An international research team led by scientists at the University of Toronto, and at the University of Pittsburgh School of Medicine, has created what it says is a first-of-its-kind resource to identify individuals with a genetic risk for elevated low-density lipoprotein (LDL), or ‘bad’ cholesterol, a major contributor to heart disease. The team classified nearly 17,000 missense coding variants of the LDL receptor (LDLR) gene along with the corresponding changes in LDL receptor protein structure and uptake, creating maps relating sequence to function, and offering up functional insights and evidence for clinical utility.
They suggest the resource could help clinicians predict patient risk for heart attacks and strokes, allowing time for prevention and early treatment. Similar to how identifying mutations in the BRCA1 breast cancer gene has saved many lives by predicting cancer risk early enough for prevention, the authors hope this resource will provide a powerful clinical diagnostic tool for heart disease.
“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,” said Frederick Roth, PhD, professor and chair of computational and systems biology at Pitt. “By identifying damaging LDL receptor variants, clinicians can initiate preventive treatment early on and mitigate risks.”
Roth is senior author of the team’s published paper in Science, titled “The functional landscape of coding variation in the familial hypercholesterolemia gene LDLR,” in which the team stated, “… we tested the impact of ~17,000 (nearly all possible) LDLR missense coding variants on both LDLR cell-surface abundance and LDL uptake, yielding sequence–function maps that recapitulate known biochemistry, offer functional insights, and provide evidence for interpreting clinical variants.”
Heart disease remains the leading cause of death in the U.S., claiming nearly 700,000 lives each year. While diet and exercise play a role, the risk of heart disease is largely dictated by genetic predisposition to the accumulation of plaque inside the arteries that supply blood to the heart. This predisposition can arise from minor variations in the gene that encodes the receptor for LDL. “Variants in the familial hypercholesterolemia gene LDLR—the most important genetic driver of cardiovascular disease—can raise circulating low-density lipoprotein (LDL) cholesterol concentrations and increase the risk of premature atherosclerosis,” the authors wrote. “Heterozygous familial hypercholesterolemia (HeFH)—defined by an increase in circulating low-density lipoprotein (LDL) cholesterol—is among the most common and severe genetic causes of cardiovascular disease,” the authors wrote. “Genetic variants in LDLR can disrupt the clearance of LDL, accounting for ~80% of molecularly diagnosed HeFH cases.”
In healthy blood vessels LDL acts as a shuttle, transporting bits of ‘good’ cholesterol, an essential component of cell membranes that is also important for food digestion and the production of hormones and vitamins, including vitamin D. However, genetic mutations that lower the amount or efficiency of the LDL receptor can lead to harmfully high levels of LDL. Identifying pathogenic LDLR variants can thus aid accurate diagnosis, support prognosis and therapeutic management above that of lipid profiling, the team suggests
While modern gene sequencing technologies can read and decode a person’s entire genetic code from a small tissue sample within hours, interpreting such a vast amount of data is challenging, especially since the functional impact of most variations in the LDL receptor gene has previously been unknown. Most LDLR coding variants, however, lack a definitive clinical classification, the team pointed out. And even where variants have been classified, quantitative estimates of variant impact are often unavailable. “Definitive classifications are lacking for nearly half of clinically encountered LDLR missense variants, limiting interventions that reduce disease burden,” Roth and colleagues continued. “This currently limits opportunities for early diagnosis and patient risk stratification for HeFH.”
For their newly reported work Roth and team classified nearly 17,000 modifications of the LDL receptor gene along with the corresponding changes in the LDL receptor protein structure. “We assayed both cellular LDL uptake and LDLR cell-surface abundance as quantitative cellular read-outs relevant to HeFH pathophysiolgy.”
The resulting table measures each protein variant based on its mechanism of action and its impact on LDL clearance efficiency, providing clinicians with potentially actionable insights into their patients’ risk of elevated LDL. “The resulting sequence–function maps not only reflect our current understanding of LDLR function, but also reveal unexpected biochemical insights, and offer the potential to inform clinical variant interpretation and improve patient risk estimation for HeFH,” the authors further stated. “Functional scores correlated with hyperlipidemia phenotypes in prospective human cohorts and augmented polygenic scores to improve risk inference, highlighting the potential of this resource to accelerate familial hypercholesterolemia diagnosis and improve patient outcomes.”
Study co-author Dan Roden, MD, a clinician-scientist at Vanderbilt University Medical Center commented, “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 study also identified a subset of LDL receptor variants for which the ability to take up LDL was inhibited by high levels of very low-density lipoprotein (VLDL), a larger 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,” said first author Daniel Tabet, PhD, at the University of Toronto.
This cholesterol-specific effort is a part of a broader research community initiative co-founded by Roth to map the functional effects of genetic variants across inherited disorders, called the Atlas of Variant Effects Alliance, which now includes more than 500 scientists from 50 countries, all working to build similarly comprehensive maps that evaluate gene variants known to affect risk of many diseases on a large scale.
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