Improving Risk Stratification in Familial Hypercholesterolemia (RISK-FH)

改善家族性高胆固醇血症的风险分层 (RISK-FH)

• 批准号: 10454015
• 负责人: Matthew Oetjens
• 金额: $ 75.27万
• 依托单位: GEISINGER CLINIC
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-07-01 至 2027-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10454015
• 关键词: Accounting; Address; Adoption; Affect; Age; Alleles; Atherosclerosis; Attitude; Cardiac; Caring; Characteristics; Cholesterol; ClinVar; Clinical; Cohort Studies; Communication; Complex; Cox Proportional Hazards Models; Data; Diabetes Mellitus; Diagnosis; Disease Outcome; Equation; Ethnic Origin; Familial Hypercholesterolemia; Family; Family history of; Foundations; Gender; Genes; Genetic; Genetic Databases; Genetic Screening; Genomics; Goals; Health; Health Services Accessibility; Healthcare; Hypertension; Individual; Investigation; LDL Cholesterol Lipoproteins; Lipids; Lipoprotein (a); Maintenance; Molecular; Outcome; Pathogenicity; Patient Care; Patients; Perception; Performance; Persons; Pharmaceutical Preparations; Phenotype; Physicians; Population; Population Heterogeneity; Population Study; Prevalence; Prevention; Provider; Race; Recording of previous events; Risk; Risk Assessment; Risk Factors; Rural; Sampling Studies; Serum; Techniques; Time; Tobacco use; Variant; Woman; atherosclerosis risk; barrier to care; biobank; blood lipid; cardiovascular disorder prevention; cardiovascular disorder risk; clinical care; clinical practice; clinical subtypes; cohort; disease phenotype; disease prognosis; early onset; genetic information; genetic variant; health disparity; high risk; hypercholesterolemia; implementation science; implementation strategy; improved; improved outcome; medication compliance; multidisciplinary; patient population; population based; precision medicine; prediction algorithm; premature; prevent; programs; rare variant; response; risk stratification; rurality; sex; social health determinants; theories; tool; translational model

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.

项目摘要 现在众所周知，家族性高胆固醇血症（FH）是未经诊断和治疗不足的 过早的动脉粥样硬化心血管疾病（ASCVD）的原因。遗传学和结果的最新进展 从基于人群的FH研究表明，FH的广泛表型定义严重升高 密度脂蛋白胆固醇（LDL-C），以及早产ASCVD或高胆固醇的积极家族史， 包括四个不同的临床亚型：1）由FH基因中的致病变异引起的单基因FH，2） 多基因高胆固醇血症由许多与许多常见等位基因相关的累积遗传引起 LDL-C的增量增加，3）脂蛋白升高（A）（LP（A））和严重的高胆固醇以及4）严重 在没有遗传原因的情况下，高胆固醇。我们假设发生ASCVD风险的差异 存在于四个FH亚型中。 FH中的风险评估与多种因素变得越来越复杂 影响结果：LDL-C水平，存在遗传变异，存在其他ASCVD风险因素， LP（a）级别，先前存在的ASCVD，年龄和性别。更复杂的风险评估是健康差异 与年龄，性别，乡村和种族/种族有关。 FH护理中当前的缺点表明了两个近期需求： 更准确的风险评估和将这些风险信息传达给多样化人群的策略 受影响。该提案的目标是1）证明FH亚型对ASCVD预后的影响，以及 2）研究将此复杂的FH风险信息传达给临床医生和患者的最佳方法 考虑健康差异是对临床医生和患者的护理障碍。 在AIM 1中，该提案将通过创建一系列的队列为实现这些目标奠定基础 超过80万人使用来自盖辛格，西奈山和英国生物银行的个人级别数据。 来自Clinvar遗传数据库的变异级数据，允许FH亚型的分子分配ASCVD 表型和风险表征。我们预期的研究样本将包括大约2,500 具有致病性FH变体的个体和50,000个具有变异性FH亚型的个体。在AIM 2中，我们 将使用此队列来确定四种亚型中的ASCVD结果，包括评估 与血脂无关的ASCVD的常规危险因素和多基因风险。我们还将评估 健康差异对结果的影响。同时，在AIM 3中，我们将使用实施科学来 调查盖辛格和山的预防性健康信息的障碍和促进者。 西奈。我们将专注于患者和提供者的态度和看法，重点是已知护理 差距及其对护理的影响。该建议将显示出精确基因组表征的好处 FH风险以及其他ASCVD风险评估的价值。通过了解对护理的障碍 临床医生和患者水平以及对已知差异的会计价值，我们将展示最佳实践 以改善临床实践和患者理解的方式传达此信息。