel cells. It may be a gene desert without any protein-coding function, but its impact on disease is extraordinary. Now that we know its role in damaging the vascular wall, we are in a better place to find novel ways to prevent it.”

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