The Variants We’re Ignoring May Be Killing

Key Takeaway: A study of over 104,000 individuals of African ancestry has revealed that genetic variants for high cholesterol currently classified as “of unknown significance” carry the same heart attack risk as variants already known to be dangerous. This finding suggests that genetic testing, which relies predominantly on European data, may be systematically underestimating cardiovascular risk in Black Americans, creating a dangerous gap in diagnosis and treatment.

A Dangerous Blind Spot in Your DNA Report

Imagine receiving a genetic test result where your cholesterol-related genetic variant is listed as “of unknown significance.” In medical jargon, this means, “we’re not sure if this matters.” You might breathe a sigh of relief. Your physician might file the result away. But what if that variant is just as deadly as one flagged as dangerous? For tens of thousands of African Americans, this is not a hypothetical scenario but a reality that a landmark study has brought into sharp, unsettling focus.

This discovery exposes a profoundly uncomfortable truth about the foundation of modern genomic medicine: the databases that determine whether a genetic variant is “benign” or “pathogenic” are built overwhelmingly with data from individuals of European descent^[2]. When a variant hasn’t been studied in diverse populations, it gets stamped with a frustrating label: variant of unknown significance, or VUS. And this research suggests that label may be costing lives.

What Did the Researchers Do?

The study pooled data from 104,300 individuals of African ancestry, drawing from three of the largest and most diverse genomic cohorts in the United States—the All of Us Research Program, BioMe, and MyCode. The researchers focused on genes associated with familial hypercholesterolemia (FH), an inherited condition that sends LDL cholesterol soaring from birth and dramatically increases the risk of an early heart attack^[3]. While FH affects about 1 in 250 people worldwide, it remains largely undiagnosed, particularly in non-European populations^[4].

The team compared the prevalence of two categories of genetic variants in FH-associated genes: known pathogenic variants (those already confirmed to cause disease) and VUS (those in the gray area of uncertainty). They then tracked whether carrying either type of variant was associated with real-world clinical outcomes—specifically, myocardial infarction.

The Findings

The first finding was superficially reassuring: the rate of known pathogenic FH variants was similar between individuals of African ancestry (1 in 306) and European ancestry (1 in 273). In other words, FH does not discriminate by race.

But the second finding was alarming. Variants of unknown significance were 1.61 times more common in individuals of African ancestry compared to their European counterparts. This excess of VUS reflects the well-documented European-centric bias in genetic reference databases—when a population is underrepresented in research, more of its variants remain unclassified.

The most critical finding, however, was this: carrying a VUS increased the risk of myocardial infarction 1.91-fold—but this risk increase was observed only in the group with African ancestry^[1]. This magnitude of risk was statistically equivalent to that of carrying a variant classified as pathogenic. Simply put, these so-called “unknown” variants appear to be just as dangerous as the ones medicine already takes seriously.

The Biological Mechanism: How It Works in the Body

Familial hypercholesterolemia typically results from mutations in the genes that govern how the body clears LDL cholesterol from the bloodstream. The most commonly affected gene, LDLR, codes for the LDL receptor—a protein on the surface of liver cells that snags LDL particles out of circulation^[5]. Mutations in the APOB and PCSK9 genes can similarly disrupt this clearance system. When any of these genes malfunctions, LDL cholesterol builds up relentlessly, seeping into artery walls and forming the fatty plaques that eventually rupture to cause a myocardial infarction.

The biological consequence of a VUS in one of these genes is no different if the variant truly impairs protein function. Cholesterol doesn’t care how a database classifies a mutation. If a variant in the LDLR gene messes with the receptor’s folding, trafficking, or binding capacity, LDL levels will rise, regardless of what the lab report says. The problem is purely one of information—our classification systems have not yet caught up to the genetic diversity of the people they are meant to serve.

This matters because FH is one of the most treatable genetic conditions in cardiology. High-intensity statins, ezetimibe, and PCSK9 inhibitors, when started early, can slash LDL levels and dramatically reduce cardiovascular events^[6]. But treatment requires a diagnosis, and diagnosis increasingly relies on genetic tests that may be systematically failing an entire population.

Limitations of the Study

No single study is generalizable, and this one has important caveats. While the cohorts were large, they were drawn from U.S.-based biobanks, meaning the findings may not generalize directly to African populations globally. The VUS category is inherently heterogeneous—some of these variants may indeed be benign, while others are truly pathogenic. Functional studies on individual variants will be required to confirm which belong in which category. Additionally, the study relied on data from electronic health records for outcomes like myocardial infarction, which can be subject to misclassification.

Final Assessment: Implications for the Future

For patients of African ancestry who have undergone genetic testing for cholesterol disorders, a VUS result should no longer be met with a shrug. This study suggests such variants deserve the same clinical urgency as a confirmed pathogenic finding—aggressive lipid monitoring, early consideration of statin therapy, and cascade screening of family members. For clinicians, the message is equally clear: if the patient before you is an individual of African ancestry with high LDL, do not let the VUS label lull you into inaction.

At a systems level, this research is a powerful indictment of the status quo in genomic medicine. The databases that classify genetic variants—ClinVar, ClinGen, and others—require a massive infusion of data from diverse populations^[7]. Without this investment, precision medicine will remain precise for some but dangerously imprecise for others. The promise of genomic science was to tailor treatment to the individual. Right now, for millions of Americans, that promise is broken. This study shows us exactly where the fracture is.

Scientific Sources

1. Winters AH, et al. A Genome-First Study of Familial Hypercholesterolemia Comparing African and European Ancestry Individuals. Circulation. 2026;153(24):1928-1939. PubMed: https://pubmed.ncbi.nlm.nih.gov/42212376/
2. Popejoy AB, Fullerton SM. Genomics is failing on diversity. Nature. 2016;538(7624):161-164.
3. Goldstein JL, Brown MS. Familial hypercholesterolemia: identification of a defect in the regulation of 3-hydroxy-3-methylglutaryl coenzyme A reductase activity associated with overproduction of cholesterol. Proc Natl Acad Sci U S A. 1973;70(10):2804-2808.
4. Nordestgaard BG, et al. Familial hypercholesterolaemia is underdiagnosed and undertreated in the general population: guidance for clinicians to prevent coronary heart disease. Eur Heart J. 2013;34(45):3478-3490.
5. Hobbs HH, Brown MS, Goldstein JL. Molecular genetics of the LDL receptor gene in familial hypercholesterolemia. Hum Mutat. 1992;1(6):445-466.
6. Raal FJ, et al. Reduction in mortality in subjects with homozygous familial hypercholesterolemia associated with advances in lipid-lowering therapy. Circulation. 2011;124(20):2202-2207.
7. Landrum MJ, et al. ClinVar: improving access to variant interpretations and supporting evidence. Nucleic Acids Res. 2018;46(D1):D1062-D1067.