Project Summary It is now well understood that familial hypercholesterolemia (FH) is an under diagnosed and under treated cause of premature atherosclerotic cardiovascular disease (ASCVD). Recent advances in genetics and results from population-based studies of FH suggest that the broad phenotypic definition of FH, severely elevated low density lipoprotein cholesterol (LDL-C), and positive family history of premature ASCVD or high cholesterol, encompasses four distinct clinical subtypes: 1) monogenic FH caused by a pathogenic variant in an FH gene, 2) polygenic hypercholesterolemia caused by the cumulative inheritance of many common alleles associated with incremental increases in LDL-C, 3) elevated lipoprotein (a) (Lp(a)) and severe hypercholesteremia, and 4) severe hypercholesteremia in the absence of a genetic cause. We hypothesize that differences in risk of incident ASCVD exist among the four FH subtypes. Risk assessment in FH has become increasingly complex with multiple factors influencing outcomes: LDL-C level, presence of a genetic variant, presence of additional ASCVD risk factors, Lp(a) level, pre-existing ASCVD, age, and gender. Further complicating risk assessment are health disparities related to age, sex, rurality, and race/ethnicity. Current shortcomings in FH care suggest two immediate needs: more accurate risk assessment and strategies to communicate this risk information to the diverse population impacted. The goals of this proposal are to 1) demonstrate the impact of FH subtype on ASCVD prognosis, and 2) study the best ways to communicate this complex FH risk information to clinicians and patients, with consideration of health disparities as barriers to care for both clinicians and patients. In Aim 1, this proposal will develop a foundation for accomplishing these goals by creating a cohort of over 800K people using individual-level data from Geisinger, Mt. Sinai, and the UK Biobank integrated with variant-level data from the ClinVar genetic database, allowing molecular assignment of FH subtypes, ASCVD phenotyping, and characterization of risk. Our anticipated study sample will include approximately 2,500 individuals with a pathogenic FH variant and 50,000 individuals with a variant-negative FH subtype. In Aim 2, we will use this cohort to determine ASCVD outcomes in the four subtypes, including assessment of the impact of conventional risk factors and polygenic risk for ASCVD independent of blood lipids. We will also assess the impact of health disparities on outcomes. At the same time, in Aim 3 we will use implementation science to investigate barriers and facilitators to the communication of preventative health information at Geisinger and Mt. Sinai. We will focus on attitudes and perceptions of patients and providers with an emphasis on known care disparities and their impact on care. This proposal will show the benefit of a precise genomic characterization of FH risk, and the value of additional ASCVD risk assessment. By understanding the barriers to care at the clinician and patient level and the value of accounting for known disparities, we will demonstrate best practices for communicating this information in a way that improves clinical practice and patient understanding.

PROJECT NARRATIVE Recent studies of familial hypercholesterolemia suggest that the broad phenotypic definition encompasses four distinct subtypes: 1) monogenic FH caused by a pathogenic variant in an FH gene, 2) polygenic hypercholesterolemia caused by the cumulative inheritance of many common alleles associated with incremental increases in LDL-C, 3) LPA gene variants that increase levels of serum lipoprotein (a) and mimic the FH phenotype, and 4) severe hypercholesterolemia and a positive family history in the absence of a genetic cause. Distinguishing among these subtypes may have clinical importance. We propose a multi-disciplinary project to examine risk among FH subtypes and use implementation science to develop strategies for the communication of this complex information between clinicians and patients for improved cardiovascular disease prevention in FH. We propose a multi-disciplinary project to examine risk among FH subtypes and use implementation science to develop strategies for the communication of this complex information between clinicians and patients to improve cardiovascular disease prevention in FH.