Highlights
- The prevalence of pathogenic variants for Familial Hypercholesterolemia (FH) is nearly identical between African (1 in 306) and European (1 in 273) ancestry populations, refuting previous assumptions of ethnic disparity in carrier frequency.
- African ancestry individuals with FH pathogenic variants exhibit a significantly higher elevation in LDL-C (approximately 20.8 mg/dL more) compared to their European counterparts, suggesting greater phenotypic severity for similar genotypes.
- Variants of Unknown Significance (VUS) are significantly more common in African ancestry individuals and are associated with a nearly two-fold increased risk of myocardial infarction, comparable to the risk of known pathogenic variants.
- Current genetic classification standards, primarily derived from European data, likely contribute to the systematic underdiagnosis and undertreatment of FH in non-European populations.
Background
Familial hypercholesterolemia (FH) is an autosomal dominant disorder, primarily involving mutations in the LDLR, APOB, and PCSK9 genes, leading to lifelong exposure to elevated low-density lipoprotein cholesterol (LDL-C) and a dramatically increased risk of premature myocardial infarction (MI). Despite being one of the most common life-threatening genetic conditions, FH remains vastly underdiagnosed worldwide. Historically, genomic research and clinical registries have been heavily skewed toward populations of European ancestry. This Eurocentric bias has limited our understanding of FH prevalence, variant interpretation, and phenotypic expression in other global populations, particularly those of African descent. As genomic screening moves toward a “genome-first” approach—where genetic results are identified before clinical symptoms manifest—bridging this knowledge gap is essential for equitable cardiovascular care.
Key Content
Prevalence and Phenotypic Expression Across Ancestries
Recent large-scale cohort analyses, including data from the NIH’s All of Us program, Mount Sinai’s BioMe, and Geisinger’s MyCode, have provided a robust comparison of FH between African and European ancestry groups. Contrary to older estimates that suggested variations in carrier frequency, recent evidence (Winters et al., 2026) indicates a remarkably similar prevalence of pathogenic variants: 1 in 306 for African ancestry and 1 in 273 for European ancestry.
However, the clinical manifestation of these variants differs. African ancestry individuals carrying a pathogenic variant show an LDL-C elevation that is 20.81 mg/dL greater than European carriers. This increased phenotypic burden suggests that the same “pathogenic” label may translate to higher cardiovascular risk in African populations, potentially due to differences in genetic background, environmental interactions, or delayed diagnosis.
The Challenge of Variants of Unknown Significance (VUS)
One of the most critical findings in recent literature is the disparity in VUS frequency and impact. African ancestry individuals have 1.61 times higher odds of carrying a VUS compared to European individuals. Crucially, in African ancestry groups, these VUSs are not benign; they are associated with an additional 10.01 mg/dL elevation in LDL-C and an odds ratio (OR) of 1.91 for myocardial infarction. In contrast, VUSs in European populations often do not reach statistical significance for increased MI risk. This suggests that many variants currently labeled as “uncertain” in African populations are likely pathogenic, but remain misclassified due to a lack of reference data.
Genomic Architecture of Lipid Traits in African Populations
Research into the broader genetic architecture of lipids supports the need for ancestry-specific studies. Meta-analyses of sub-Saharan African GWAS (Fattwan et al., 2022) have identified novel loci, such as the GATB region, associated with LDL-C that were not previously highlighted in European-centric studies. Furthermore, polygenic risk scores (PRS) for LDL-C lose predictive accuracy as the genetic distance between the discovery population (usually European) and the target population increases. This underscores that even beyond monogenic FH, the polygenic contributors to hypercholesterolemia require diverse genomic references to be clinically useful.
PCSK9 and Ethnic Heterogeneity
Studies on PCSK9, a major regulator of LDL receptors, further illustrate this heterogeneity. Meta-GWAS data (Haas et al., 2022) identified novel loci at APOB and TM6SF2 regulating PCSK9 levels. Notably, specific PCSK9 variants associated with lipid levels in African Americans differ from those in Europeans, even though the overall causal pathway—PCSK9 degrading LDL receptors—remains consistent. This ethnic heterogeneity at the locus level means that a negative genetic test for a “European” variant does not rule out a genetic cause of high PCSK9 or LDL-C in a person of African ancestry.
Expert Commentary
The findings from these genome-first studies represent a call to action for the cardiovascular community. The current reliance on ClinVar and ClinGen databases, which are disproportionately populated with European genetic data, creates a “diagnostic ceiling” for minority populations. When a clinician receives a VUS result for an African American patient with severe hypercholesterolemia, they are often left in a state of clinical ambiguity, whereas a similar phenotypic presentation in a European patient might be confirmed with a known pathogenic variant.
From a mechanistic perspective, the higher LDL-C impact observed in African ancestry individuals suggests that our current variant curation may be missing modifiers or that the cumulative burden of “minor” variants in these populations is higher. The fact that VUSs in African ancestry individuals carry an MI risk equivalent to pathogenic variants confirms that our current classification system is failing this demographic. Clinical guidelines must evolve to incorporate ancestry-informed variant interpretation, and health systems must prioritize the inclusion of diverse populations in biobanks to improve the granularity of our genetic catalogs.
Conclusion
The paradigm of FH management is shifting from clinical-first to genome-first. Current evidence demonstrates that while the genetic frequency of FH is similar across ancestries, the tools used to diagnose and assess risk are biased. African ancestry individuals face higher phenotypic severity and a disproportionate burden of unclassified genetic variants that nonetheless drive cardiovascular disease. Future research must focus on functional assays and larger diverse cohorts to reclassify VUSs. Clinically, a high degree of suspicion for FH should be maintained in African ancestry patients with high LDL-C, even if genetic testing yields only a “Variant of Unknown Significance.”
References
- Winters AH, Kelly MA, Syed MG, et al. A Genome-First Study of Familial Hypercholesterolemia Comparing African and European Ancestry Individuals. Circulation. 2026. PMID: 42212376.
- Fattwan A, et al. Meta-analysis of sub-Saharan African studies provides insights into genetic architecture of lipid traits. Nat Commun. 2022;13(1):2578. PMID: 35546142.
- Haas ME, et al. Meta-GWAS of PCSK9 levels detects two novel loci at APOB and TM6SF2. Hum Mol Genet. 2022;31(6):999-1011. PMID: 34590679.
- Damrauer SM, et al. Effects of Genetic Variants Associated with Familial Hypercholesterolemia on Low-Density Lipoprotein-Cholesterol Levels and Cardiovascular Outcomes in the Million Veteran Program. Circ Genom Precis Med. 2018;11(12):e002192. PMID: 31106297.
