Uncovering early signals of hereditary TTR amyloidosis in minority populations at high genetic risk

揭示高遗传风险少数人群遗传性 TTR 淀粉样变性的早期信号

• 批准号: 10606479
• 负责人: Amy R. Kontorovich
• 金额: $ 75.2万
• 依托单位: ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-04-01 至 2026-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10606479
• 关键词: Address; Adult; Affect; African American; African American population; Age; Amyloid; Amyloid deposition; Amyloidosis; Apical; Bypass; Cardiac; Caring; Carpal Tunnel Syndrome; Characteristics; Clinical; Collaborations; Counseling; Diagnosis; Diagnostic; Diphosphates; Disease; Early Diagnosis; Early identification; Echocardiography; Electronic Health Record; Enrollment; Exposure to; Familial Amyloid Neuropathies; Future; Gadolinium; Genetic; Genetic Risk; Genotype; Guidelines; Health; Health system; Heart Abnormalities; Heart Diseases; Heart failure; Hispanic; Hybrids; Individual; Ionizing radiation; Knowledge; Latino; Latino Population; Learning; Link; Magnetic Resonance Imaging; Methods; Minority Groups; Modality; Natural History; Nerve; New York City; Nomenclature; Non-Invasive Detection; Nuclear; Pathogenicity; Patients; Penetrance; Phase; Phenotype; Polyneuropathy; Population; Positron-Emission Tomography; Prealbumin; Prevalence; Prospective Studies; Radionuclide Imaging; Research Infrastructure; Retrospective Studies; Risk; Signal Transduction; Signs and Symptoms; Spinal Stenosis; Symptoms; Therapeutic; Tracer; Variant; age related; associated symptom; biobank; cardiac amyloidosis; clinical diagnosis; clinical infrastructure; cohort; disease natural history; early screening; empowerment; genetic approach; genomic data; health care disparity; heart imaging; hereditary risk; high risk; imaging approach; imaging modality; imaging study; improved; improved outcome; minority patient; multimodality; noninvasive diagnosis; novel; novel therapeutics; phenome; pre-clinical; prospective; recruit; screening; surveillance imaging; surveillance strategy; timeline; trait; translational genomics; uptake

PROJECT SUMMARY The odyssey to a diagnosis for patients with hereditary TTR amyloidosis (hATTR) often lasts years because the signs and symptoms are non-specific. Meanwhile, patients can progress to advanced heart disease (cardiac amyloidosis) and nerve disease (polyneuropathy). A common pathogenic TTR variant impacting African American (4%) and Hispanic/Latino (1%) patients, V142I, confers particularly high risk for cardiac amyloidosis, but diagnostic delays keep these groups at the margins of care. Novel therapies are now available to delay hATTR progression; however, they cannot reverse the disease. For this reason, it is imperative to diagnose hATTR at the earliest possible stages, when these therapies are likely to be most beneficial. Because the gold standard for non-invasive diagnosis of hATTR-related cardiac amyloidosis, nuclear scintigraphy, involves exposure to ionizing radiation and the sensitivity in asymptomatic patients is unknown, widespread screening by this method is not yet justified. Traditional phenotype-first studies have identified non-cardiac red flag signs and symptoms that herald future heart disease, but the complete phenotypic spectrum and natural history of hATTR are not well understood, particularly in individuals at high genetic risk. To date, large diverse cohorts of individuals with pathogenic TTR variants (TTR+) have not been extensively studied to understand the full range of clinical features of hATTR. We propose a genotype-first study of predominantly African American and Hispanic/Latino TTR+ individuals from the electronic health record (EHR)-linked BioMe Biobank in New York City. First, we will perform retrospective deep phenotyping using EHRs to characterize the scope and develop a timeline of cardiac and non-cardiac features of hATTR, and estimate age-dependent penetrance. We will perform a well-powered phenome-wide association study, in collaboration with other biobanks, to identify novel health traits associated with V142I. Clinical characteristics found to be enriched in TTR+ individuals will be accrued into a phenotype risk score to help identify patients at risk for hATTR in health systems. In addition, we will conduct a prospective study to generate evidence informing guidelines for optimal mode and timing of cardiac imaging surveillance in high-risk TTR+ individuals across adulthood. We will recruit 100 TTR+ individuals from BioMe into a multimodal cardiac imaging study using gold standard and cutting-edge experimental imaging approaches. Through these endeavors, we will delineate a timeline of anticipatory systemic and cardiac imaging signatures unique to individuals at high genetic risk for hATTR. The results will empower clinicians to recognize the disease at its earliest stages so patients may maximally benefit from therapy. We posit that although hATTR is currently grossly underdiagnosed in U.S. minority patients, it is in fact amenable to earlier detection through discovery of prescient signs and symptoms, implementation of EHR-based phenotype risk scores and well-timed cardiac imaging. These approaches will uproot disparities in the care of diverse patients at high risk for hATTR.

项目摘要 遗传性TTR淀粉样变性患者（HATTR）的诊断的奥德赛通常会持续数年 体征和症状是非特异性的。同时，患者可以发展为晚期心脏病（心脏病 淀粉样变性）和神经病（多神经病）。一种影响非洲的常见致病性TTR变体 美国人（4％）和西班牙裔/拉丁裔（1％）患者，V142i，心脏淀粉样变性的风险特别高， 但是诊断延迟使这些组保持在护理的边缘。现在可以推迟新颖的疗法 hattr的进展；但是，它们无法扭转疾病。因此，必须诊断 当这些疗法可能是最有益的时，哈特特（Hattr）最早可能会阶段。因为黄金 HATTR相关心脏淀粉样变性的非侵入性诊断的标准，核闪烁显像涉及 暴露于无症状患者的电离辐射和灵敏度的暴露尚不清楚，通过 此方法尚未证明是合理的。传统的表型优先研究已经确定了非心脏危险信号和 预示未来心脏病的症状，但是Hattr的完整表型谱和自然历史 不太了解，特别是在具有高遗传风险的个体中。迄今为止，大量的人群 尚未对致病性TTR变体（TTR+）进行广泛研究以了解全部临床 Hattr的功能。我们提出了一项主要是非裔美国人和西班牙裔/拉丁裔的基因型优先研究 纽约市电子健康记录（EHR）连接的生物群生物库的TTR+个人。首先，我们会的 使用EHR进行回顾性深度表型来表征范围并发展心脏时间线 HATTR的非心脏特征，以及估计年龄依赖性的外观。我们将表现出充分的动力 全球整个协会的研究与其他生物库合作，以识别相关的新型健康特征 与v142i。发现富含TTR+个体的临床特征将被纳入表型风险中 得分以帮助识别卫生系统中有HATTR风险的患者。此外，我们将进行前瞻性 研究为最佳模式和心脏成像监视时机的指南提供证据。 在成年期间，高风险的TTR+个体。我们将招募100个TTR+个人从Biome招募到多模式 心脏成像研究使用金标准和尖端实验成像方法。通过这些 努力，我们将描述一个预期性的系统性和心脏成像特征的时间表 患有HATTR遗传风险的个人。结果将使临床医生能够在其疾病中识别该疾病 最早的阶段，因此患者可以从治疗中受益最大。我们认为，尽管Hattr目前非常严重 在美国少数民族患者中诊断不足，实际上可以通过发现先知来早期检测 体征和症状，基于EHR的表型风险评分的实施和及时的心脏成像。 这些方法将在护理HATTR风险高风险的不同患者的护理方面取消差异。