University of Pittsburgh scientists have developed a pioneering resource to identify genetic variants linked to high “bad” cholesterol, offering a revolutionary tool for early prediction and prevention of heart attacks and strokes.
In a landmark study published on Oct. 30 in the journal Science, an international research team led by a scientist from the University of Pittsburgh School of Medicine has unveiled a pioneering resource to identify individuals at genetic risk for elevated ‘bad’ cholesterol, a major contributor to heart disease.
The study promises to revolutionize the field of cardiology by enabling clinicians to predict patient risk for heart attacks and strokes much earlier, allowing for timely intervention and preventive treatment measures.
Heart disease remains the leading cause of death in the United States, claiming nearly 700,000 lives annually. While lifestyle factors like diet and exercise contribute to heart health, a significant portion of heart disease risk is attributed to genetics.
Minor variations in the gene encoding the receptor for LDL, or low-density lipoprotein — often labeled as “bad” cholesterol — can result in the build-up of harmful plaque in the arteries.
“Even with normal LDL levels, a person might be at an elevated risk of a heart attack due to disease-causing variants in the LDL receptor,” senior author Frederick P. Roth, the John K. Vries Professor of Computational Biology and chair of computational and systems biology at Pitt, said in a news release. “By identifying damaging LDL receptor variants, clinicians can initiate preventive treatment early on and mitigate risks.”
LDL acts as a shuttle in healthy blood vessels, transporting “good” cholesterol essential for various bodily functions, including the production of hormones and vitamins. However, genetic mutations that lower the quantity or efficiency of the LDL receptor protein can lead to dangerously high LDL levels.
Advanced gene sequencing technologies now allow scientists to decode an individual’s entire genetic code rapidly. Nonetheless, interpreting the vast amount of genetic data to determine which variations affect health has remained a major challenge.
This new resource addresses this issue by classifying nearly 17,000 modifications of the LDL receptor gene and correlating them with changes in the LDL receptor protein’s structure and function.
“New unclassified variants are seen all the time in the clinic, and we often don’t have the evidence we need to inform patient care,” added co-author Dan Roden, a clinician-scientist at Vanderbilt University Medical Center (VUMC). “These variant impact scores have the potential to increase the number of diagnoses of familial high cholesterol for those with unclassified variants by a factor of ten.”
This cholesterol-specific initiative is part of a larger project known as the Atlas of Variant Effects Alliance, co-founded by Roth. The alliance boasts over 500 scientists from 50 countries focused on mapping the functional effects of genetic variants across various inherited disorders.
The study also revealed a surprising finding: a subset of LDL receptor variants showed reduced LDL uptake due to high levels of very low-density lipoprotein (VLDL), a precursor of LDL.
“The influence of VLDL on LDL uptake was an unexpected finding. We’re excited about investigating this further and understanding potential implications for human health,” added lead author Daniel Tabet, of the University of Toronto.