Genetic variant linked to Amish community could pave way for new heart disease therapies

Scientists have known about rare and common genetic variants that influence cardiovascular disease, but few gene mutations have been found to impact more than one risk for coronary artery disease. That gap in knowledge has limited the development of new treatments targeted to individual risk factors.

Now, scientists at the University of Maryland say they have found a genetic variant in the Old Order Amish population in Pennsylvania that could inform new medical approaches to decreasing or preventing the world’s leading cause of morbidity and death. The population was found to have increased levels of heart protection, ameliorating their risk for heart disease, the researchers explained in new findings published in the journal Science.

Using exome sequencing, the researchers found that people in the Old Order Amish community have a "missense" variant, or a single base pair substitution, in the gene B4GALT1. That correlates with a lower risk of cardiovascular disease. The gene codes for a protein that transfers the sugar molecule galactose across the cell membrane.

The University of Maryland team delivered the gene mutation to mouse models of cardiovascular disease using CRISPR-Cas9 technology. Animals with the variant experienced a 38% drop in blood low-density lipoprotein cholesterol, or LDL-C, and also saw a decline in the amount of the blood-clotting protein fibrinogen.

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The University of Maryland has studied the Old Order Amish since 1993, with more than 7,000 Amish adults participating in at least one study on genetic determinants of cardiometabolic health as part of a research program at the institution.

The group comprises about 40,000 in people in the Lancaster County, Pennsylvania, region, and most of the individuals can trace their ancestry back 15 generations to the 750 or so founders of the community.

While the group is relatively small—and variants such as the one found in B4GALT1 are typically rare or absent in the broader population—the new findings could still point to therapeutic targets that would pave the way for treatments relevant to most people, the scientists suggested.

Other academics and biopharmas are looking at genetic approaches to heart disease. A team at the University of Virginia, for example, found that several naturally occurring gene variants influence the buildup of fatty plaques in blood vessels, which can lead to heart attacks or strokes. The team also found that one gene, MIA3, plays a central role in forming protective caps to stabilize plaque lesions in blood vessels.  

Researchers across Harvard University and Imperial College London have built an atlas of the 500,000 cells in the heart that keep humans on the go. The cross-institutional team found that each of the six regions of the heart has its own subsets of cells, which could shed light on variable responses to treatments for cardiac diseases.