Broad scientists show how 1 bad gene takes a toll on 5 vascular diseases

human heart
Understanding the role of a particular genetic variant may lead to better detection of coronary artery disease and related disorders.

Migraines, coronary artery disease, high blood pressure—they may seem like different diseases but they all share a single genetic variant. Just how this abnormality raises the risk of all these diseases, however, has puzzled scientists for quite some time. Now a team of researchers at the Broad Institute of MIT and Harvard University believe they’ve uncovered the link between this particular variant and vascular disease.

The variant occurs on a chromosome called 6p24. In addition to being implicated in migraine, heart disease and hypertension, the variant raises the risk of cervical artery dissection, a blood-vessel tear that can lead to stroke, and fibromuscular dysplasia (FMD), a condition marked by abnormal cells in artery walls.

The researchers discovered that the genetic variant boost the activity of the gene endothelin-1 (EDN1). This gene promotes hardening of the arteries, as well as narrowing of blood vessels, or “vasoconstriction.” The research was published in the journal Cell.

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The Broad scientists made the discovery by examining data from more than 200,000 people participating in the 1000 Genomes Project, UK Biobank and CARDIOGRAMplusC4D—a research consortium that’s examining multiple studies to try to uncover genetic risks for heart disease. That led them to rs9349379, a single-nucleotide polymorphism (SNP), which they then showed has a direct impact on EDN1.

One form of rs9349379 was present in 36% of people of European descent whose data is stored in the UK Biobank, according to the Broad. That may suggest that screening for rs9349379 could help identify people at risk for vascular diseases, the research team believes.

"The main value of our research is the pinpointing of the importance of endothelin-1 and blood vessel constriction to multiple vascular diseases," said senior author Sekar Kathiresan, a cardiologist at the Broad Institute of MIT and Harvard University, in a press release. In particular, they discovered that the genetic variant correlates with higher levels of a precursor protein called Big endothelin-1 (ET-1), which is known to promote arterial plaques.

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The gene editing technique CRISPR/Cas9 also played an important role in this research. The team used the technology to erase a small section of rs9349379 DNA in human stem cells. They then coaxed those cells to become vascular cells and observed how rs9349379 influenced the EDN1 gene. That helped prove the link.

Interestingly, some people with coronary artery disease also have migraines or one of the other three diseases—lending credence to the idea that ET-1 production may be at the root of these problems. But more research is needed to further elucidate the role of this genetic variation in so many diseases, the scientists acknowledge.