UM School of Medicine & Regeneron researchers link new gene variant in Amish population to lower risk of heart disease

University of Maryland School of Medicine (UMSOM) researchers, working with scientists from the Regeneron Genetics Center (RGC), discovered a new gene variant associated with lower levels of heart-damaging LDL cholesterol and a blood clotting protein called fibrinogen that appears to significantly lower a person’s risk of heart disease. While the gene variant is extremely rare in the general population (less than 1 in 10,000), it is found in about 12 percent of those living in the Lancaster county, Pennsylvania Amish community, according to the study published today in the journal Science.

Researchers have long known about gene mutations linked to cholesterol levels. This is the first time, however, they have found a gene variant that can significantly reduce the level of two heart disease risk factors and subsequently reduce a person’s risk of heart disease. The finding could potentially lead to novel treatments that may help prevent clogged arteries, blood clots, and cardiovascular disease.

“Leveraging data from more than 500,000 from the general population, it was found that those who carried this variant had a 35 percent lower risk of heart disease compared to those who did not,” said study leader May Montasser, PhD, Assistant Professor of Medicine at UMSOM and a member of UMSOM’s Program for Personalized and Genomic Medicine. “The genetic variant appears to either control the synthesis of cholesterol and fibrinogen or accelerate their clearance from the blood, which protects the heart. This finding could lead to targeted drugs that mimic the action of this variant to keep arteries free of plaque and clots.”

Genetic sequencing  of samples from nearly 7,000 Amish study participants who have been participating in genetic research with UMSOM since 1995 was performed at the RGC. The researchers found a genetic variant in the gene B4GALT1 was associated with a nearly 14 mg/dL lower LDL cholesterol and nearly 30 mg/dL lower fibrinogen. After the variant was identified, they tested its effects in mice that were genetically modified to express the variant.

“The mouse model, encoding for this gene mutation, also showed decreased levels of LDL cholesterol and fibrinogen, confirming the effect of this variant,” said Giusy Della Gatta, PhD, study leader and RGC senior staff scientist. “This model represents an invaluable tool to unravel the molecular mechanisms that help protect against cardiovascular disease.”

The Amish community is ideal for genetic studies due to its common lineage and homogeneous lifestyle that makes finding novel links between genes and health easier for scientists. Study co-author Alan Shuldiner, MD, John L. Whitehurst Professor of Medicine and Associate Dean for Personalized & Genomic Medicine at UMSOM, founded the Amish Research Clinic in Lancaster, PA. The clinic's research has discovered genes playing a role in type 2 diabetes and heart disease, as well as a gene that plays a role in determining why some people don't respond to the anti­clotting medicine Plavix.

Dr. Shuldiner is also a Vice President at the Regeneron Genetics Center. Other UMSOM co-authors include: Simeon I. Taylor, MD, PhD, Professor of Medicine; Jeffrey O’Connell, PhD, Associate Professor of Medicine; Elizabeth A. Streeten, MD, Professor of Medicine and Braxton Mitchell, PhD, Professor of Medicine. The study was funded by the National Institutes of Health, the American Heart Association, and the Regeneron Genetics Center.

“This is a ground-breaking finding and would not have been possible without the participation and partnership of the Amish community,” said E. Albert Reece, MD, PhD, MBA, Executive Vice President for Medical Affairs, UM Baltimore, and the John Z. and Akiko K. Bowers Distinguished Professor and Dean, University of Maryland School of Medicine. "We are so grateful for their continuing commitment to research and advancement of precision medicine.”

About the University of Maryland School of Medicine

Now in its third century, the University of Maryland School of Medicine was chartered in 1807 as the first public medical school in the United States. It continues today as one of the fastest growing, top-tier biomedical research enterprises in the world -- with 46 academic departments, centers, institutes, and programs, and a faculty of more than 3,000 physicians, scientists, and allied health professionals, including members of the National Academy of Medicine and the National Academy of Sciences, and a distinguished two-time winner of the Albert E. Lasker Award in Medical Research.  With an operating budget of more than $1.2 billion, the School of Medicine works closely in partnership with the University of Maryland Medical Center and Medical System to provide research-intensive, academic and clinically based care for nearly 2 million patients each year. The School of Medicine has nearly $600 million in extramural funding, with most of its academic departments highly ranked among all medical schools in the nation in research funding.  As one of the seven professional schools that make up the University of Maryland, Baltimore campus, the School of Medicine has a total population of nearly 9,000 faculty and staff, including 2,500 students, trainees, residents, and fellows. The combined School of Medicine and Medical System (“University of Maryland Medicine”) has an annual budget of over $6 billion and an economic impact of nearly $20 billion on the state and local community. The School of Medicine, which ranks as the 8th highest among public medical schools in research productivity (according to the Association of American Medical Colleges profile) is an innovator in translational medicine, with 606 active patents and 52 start-up companies.  In the latest U.S. News & World Report ranking of the Best Medical Schools, published in 2021, the UM School of Medicine is ranked #9 among the 92 public medical schools in the U.S., and in the top 15 percent (#27) of all 192 public and private U.S. medical schools.  The School of Medicine works locally, nationally, and globally, with research and treatment facilities in 36 countries around the world. Visit medschool.umaryland.edu

About the Regeneron Genetics Center

The Regeneron Genetics Center LLC (RGC) is a wholly owned subsidiary of Regeneron Pharmaceuticals, Inc. that focuses on early gene discovery and functional genomics. The primary goal of the RGC is to improve patient outcomes by identifying novel drug targets, clinical indications for development programs, and genomic biomarkers for pharmacogenomic applications. The RGC is tackling large-scale sequencing and analytical approaches and has established numerous collaborations with leading human genetics researchers. To enable this large-scale sequencing and analysis program, the RGC utilizes fully automated sample preparation and data processing, as well as cutting-edge cloud-based informatics. Visit www.regeneron.com/science/genetics-center