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Variant Identified in Amish Population Appears to Protect From Cardiovascular Disease

Old Order Amish horse and buggy

NEW YORK – New research suggests that a rare missense variant in the beta-1,4-galactosyltransferase 1 gene B4GALT1, initially detected in an Amish founder population, is linked to lower-than-usual levels of cardiovascular disease markers in the blood and may dial down heart disease risk.

"Our data suggest that modulation of B4GALT1 expression and/or activity may have pleiotropic effects for cardioprotection," co-first author and corresponding author May Montasser, a researcher at the University of Maryland, and her co-authors wrote. "Further understanding of the underlying mechanisms, including potential adverse consequences, may divulge new targets and pathways for the treatment and prevention of [cardiovascular disease]."

As they reported in Science on Thursday, the researchers, from the University of Maryland School of Medicine, Regeneron Genetics Center, the International Laboratory for Human Genome Research in Mexico, and elsewhere, started with sequencing the exomes of 6,890 Old Order Amish individuals, narrowing in on a missense B4GALT1 coding variant called rs551564683 that coincided with reduced blood levels of both low-density lipoprotein cholesterol (LDL-C) and plasma protein fibrinogen, which is also related to coronary artery disease.

Although the B4GALT1 variant turned up in around 6 percent of individuals from the Old Order Amish population, the team tracked down just eight copies of the proposed cardioprotective allele in whole-genome sequence data from 140,000 non-Amish individuals participating in the National Heart, Lung, and Blood Institute's "Trans-omics for precision medicine" (TOPMed) project, which includes many different ancestries, suggesting the variant is extremely rare in populations from other parts of the world.

The same variant showed ties to LDL-C levels in the blood when the researchers performed an association analysis that included almost 1,100 Old Order Amish individuals who had their genomes sequenced for TOPMed. It belonged to a broader haplotype that spanned 21 variants in linkage disequilibrium with one another — information they used to impute variants from array-based genotyping profiles for another 5,890 Old Order Amish participants from TOPMed.

From these and other analyses, the team found that rs551564683 was the top causal candidate, prompting a closer look at its possible associations with other heart disease-related markers such as total cholesterol, high-density lipoprotein cholesterol (HDL-C), non-HDL-C, and triglyceride levels in the blood.

Together with follow-up experiments in blood serum samples from more than two dozen individuals with or without B4GALT1 variants, an African green monkey cell line, and B4GALT1 variant or knockout mouse models, the analyses suggested that the B4GALT1 gene variant produced versions of the galactosyltransferase enzyme with around half its normal activity levels, the researchers reported, altering the way it processes the N-linked oligosaccharide portion of some glycoproteins.

They went on to explore B4GALT1 variant associations with heart disease risk using exome sequence data for 544,955 individuals profiled for the Geisinger Health System DiscovEHR project and the UK Biobank, or UKBB, study.

Because the variant found in the Old Order Amish population was so uncommon in other populations, the investigators relied on a multi-variant burden testing to find an overrepresentation of rare deleterious or loss-of-function variants in B4GALT1 in individuals with reduced blood plasma levels of LDL-C and higher-than-usual levels of an aspartate transaminase enzyme, which has been linked to B4GALT1 variation in the past, along with reduced coronary artery disease risk.

"The association was protective in both the DiscovEHR and UKBB data, although the effect was much more significant in the UKBB data," the authors wrote, noting that the "rare nature of these variants will require additional large sequence-based cohorts to validate this association."

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