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Heart disease remains a leading cause of death globally. A gene mutation found among members of the Amish community could pave the way for new treatments, a research team recently reported.

The scientists delved into plasma’s depths to understand how a specific mutation of a gene involved in posttranslational modification of proteins via covalently adding carbohydrates, a process known as glycosylation, can affect our plasma proteome, lipid levels and potentially heart health.

In a study recently published in the journal Molecular & Cellular Proteomics, Yunlong Zhao and a team of scientists from Regeneron Pharmaceuticals in New York and the University of Maryland focused on the B4GALT1 gene. This gene directs the synthesis of the enzyme beta-1,4-galactosyltransferase 1, or B4GALT1. This enzyme catalyzes the addition of 脽-galactose sugar to core N-glycan structures during stepwise protein glycosylation in the Golgi apparatus.

Specifically, the researchers were interested in a naturally occurring mutation of B4GALT1 called N352S. This variant is exceedingly rare in the general population (fewer than one in 10,000 people have it), but it is found in about 12% of individuals in the Lancaster County, Pennsylvania, Amish community. The N352S mutation correlates with lower cardiovascular disease levels. The research team aims to understand how this variant alters B4GALT1 activity and how this affects levels of plasma glycoproteome and lipids, such as low-density lipoprotein cholesterol, which plays a role in atherosclerosis.

The team used plasma for a couple of reasons. “Plasma is an ideal starting point for our research. It can be directly drawn from individuals with this naturally occurring mutation and readily linked to other clinical indices,” Zhao said. “But it’s not just about convenience. Plasma contains proteins that regulate circulating lipid levels, making it relevant for their study.”

The team used tandem mass tag, or TMT, labeling proteomic and glycoproteomic approaches to look at proteins and their glycosylation patterns in plasma samples. They found that the N352S mutation primarily influences glycosylation patterns of plasma proteins without significantly altering the expression levels of most identified proteins, except the ones involved in the coagulation and immune response pathways.

“We are still in the process of fully understanding how the initial action leads to the final outcome,” Zhao said.

So, what does this mean for human health? The study highlights the potential of targeting glycosylation for treating heart diseases by regulating circulating lipid levels.

“While our findings are promising,” Zhao said, “it’s still too early to state that B4GALT1 could serve as a potential drug target, or that manipulating glycosylation could be a valid approach to treating atherosclerosis and cardiovascular disease.”

Zhao continued: “Currently, we are advancing our research through further validation studies using animal models and large-scale clinical sample analysis, aiming to confirm our initial findings and elucidate the underlying mechanisms, in collaboration with our partners. Our ultimate goal is to translate these findings into therapeutic value, but more research is needed before we can reach that point.”