Health In Focus
  • The major heart disease risk locus has been cut-out from DNA by genome editing technology
  • The high-risk disease locus causes damage to the blood vessel walls
  • Novel therapies could be developed that target the cells of the blood vessel walls
  • This will prevent many deaths from heart disease

A large segment of DNA is present in the human genome that is suspected to be responsible for increasing the risk for serious cardiovascular diseases (CVD) in billions of people around the globe, in spite of following a strict regimen of a healthy diet, adequate exercise and regular medications. It has not been possible to avert the complications of CVD arising from this specific region of DNA, until now.
Genome Editing Removes Major Heart Disease Risk Locus from DNA

Scientists at the Scripps Research Institute, La Jolla, California, USA have addressed the issue by excising (cutting out) the incriminating DNA segment. This prevented complications such as vascular abnormalities that are associated with CVD. Moreover, the research team has identified the DNA region to be the 9p21.3 cardiovascular risk haplotype, which is responsible for a host of abnormalities associated with the cardiovascular system, including atherosclerosis, heart attack and stroke.

Scientists have also found that the 9p21.3 cardiovascular risk haplotype influences the functions of a network of at least a third of all genes associated with the occurrence of coronary artery disease (CAD). Importantly, this finding could pave the way for the development of therapies that target the cells of blood vessel walls. The study has been published in the journal Cell, a publication of Cell Press.

"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 10-15 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 Dr. Kristin Baldwin, Ph.D., who is a Professor in the Department of Neuroscience at Scripps Research and senior author of the paper. "Now, with strong evidence suggesting the 9p21.3 haplotype undermines the stability and function of vascular muscle cells, we may have opened a new route to interventions that could impact many millions of people worldwide."

Cardiovascular Disease (CVD) - Facts & Figures

CVD is a group of disorders of the heart and blood vessels.

The following information is based on data from the World Health Organization (WHO):
  • CVD is the number 1 cause of death in the world - it kills more people than any other disease.
  • The annual mortality rate of CVD is 17.9 million worldwide, which represents 31 percent of all global deaths.
  • Over 85 percent of all CVD deaths are due to heart attack and stroke.
  • Over 75 percent of CVD deaths occur in low- and middle-income countries.
  • Out of 17 million premature deaths (below 70 years of age) due to non-communicable diseases, 37 percent are caused by CVD.
  • Factors that increase the risk of CVD include smoking, high cholesterol, high blood pressure, diabetes, lack of exercise, unhealthy diet, and obesity.

What Hurdles Did the Scientists Face?

Although it was known that the 9p21.3 haplotype increased the risk of CVD, it was not known how it functioned within the body. While trying to shed some light on this aspect, the scientists faced two major hurdles:
  • This disease risk 9p21.3 haplotype is only present in humans and there is no equivalent in mice or other lab animals. This prevented studying the gene function in the lab.
  • This DNA region with the 9p21.3 haplotype doesn't have any protein-coding genes which could be used to study protein expression to see how the gene functioned.
Dr. Ali Torkamani, PhD, who is an Associate Professor in the Department of Integrative Structural and Computational Biology at Scripps Research and Director of Genome Informatics at Scripps Research Translational Institute, and co-author of the paper, indicated that these DNA regions are called 'gene deserts', which were regarded as 'junk DNA' and therefore, largely neglected by researchers in the past. However, with major advances in genome sequencing and analysis, these regions have been found to be responsible for the emergence of various diseases.

How Did the Scientists Overcome the Hurdles?

The hurdles were overcome by using cell culture techniques to produce human blood vessel cells and subjecting them to gene editing technology. Blood samples were obtained from people having high risk or low-risk haplotype. These blood cells were transformed into induced pluripotent stem (iPS) cells and genetically engineered using TALE (transcription activator-like effector) nucleases that act like molecular scissors. These nucleases edit-out the harmful (risk-promoting) and harmless (benign) DNA sequences in the affected and unaffected donor cells. These edited stem cells were then induced to differentiate into blood vessel smooth muscle cells, which were studied in minute detail by gene profiling and bioengineering approaches.

What Did the Study Find?

The study found the following:
  • Cells of high risk individuals exhibited numerous abnormalities, involving over 3,000 genes, accounting for approximately 10 percent of the total gene pool in humans.
  • Computerized analysis of the genes indicated that the muscle cells were lacking specific functions related to the disease.
  • Further investigation showed that the high risk vascular smooth muscle cells (VSMC) were weaker than the low risk VSMCs, with reference to their force of contraction and adherence to surrounding structures.
  • Study of the influence of the 3,000 genes on 100 other genes linked to CAD, revealed that the high-risk VSMCs showed changes in the activity of over a third (38) of the genes, which indicates that the 9p21.3 haplotype could be controlling the functioning of these gene networks.
  • A key gene regulator termed ANRIL (antisense non-coding RNA in the INK4 locus) was identified that produces genetic components called long non-coding RNA (ribonucleic acid). High risk VSMCs contained higher levels of ANRIL RNA.
  • When ANRIL RNAs were added to healthy cells, they developed signs of disease, which indicates that ANRIL is the master gene regulator that controls the switch between healthy and diseased vascular cells.

Expert Comments

"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," says Dr. Valentina Lo Sardo, Ph.D., a Staff Scientist at Scripps Research and the lead author of the 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."

"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," says Dr. Eric Topol, MD, who is a Professor of Molecular Medicine and Executive Vice President of Scripps Research, and a co-author of the paper. "It may be a gene desert without any protein-coding function, but its impact on disease is extraordinary. Now that we know it's role in damaging the vascular wall, we are in a better place to find novel ways to prevent it."

Funding Source

The study was supported by grants from the National Institutes of Health (NIH), Bethesda, Maryland, USA.

Reference :
  1. Unveiling the role of the most impactful cardiovascular risk locus through haplotype editing - (

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