Why Amish DNA is a “goldmine” for heart disease research

The Amish of Lancaster County, Pennsylvania, know exactly where they came from, and when. The people in the community today can trace their family trees back to a single group who emigrated from Western Europe in the late 1700s. Today, they still marry within the group — and that makes them a “goldmine” for geneticists.

The Amish of Lancaster County are an example of a “founder population,” an isolated population of people who are all relatively similar in terms of their genes, meaning this subset has less genetic variation than the entire U.S. population. In turn, their genetic architecture offers scientists a distinct study opportunity — the ability to pinpoint genes associated with specific diseases.

“To me, it’s a goldmine of identifying genetic variants,” May Montasser, a University of Maryland genetic researcher, tells Inverse.

Now, Montasser and her colleagues report they have struck a nugget.

What’s new — In a new study in Science, Montasser and her team describe their discovery of a genetic variant among a group of 7,000 Old Order Amish that is correlated with lower levels of “bad” cholesterol (low-density lipoprotein (LDL) cholesterol, in science terms). This is the cholesterol that builds up around arteries, and that can lead to and worsen heart disease.

They followed that discovery to unlock some additional information on how the gene’s expression may safeguard heart health.

Why It Matters — Cardiovascular diseases are the leading cause of death worldwide, killing about 18 million people a year and representing almost a third of all deaths. While one’s environment plays a large role in disease, there is a genetic component to heart disease that may respond to gene therapy or a drug.

Ultimately, understanding how the gene works to protect the heart could offer a new “therapeutic approach” to preventing heart disease before it sets in, the paper notes.

Digging into the details — Since 1995, the Amish Research Program at the University of Maryland School of Medicine has partnered with the Amish community, many of whom have offered blood samples and health histories, leading to some discoveries about the genetic underpinnings of type 2 diabetes, heart disease, blood pressure, and weight gain.

In the new study, the researchers analyzed genetic sequencing data from 7,000 Old Order Amish volunteers. They found a missense variation in a gene-encoding protein — “missense” means there is a change to one amino acid, or building block, in the protein. Some 12 percent of the Amish group have the mutation — but is exceedingly rare in the general population; the researchers found just eight copies of the mutation after searching through 140,000 whole-genome sequences stored in a reference biobank.

Here’s the background — Concentrated in Pennsylvania and Ohio, the Amish are a Christian sect known for their simple dress and refusal of modern technology. They rely on manual labor, communal planning, and work animals to power their self-sufficient homesteads.

“It is altruistic. They believe in voluntarily helping fellow Amish and non-­Amish.”

In the case of this study, the population is part of what is known as Old Order Amish by scientists and a few others. Generally, the term Amish is used synonymously with Old Order Amish.

The Amish have a religious dedication to the “Good Samaritan” principle. For some, this extends to donating their genetic material to scientists at the University of Maryland (located about 70 miles from Lancaster) for use in medical discoveries.

“It is altruistic,” Alan Shuldiner, a genetics researcher and the founder of the Amish Research Program explains in a University of Maryland article. “They believe in voluntarily helping fellow Amish and non-­Amish.”

Going further — The variant discovered in the study is associated with lower levels of LDL cholesterol. To test the idea further, the researchers used genetically modified lab mice. The mice with a genetic variant similar to the one found in the Amish had an average of 38 percent less LDL cholesterol when compared to typical levels for that species of mice.

Researchers found another pleasant surprise, too. They discovered a decrease in fibrinogen, a protein that is associated with blood clots that is another risk factor for heart disease.

Lastly, the researchers looked through a biobank for other genetic variants that cause the same effect as the variant they had discovered. People with functionally similar variations in their genes also had 35 percent fewer instances of cardiovascular disease than the general population.

What’s Next — Before developing a gene therapy based on this variant, researchers have two major tasks, Montasser says:

• They need to understand why the variant appears to have a protective effect on heart health
• They need to determine if the variant has any harmful effects

They will also need to determine if the genetic variant is the sole actor when it comes to keeping bad cholesterol at bay. Ultimately, though, Montasser says developing a drug based on this genetic information may be possible.

The more immediate application of this work is better understanding the role of genetics in major health conditions, says Montasser.

“We are finding genetic components to everything,” she adds.

Abstract: Increased blood levels of LDL-C and fibrinogen are independent risk factors for cardiovascular disease (CVD). We identified associations between an Amish-enriched missense variant (p.Asn352Ser) in a functional domain of beta-1,4-galactosyltransferase 1 (B4GALT1) and 13.9 mg/dl lower LDL-C (p=4.1E-19), and 29 mg/dl lower plasma fibrinogen (p=1.3E-05). B4GALT1 gene-based analysis in 544,955 subjects showed association with decreased coronary artery disease (OR=0.64, p=0.006). The mutant protein had 50% lower galactosyltransferase activity compared to the wild type protein. N-linked glycan profiling of human serum found 352Ser to be associated with decreased galactosylation and sialylation of ApoB100, fibrinogen, immunoglobulin G, and transferrin. B4galt1 353Ser knock-in mice showed significant decreases in LDL-C and fibrinogen. Our findings suggest that targeted modulation of protein galactosylation may represent a therapeutic approach to decrease CVD.