Genetic variation impact scores: A new tool for earlier heart disease detection

An international research consortium co-led by scientists from Vanderbilt University Medical Center, the University of Toronto and University of Pittsburgh has mapped the functional impact of more than 17,000 variants in a major gene associated with the development of premature atherosclerotic heart disease.

The study, reported Oct. 30 in the journal Science, will go a long way to improving the early diagnosis and treatment of familial hypercholesterolemia (FH), a common genetic driver of cardiovascular disease that occurs in an estimated 1 in every 250 individuals, the researchers noted.

FH is underdiagnosed and undertreated, in part because of the lack of classification, or determination of pathogenicity (the ability to cause disease), for most new variants detected during genetic testing in the clinic.

The new variant impact scores “have the potential to increase the number of (FH) diagnoses for those with unclassified variants by a factor of 10,” predicted Dan Roden, MD, a co-author of the report and Senior Vice President for Personalized Medicine at VUMC.

Roden, the Sam L. Clark, MD, PhD Professor of Medicine, Pharmacology and Biomedical Informatics, is co-principal investigator of a four-year, $8.2 million grant awarded in 2022 by the National Heart, Lung, and Blood Institute of the National Institutes of Health (NIH) to map genetic variations that negatively affect heart function.

The grant supported establishment of the multi-institutional CardioVar Consortium, which is generating a comprehensive atlas of “variant effect maps” to distinguish disease-causing variants from those that are harmless.

Co-investigators (and co-authors of the Science paper) are Frederick Roth, PhD, University of Pittsburgh School of Medicine; Euan Ashley, MBChB, DPhil, and Victoria Parikh, MD, Stanford University School of Medicine; Calum MacRae, MD, PhD, Harvard Medical School; and Andrew Glazer, PhD, and Brett Kroncke, PhD, assistant professors of Medicine at VUMC.

Roth, who is internationally known for his work in computational biology and genomics, led the study, which was conducted primarily at the University of Toronto and Sinai Health in Toronto. Currently he chairs the Department of Computational and Systems Biology at Pitt.

The study focused on variations in the gene for the low-density lipoprotein receptor (LDLR), which normally clears the blood of LDL cholesterol, a major culprit in the buildup of atherosclerotic plaque on blood vessel walls.

The researchers developed, optimized and validated a range of high-throughput cellular assays to measure variant function and discriminate pathogenic from benign variants. They used cutting-edge techniques to determine the functional impact of thousands of LDLR gene variants on LDL clearance and on the abundance of LDL receptors at the cell surface.

The goal is to develop a variant-centric decision support system that will be shared widely to help clinicians evaluate functional evidence of heart disease in patients undergoing genetic testing, thereby facilitating personalized care.

“By identifying damaging LDL receptor variants, clinicians can initiate preventive treatment early on and mitigate risks,” Roth said in a news release.

Postdoctoral fellow Daniel Tabet, PhD, and senior research associate Atina Coté, PhD, at the University of Toronto, led key experimental work in the study and are the paper’s first authors. Former VUMC clinical fellow Megan Lancaster, MD, PhD, now at Ohio State University, helped evaluate the data.

Other co-authors are from Western University of London, Ontario, the University of Helsinki, Case Western Reserve University, University of Washington, University of Lisbon, and the Broad Institute of MIT and Harvard.

The research was supported by NIH grants R01HL164675 and RM1HG010461; the One Brave Idea Initiative, jointly funded by the American Heart Association, Verily Life Sciences LLC and Astra-Zeneca Inc.; the Canada Foundation for Innovation; Canadian Institutes of Health Research Foundation; Canada Excellence Research Chairs Program; EU Horizon and the La Caixa Foundation.