ABOVE: An artist’s rendition of cholesterol blocking an artery © ISTOCK.COM, RASI BHADRAMANI

A gene variant initially uncovered in the genomes of people belonging to the Old Order Amish has been linked in a new study to lower levels of fibrinogen (a blood clotting factor) and low-density lipoprotein (LDL) cholesterol—both of which, when elevated, increase a person’s risk of developing cardiovascular disease. The work, published today (December 2) in Sciencenot only connects a missense mutation in the enzyme-coding gene beta-1,4-galactosyltransferase 1 (B4GALT1) with heart health in humans, but confirms the link in mice.

“This is a very good example of the utility of small founder or isolated populations in predicting genetic effects of genes that could not easily be identified even in the very big human biobanks that are available worldwide,” Caroline Hayward, who studies human genetics at the University of Edinburgh and did not participate in the study, writes in an email to The Scientist. 

May Montasser, a genetic epidemiologist at the University of Maryland School of Medicine, and colleagues study the genomes of the Old Order Amish because approximately 35,000 people alive today can trace their family history back to a small number of founder families. Due to the small pool of genetic starting material, this population harbors less genetic diversity than the general population, meaning that variants that might disappear in larger groups can be maintained in Old Order Amish populations and therefore be easier to spot.

See “Human Mutation Rates Steady Across Groups—Except in the Amish

In the new study, Montasser and colleagues sequenced the exons of 6,890 Old Order Amish subjects and found a missense mutation in B4GALT1, which is expressed throughout the body and encodes an enzyme that transfers galactose to proteins. The variant was associated with lower LDL cholesterol and was present in six percent of the Amish genomes but is much rarer outside the Amish community. The researchers found it in only eight of 140,000 non-Amish genomes that are part of a National Heart, Lung, and Blood Institute database.

When the team looked at other factors related to cardiovascular health in people carrying the missense mutation, they found no association with triglycerides and a small association with high density lipoprotein cholesterol. The blood clotting factor fibrinogen, which can be a risk factor for cardiovascular disease when elevated, was lower in people with the variant.

To assess whether the missense mutation in B4GALT was linked with overall cardiovascular health, the researchers shifted their focus outside the relatively healthy Amish population to the Geisinger Health System and the UK Biobank, two larger genomic databases. Because the specific variant they identified in the Amish is so rare in the general population, Montasser and her colleagues pulled out genomes with any variant of B4GALT. These individuals had decreased LDL, fibrinogen, and a 35 percent reduction in cardiovascular disease.

When the researchers generated knock-in mice with the B4GALT variant, the animals also had lower LDL and fibrinogen. Knocking the gene down just in the rodents’ livers led to lower levels of circulating LDL. The authors explain in the paper that this finding could point to the usefulness of targeting B4GALT expression in the liver therapeutically to lower LDL cholesterol. 

“The study provides strong evidence that this newly discovered mutation is relevant across population and species,” Kari North, a genetic epidemiologist at the University of North Carolina at Chapel Hill who did not participate in the work, writes in an email to The Scientist. B4GALT “may represent a new drug target for decreasing LDL-cholesterol and downstream [cardiovascular disease]. However, years of work are still needed to develop this new discovery into a new pharmaceutical target,” she adds. 

Before getting to the point of clinical relevance, “we have to make sure that there are not any harmful side effects [associated with] having this variant,” Montasser explains. “Having low LDL is great; having low fibrinogen is great, but is there anything else harmful? So far, based on all the other information we have, everything looks good. Those people look perfectly healthy, but we are doing even more deep phenotyping right now to make sure that we are not missing anything.” 

Another issue is that “it’s not clear how we go from having this variant to having low LDL and low fibrinogen and protection from cardiovascular disease,” she says. The research team is trying to characterize that mechanism in animal models and human samples now. Montasser says they will “keep working on it [and] hopefully someday we’ll have some form of therapy based on this.”