Background
Familial hypercholesterolemia (FH) is a common inherited condition that causes lifelong high levels of low-density lipoprotein cholesterol (LDL-C), often called “bad cholesterol.” Because LDL-C remains elevated from birth, people with FH face a much higher risk of early atherosclerosis, heart attack, and other cardiovascular complications if the condition is not recognized and treated early. Standard care usually includes intensive lifestyle counseling, statin therapy, and, when needed, additional lipid-lowering medicines such as ezetimibe or PCSK9 inhibitors.
Most FH research has historically focused on people of European ancestry. As a result, the way we define and classify genetic variants linked to FH has been shaped heavily by European reference data. This can create problems when those same classification systems are applied to people from other ancestry groups, especially African ancestry individuals, whose genetic variation may be underrepresented in current databases. One concern is that variants of uncertain significance, or VUSs, may be more common in African ancestry groups and may not be properly recognized as clinically important.
What this study set out to examine
This genome-first study asked two main questions: first, whether the prevalence of pathogenic FH variants differs between African and European ancestry individuals; and second, whether variants classified as uncertain have similar clinical meaning across ancestry groups. The investigators also looked at whether these variants were associated with LDL-C levels and the risk of myocardial infarction.
How the study was done
The researchers analyzed data from 104,300 African ancestry individuals enrolled in three large United States cohorts: the National Institutes of Health’s All of Us Research Program, Mount Sinai’s BioMe Biobank, and Geisinger’s MyCode Community Health Initiative. For comparison, participants with European ancestry were also included. Genetic ancestry was assigned using similarity to reference populations rather than self-report alone, allowing a more biologically grounded comparison.
Genetic variants linked to FH were reviewed using standards from the Clinical Genome Resource FH Variant Curation Expert Panel. Variants were grouped into two clinically important categories: pathogenic variants, which are considered disease-causing, and variants of unknown significance, which are changes in DNA that cannot yet be confidently labeled as harmful or benign.
The main clinical outcomes were LDL-C levels and myocardial infarction. Analyses were adjusted for age and sex, and results from the three cohorts were combined using meta-analysis.
Key findings
The study found that pathogenic FH variants were similarly common in both ancestry groups. The prevalence was about 1 in 306 among African ancestry individuals and 1 in 273 among European ancestry individuals. In other words, the overall burden of clearly pathogenic FH variants did not differ meaningfully between the two groups.
However, the effect of these variants on LDL-C was not identical. Among people carrying pathogenic variants, those with African ancestry had LDL-C levels that were 20.81 mg/dL higher, on average, than those with European ancestry carrying similar variants. This suggests that the relationship between genotype and lipid levels may vary by ancestry, likely due to a combination of genetic background, polygenic influences, and environmental factors.
The study also found that African ancestry individuals had 1.61 times higher odds of carrying a VUS than European ancestry individuals. Even more importantly, African ancestry individuals with a VUS had LDL-C levels that were 10.01 mg/dL higher than European ancestry individuals with a VUS. This raises concern that some variants currently labeled as uncertain may actually have clinically meaningful effects in African ancestry populations.
When the investigators looked at myocardial infarction risk, pathogenic variants increased risk by roughly 2- to 3-fold in both ancestry groups, consistent with prior FH research. Strikingly, VUSs were associated with increased myocardial infarction risk only in the African ancestry group, with an odds ratio of 1.91. This finding suggests that certain variants treated as uncertain in current databases may not be benign in this population.
Why these findings matter
These results have important implications for diagnosis and equity in cardiovascular care. If variant classification systems rely too heavily on European ancestry data, then FH may be underdiagnosed in people of African ancestry. A variant that appears ambiguous in one population may carry a stronger disease signal in another. When that happens, patients may miss the opportunity for early treatment, family screening, and prevention of heart disease.
FH is one of the clearest examples of a condition where early genetic diagnosis can change outcomes. Identifying affected individuals allows clinicians to start aggressive LDL-C lowering before major cardiovascular damage occurs. It also supports cascade screening, a process in which relatives are tested so that others with the same inherited risk can be identified and treated.
This study shows that expanding and diversifying genetic databases is not just a scientific priority, but a clinical necessity. More inclusive variant curation can help reduce health disparities, improve diagnostic accuracy, and ensure that genome-based medicine benefits all populations more equally.
Clinical interpretation
For clinicians, the key message is that a VUS should not automatically be dismissed, especially when the patient has a strong lipid phenotype or family history suggestive of FH. In African ancestry populations, the study suggests that some VUSs may warrant closer attention, additional evidence review, and perhaps more proactive management while classification remains unresolved.
At the same time, the study does not mean that every VUS should be treated as definitively pathogenic. Instead, it highlights the need for cautious interpretation, integration of genetic results with clinical findings, and improved ancestry-aware variant databases. LDL-C levels, personal history of premature cardiovascular disease, and family history remain central to diagnosis.
Limitations
Like all observational studies, this one has limits. The results come from large U.S.-based cohorts, so they may not reflect all African-ancestry populations globally. The study also depends on current variant classification systems, which are themselves incomplete and continuously evolving. In addition, LDL-C levels and myocardial infarction risk are influenced by many factors beyond FH variants, including access to care, diet, medication use, and social determinants of health.
Even so, the large sample size and use of multiple cohorts strengthen the findings. The consistency of the signal across datasets makes the conclusions clinically important and worthy of further study.
Conclusion
This genome-first study found that pathogenic FH variants are similarly prevalent in African and European ancestry individuals, but variants of uncertain significance are more common in African ancestry groups and may carry meaningful cardiovascular risk. The findings suggest that current variant classification resources, if used without ancestry-aware refinement, may contribute to missed or delayed diagnosis of FH in people of African ancestry.
The broader takeaway is clear: precision medicine must be inclusive to be truly precise. For FH, that means improving genetic reference datasets, re-evaluating uncertain variants with diverse populations, and ensuring that all patients have an equal chance of early diagnosis and prevention of heart disease.
