Improving Risk Stratification in Familial Hypercholesterolemia (RISK-FH)

项目摘要 现在很好地理解，家族性高胆固醇血症（FH）是一个诊断和治疗不足， 导致过早动脉粥样硬化性心血管疾病（ASCVD）。遗传学的最新进展和结果 基于人群的FH研究表明，FH的广泛表型定义，严重升高低 密度脂蛋白胆固醇（LDL-C），以及过早ASCVD或高胆固醇的阳性家族史， 包括四种不同的临床亚型：1）由FH基因中的致病性变体引起的单基因FH，2） 多基因高胆固醇血症是由许多常见等位基因的累积遗传引起的， LDL-C增量增加，3）脂蛋白（a）（Lp（a））升高和重度高脂血症，以及4）重度 在没有遗传原因的情况下高脂血症。我们假设ASCVD发生风险的差异 在四种FH亚型中存在。FH的风险评估由于多种因素而变得越来越复杂 影响结局：LDL-C水平，存在遗传变异，存在其他ASCVD风险因素， Lp（a）水平、既存ASCVD、年龄和性别。使风险评估进一步复杂化的是健康差异 与年龄、性别、农村和种族/民族有关。目前FH护理的缺点表明两个迫切需要： 更准确的风险评估和战略，以向不同人群传达这一风险信息 受影响该提案的目标是：1）证明FH亚型对ASCVD预后的影响， 2)研究将这种复杂的FH风险信息传达给临床医生和患者的最佳方式， 将健康差异视为临床医生和患者护理的障碍。 在目标1中，该提案将通过创建一个 超过80万人使用来自Geisinger，Mt.西奈半岛，英国生物银行与 来自ClinVar遗传数据库的变体水平数据，允许FH亚型、ASCVD的分子分配 表型分析和风险表征。我们预期的研究样本将包括大约2500名 具有致病性FH变体的个体和具有变体阴性FH亚型的50，000个体。在目标2中， 将使用该队列来确定四种亚型的ASCVD结局，包括评估 ASCVD的传统危险因素和多基因危险因素独立于血脂。我们亦会评估 健康差距对结果的影响。与此同时，在目标3中，我们将使用实施科学， 调查在盖辛格和山预防性健康信息的沟通的障碍和促进因素。 西奈我们将重点关注患者和提供者的态度和看法，并强调已知的护理 差异及其对护理的影响。该提案将显示精确的基因组表征的益处， FH风险，以及额外ASCVD风险评估的价值。通过了解在护理方面的障碍， 临床医生和病人的水平和价值的会计已知的差距，我们将展示最佳做法 用于以改进临床实践和患者理解的方式传达该信息。

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.