Familial hypercholesterolemia: missed opportunities and potential disparities in atherosclerotic cardiovascular disease prevention - Familial hypercholesterolemia (FH) is a genetic condition that, if untreated, results in premature atherosclerotic cardiovascular disease (ASCVD) due to lifelong exposure to elevated low-density lipoprotein cholesterol (LDL- C) levels. Untreated FH escalates the risk of ASCVD by 10 to 20-fold, with males facing a 50% heart attack risk by age 50 and females a 30% risk by age 60. Treatment involving aggressive LDL-C-lowering medications and LDL apheresis, if needed, as well as lifestyle changes is crucial to reduce the risk of ASCVD events. In addition, since cumulative exposure to high LDL-C levels over time leads to atherosclerotic plaque formation and subsequent ASCVD events, there is a critical need for early diagnosis of FH so that affected individuals can be treated as soon as possible to reduce the risk of adverse outcomes. Despite its severity, FH is often underdiagnosed in the U.S. and globally. 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 being diagnosed. Significant population-specific variations in diagnosis and treatment rates have been documented, particularly across sex and other sociodemographic variables. Moreover, diagnosis typically occurs later in life, and often not until an ASCVD event has occurred. Distinguishing FH from usual hypercholesterolemia is critical for ASCVD prevention, especially considering the more stringent LDL-C targets and specialized therapies for FH patients. Thus, the observed heterogeneity in diagnosis and treatment patterns present a tremendous opportunity for ASCVD prevention. The low rate of FH diagnosis has been partially attributed to its heterogeneous clinical presentation. However, the most current diagnostic criteria include genetic testing as a key approach to making the diagnosis of definite FH. Detection of a pathogenic mutation in LDLR, ApoB, or PCSK9 allows a definitive diagnosis of FH to be made even in the absence of clinical criteria. Our precision medicine study aims to examine the prevalence, underdiagnosis, and undertreatment of FH in the U.S., leveraging data from the All of Us Research Program, an ongoing cohort with >633,000 individuals, whole genome sequencing and electronic health record (EHR) data. Our secondary goal is to examine the penetrance of FH-associated gene variants. Our study will result in a better understanding of the current state of FH prevalence, underdiagnosis and undertreatment in the U.S. across demographic variables, which we hope will raise awareness and inform the design, implementation, and policy of future precision medicine approaches to increase the rates of genetic screening, diagnosis and treatment to improve cardiovascular health for all Americans.
