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Rare Gene Variant Found in Amish Could Lead to New Treatments for Heart Disease - Everyday Health

Researchers have identified a new gene variant associated with lower levels of LDL (also known as “bad”) cholesterol and fibrinogen, a protein involved in blood clotting, that appears to significantly lower a person’s risk of heart disease.

Although the gene variant is found in fewer than 1 in 1,000 people in the general population, it’s present in approximately 12 percent of people living in the Amish community in Lancaster County, Pennsylvania, according to a study published December 2 in the journal Science . 

These findings are important because they can be used to study therapies that could reduce the risk of cardiovascular disease, says May Montasser, PhD, an assistant professor of medicine at the University of Maryland School of Medicine, a member of the university’s program for personalized and genomic medicine, and the lead author of the study. “If we could find a way to lower LDL and fibrinogen, it should result in better cardiovascular outcomes,” she says.

How LDL Cholesterol and Fibrinogen Affect Heart Health

Heart disease is the number one cause of death in the United States, according to the Centers for Disease Control and Prevention (CDC). It’s estimated that about 659,000 people, one out of every four, die of heart disease.

Too much low-density lipoprotein, called LDL or “bad” cholesterol, can cause plaque to build up on the walls of the blood vessels, according to the CDC. This causes the insides of the vessels to narrow, which can impede blood flow to and from the heart and other organs. If the blood flow is blocked, it can cause chest pain or even a heart attack.

Fibrinogen is a protein that is involved in blood viscosity and platelet aggregation (how platelets clump together) and is part of the final step of clot formation. During an inflammatory response, fibrinogen levels increase. Major heart studies, including the Framingham heart study, have found a significant association between elevated fibrinogen and the risk of cardiovascular events.

According to the authors, this is the first time that scientists have discovered a gene that lowers two different heart disease risk factors.

Findings Confirmed in More Than Half a Million People and in Mice Models

Using the genetic sequencing of samples from nearly 7,000 Amish study participants, researchers found a genetic variant in the gene B4GALT1 to be associated with LDL cholesterol that was lower by nearly 14 milligrams per deciliter (mg/dL) and nearly 30 mg/dL lower fibrinogen.

The Amish community is ideal for genetic studies because of its common lineage and homogeneous lifestyle, says Dr. Montasser. “All of the approximately 40,000 Amish living in the Lancaster community are descendants of the about 1,000 or so people who immigrated in the late 18th century from northern Europe. This has created a unique genetic architecture that allows some variants to increase over time. Some variants that are extremely rare in the general population might be enriched in this population,” she says.

After finding the variant in the Amish, investigators used a data bank to look for it in more than 500,000 people from the general population. “We found that the variant was associated with lower levels of heart disease. Those who carried this variant had a 35 percent lower risk of heart disease than those who did not,” says Montasser.

To further verify the findings that the variant was linked to LDL and fibrinogen, the gene mutation was delivered to mouse models of cardiovascular disease. The genetically modified mice with the variant experienced a 38 percent drop in LDL and a decline in fibrinogen.

“By duplicating the findings in the mouse model, it gives us confidence in these findings. Here we have consistency across populations and across species,” says Montasser.

Findings May Be Used to Create New Therapies for Heart Disease

The research team is now working to trying to understand the variant’s mechanism of action — why does it cause LDL and fibrinogen to be lower. “Then we should find a way to create a drug that mimics the same action of the variant to help keep arteries free of plaque and clots,” she says.