Resource Identifies Genetic Risk for Elevated Bad Cholesterol and Heart Disease

An international team led by researchers at the University of Pittsburgh School of Medicine has developed a novel resource to identify people with a genetic risk for elevated levels of low-density lipoprotein (LDL), commonly known as bad cholesterol, a major contributor to heart disease. Published in Science, this resource allows clinicians to better predict patient risk for heart attacks and strokes, enabling earlier prevention and treatment.

Heart disease remains the leading cause of death in the United States, accounting for nearly 700,000 deaths each year. While lifestyle factors such as diet and exercise influence cardiovascular health, genetic predisposition plays a key role. Variations in the gene encoding the LDL receptor (LDLR), responsible for removing LDL from the bloodstream, can cause the accumulation of waxy plaques inside arteries that supply blood to the heart. These plaques stiffen arteries and increase the likelihood of heart attacks and strokes.

Senior author Frederick Roth explained, “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.” By identifying damaging LDL receptor variants, clinicians can initiate preventive treatment earlier to mitigate risks.

The study classified nearly 17,000 LDLR gene variants along with their corresponding impacts on LDL receptor protein structure and function. This classification allows clinicians to assess how each variant influences LDL clearance efficiency, providing potentially actionable insights. Co-author Dan Roden noted, “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. 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.”

The research also uncovered that some LDL receptor variants show reduced ability to take up LDL due to inhibition by very low-density lipoprotein (VLDL), a larger precursor to LDL.

This resource forms part of the Atlas of Variant Effects Alliance, a global scientific effort co-founded by Roth to map functional effects of genetic variants across inherited disorders. Similar to how BRCA1 gene mutation screening helps predict breast cancer risk, this resource aims to enhance early detection and treatment of heart disease by illuminating the genetic causes behind elevated bad cholesterol.