Variant identified in Amish population appears to protect against cardiovascular disease


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

“Our data suggest that modulation of B4GALT1 expression and / or activity may have pleiotropic effects for cardioprotection,” wrote co-first author and corresponding author May Montasser, researcher at the University of Maryland. , and its co-authors. “A better understanding of the underlying mechanisms, including potential adverse consequences, could reveal new targets and new avenues for the treatment and prevention of [cardiovascular disease]. “

As they reported in Science On Thursday, researchers at the University of Maryland School of Medicine, the Regeneron Genetics Center, the International Human Genome Research Laboratory in Mexico and elsewhere, began by sequencing the exomes of 6,890 Amish individuals from the ‘old order, narrowing down on a B4GALT1 misunderstanding. coding variant called rs551564683 which coincided with reduced blood levels of low density lipoprotein cholesterol (LDL-C) and plasma protein fibrinogen, which is also linked to coronary artery disease.

Although the B4GALT1 variant appeared in approximately 6% of individuals in the Old Order Amish population, the team found only eight copies of the proposed cardioprotective allele in whole-genome sequence data from 140,000 non-Amish individuals. National Heart participant, Lung, and the Blood Institute’s Trans-omics for Precision Medicine (TOPMed) project, which includes many different ancestries, suggesting the variant is extremely rare in populations in other parts of the world.

The same variant showed links to blood LDL-C levels when researchers performed an association analysis that included nearly 1,100 Old Order Amish individuals whose genomes had been sequenced for TOPMed. It belonged to a larger haplotype that spanned 21 variants in linkage disequilibrium with each other – information they used to impute variants from matrix-based genotyping profiles for 5,890 other Amish Old Order participants from TOPMed.

From these and other analyzes, the team found that rs551564683 was the primary causative candidate, prompting further examination of its possible associations with other markers linked to heart disease such as total cholesterol. , high density lipoprotein cholesterol (HDL-C), non-HDL-C and triglyceride levels in the blood.

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 a B4GALT1 variant or knockout mouse models, the analyzes suggested that the B4GALT1 gene variant produced versions of the enzyme galactosyltransferase with about half of its normal activity levels, the researchers reported, altering the way it processes the N-linked oligosaccharide part of certain glycoproteins.

They then explored associations of B4GALT1 variants with heart disease risk using exome sequence data for 544,955 individuals profiled for the Geisinger Health System DiscovEHR project and the UK Biobank study, or UKBB.

Because the variant found in the Old Order Amish population was so rare in other populations, investigators relied on a multivariate load test to find an overrepresentation of deleterious or rare loss of function variants in B4GALT1 in B4GALT1. people with reduced blood plasma levels of LDL-C and higher than usual levels of an aspartate transaminase enzyme, which has been linked to variation in B4GALT1 in the past, as well as a reduced risk of coronary heart disease .

“The combination 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 large cohorts additional sequence-based tests to validate this association. “


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