Finding a gem in GARNET

University of Virginia researchers seeking genetic markers for stroke, cardiovascular disease make breakthrough through NHGRI-supported program

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CHARLOTTESVILLE, Va.—After studying the genomes of nearly 5,000 people, scientists at the University of Virginia have discovered a genetic marker tied to an increased risk for stroke, as well as a key metabolic pathway to possibly pave the way for new prevention and treatment options for cardiovascular and other diseases. If successful, thousands of sudden paralyzing strokes and fatal heart attacks could be relegated to the past.
Stroke is the fourth-leading cause of death and a major cause of adult disability in the United states, yet its underlying genetics have been difficult to understand, says Dr. Stephen R. Williams, a postdoctoral fellow at the University of Virginia Cardiovascular Research Center and the University of Virginia Center for Public Health Genomics who adds, simply, “Our goals were to break down the risk factors for stroke.”
Williams, along with fellow University of Virginia faculty Dr. Michele Sale, an associate professor of medicine, and Dr. Brad Worrall, a professor of neurology and public health sciences, and their team reported their study findings March 20 in PLoS Genetics. Their work has been supported by the National Human Genome Research Institute (NHGRI) Genomics and Randomized Trials Network (GARNET) program.
The study focused on a biochemical pathway called the folate one-carbon metabolism (FOCM) pathway. Researchers knew that abnormally high blood levels of the amino acid homocysteine are associated with an increased risk of common diseases such as stroke, cardiovascular disease and dementia.
Homocysteine is a breakdown product of methionine, which is part of the FOCM pathway, Williams says. The same pathway can affect many important cellular processes, including the methylation of proteins, DNA and RNA. DNA methylation is a mechanism that cells use to control which genes are turned on and off, and when.
“But clinical trials of homocysteine-lowering therapies have not prevented disease, and the genetics underlying high homocysteine levels—and methionine metabolism gone awry—are not well defined,” he adds.
The University of Virginia researchers did their homework, conducting genome-wide association studies of participants from two large long-term projects: the Vitamin Intervention for Stroke Prevention (VISP), a trial looking at ways to prevent a second ischemic stroke, and the Framingham Heart Study (FHS), which has followed the cardiovascular health and disease in a general population for decades. They also measured methionine metabolism—the ability to convert methionine to homocysteine—in both groups. In all, they studied 2,100 VISP participants and 2,710 FHS subjects.
“We identified variants in five genes in the FOCM pathway that were associated with differences in a person’s ability to convert methionine to homocysteine,” Williams says. “They found that among the five genes, one—the ALDH1L1 gene—was also strongly associated with stroke in the Framingham study.”
When the gene is not working properly, it has been associated with a breakdown in a normal cellular process called programmed cell death and cancer cell survival, he said.
“Probably the most significant molecular part of this study is our discovery—at least in part—is how we found how GNMT (glycine N-methyltransferase) is controlled through sequence variation in the regulatory region of the GNMT gene,” Williams tells DDNews. “We also came up with some new techniques in the lab to recapitulate the post-methionine load test in cultured cells and discover how the GNMT gene reacts to this test based on differences in gene sequence.
“GNMT produces a protein that converts methionine to homocysteine,” he explains. “Of the five genes that we identified, it was the one most significantly associated with this process. The analyses suggest that differences in GNMT are the major drivers behind the differences in methionine metabolism in humans.”
The next step, of course: More research.
 “We have to identify how other genes in the one-carbon metabolism pathway react to methionine metabolism based on their DNA sequence,” Williams says. “And for that matter, we must see how different combinations of gene sequences react in the presence of each other. This is where our genetic risk score really comes in handy.”
Among their specific findings, the group determined that their five identified genes accounted for 6 percent of the difference in individuals’ ability to process methionine into homocysteine among those in the VISP trial. The genes also accounted for 13 percent of the difference in those participants in the FHS, a remarkable result given the complex nature of methionine metabolism and its impact on cerebrovascular risk, Williams notes, pointing out that in many complex diseases, genomic variants often account for less than 5 percent of such differences.
“Taking a pharmacogenetic approach. I’d say that clinical trials are not right around the corner, because we first need to completely characterize the functional consequences of DNA variation in the genes we identified,” Williams notes. “We can then apply interventions in the clinic whether they be with a drug of some sort or even basic lifestyle changes that an individual may not have thought about. If I had to guess, I’d say one day our work will help to prevent stroke at some level.”
The research may be too late for patients currently suffering from the effects of stroke and cardiovascular disease.
“Right now, this information is probably most important for those that are at risk but have not yet had a stroke,” Williams says. “This work may be important someday in how one recovers from a stroke. But our focus is to prevent the stroke from happening in the first place.”
The research is also “very significant for the general public,” he maintains. “With more and more people gaining access to their genetic information, it is imperative that they have the solid research to lean on before making any sort of lifestyle or treatment decisions. I believe that is what we have brought to the table.”
The investigators plan to study the other four genes in the pathway to try to better understand their potential roles in stroke and cardiovascular disease risk.
“In fact, we are in the process of understanding the function of other genes aside from GNMT,” Williams says. “Most importantly, we are trying to understand how difference combinations of genes may put one at risk.
“I’m not going to say that it is the most important research to date in vascular disease,” Williams notes. “However, I do believe that this work is very important and should be held in high regard. Everyone involved in this project did a stellar job. Also, research has shown that this pathway is targetable and that is great news. We now need to identify those individuals that are the best candidates.”
“This is a great example of the kinds of successful research efforts coming out of the GARNET program,” according to Program Director Dr. Ebony Madden. “GARNET scientists aim to identify variants that affect treatment response by doing association studies in randomized trials. These results show that variants in genes are associated with the differences in homocysteine levels in individuals.”

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