Introduction: Familial hypercholesterolemia (FH) is a genetic condition that, if untreated, results in premature atherosclerotic cardiovascular disease due to lifelong exposure to elevated low-density lipoprotein cholesterol (LDL-C) levels. While the prevalence of FH has been estimated to be as high as 1 in 188 in the general population, <10% of affected individuals are diagnosed. We sought to achieve a better understanding of the prevalence of FH-related genetic variants and rates of underdiagnosis and undertreatment in the U.S. Hypothesis: We hypothesized that genetic screening using updated pathogenic/likely pathogenic (P/LP) variant classifications would reveal higher rates of FH prevalence in our cohort compared to previous studies, and substantial rates of underdiagnosis and undertreatment. Methods: We conducted a cross-sectional study using data from the NIH All of Us Research Program. Prevalences of P/LP variants in LDLR , ApoB , and PCSK9 were evaluated according to ClinVar classifications. Underdiagnosis and undertreatment were examined using electronic health record data with ICD diagnosis codes and LDL-C measurements. Results: Of the 414,830 study participants with genomic data available, 3,466 (1 in 120) had at least one P/LP variant in LDLR , PCSK9 , or ApoB . Gene-specific P/LP variant prevalence was highest in non-Hispanic Black participants for LDLR (0.62%), non-Hispanic Asian participants for PCSK9 (0.28%), and both non-Hispanic Asian (0.38%) and non-Hispanic White (0.35%) participants for ApoB . Non-Hispanic Asian participants had the highest prevalence of having any P/LP variant (1 in 86) while Hispanic participants had the lowest (1 in 147). Among participants with a P/LP variant and LDL-C measurements available (n=1,371), <5% had an FH diagnosis in their EHR. Among participants taking a cholesterol-lowering medication (n=816), 57.5% of participants with a P/LP variant in LDLR , 26.5% in PCSK9 , and 45.7% in ApoB still had LDL-C levels exceeding the recommended target of <100 mg/dl. Conclusion: Our results reveal a higher rate of FH prevalence than previously estimated in the U.S. Prevalence of having a P/LP variant differed between racial/ethnic groups. Among participants with P/LP variants, there was a significant rate of underdiagnosis and undertreatment. In conclusion, our study suggests that genetic screening can improve the diagnosis and treatment of individuals with FH, with the goal of preventing atherosclerotic cardiovascular disease.
Ghaem-Maghami et al. (Tue,) studied this question.