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

基本信息

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
项目类别：
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

项目摘要

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.

项目概要遗传性 TTR 淀粉样变性 (hATTR) 患者的诊断过程通常会持续数年，因为体征和症状是非特异性的。与此同时，患者可能会进展为晚期心脏病（心脏病）淀粉样变性）和神经疾病（多发性神经病）。影响非洲的常见致病性 TTR 变异美国 (4%) 和西班牙裔/拉丁裔 (1%) 患者，V142I，患心脏淀粉样变性的风险特别高，但诊断延迟使这些群体处于护理边缘。现在有新的疗法可以延迟 hATTR进展；然而，他们无法逆转这种疾病。为此，必须进行诊断 hATTR 在尽可能早的阶段进行，此时这些疗法可能是最有益的。因为黄金 hATTR 相关心脏淀粉样变性的无创诊断标准，核闪烁扫描，涉及暴露于电离辐射和无症状患者的敏感性尚不清楚，通过广泛筛查这种方法尚不合理。传统的表型优先研究已经确定了非心脏危险信号标志和预示着未来心脏病的症状，但 hATTR 的完整表型谱和自然史尚不清楚，特别是对于具有高遗传风险的个体。迄今为止，大量不同的个人群体致病性 TTR 变异 (TTR+) 尚未得到广泛研究以了解临床的全部范围 hATTR 的特点。我们建议对主要是非裔美国人和西班牙裔/拉丁裔进行基因型优先研究来自纽约市电子健康记录 (EHR) 关联的 BioMe 生物银行的 TTR+ 个人。首先，我们将使用 EHR 进行回顾性深度表型分析，以描述心脏疾病的范围并制定时间表 hATTR 和非心脏特征，并估计年龄依赖性外显率。我们将演绎一场充满力量的与其他生物库合作进行全表组关联研究，以确定相关的新健康特征与V142I。 TTR+ 个体中发现丰富的临床特征将累积为表型风险评分以帮助识别卫生系统中面临 hATTR 风险的患者。此外，我们还将进行前瞻性研究旨在为心脏成像监测的最佳模式和时机提供证据指导整个成年期的高风险 TTR+ 个体。我们将从 BioMe 招募 100 名 TTR+ 人员加入多式联运使用黄金标准和尖端实验成像方法的心脏成像研究。通过这些通过努力，我们将描绘出一个独特的预期全身和心脏成像特征的时间表 hATTR 遗传风险高的个体。研究结果将使临床医生能够及时识别这种疾病最早阶段，以便患者可以最大程度地从治疗中受益。我们假设虽然 hATTR 目前严重在美国少数族裔患者中诊断不足，实际上可以通过先见之明的发现来早期发现体征和症状，实施基于 EHR 的表型风险评分和及时的心脏成像。这些方法将消除 hATTR 高风险不同患者的护理差异。