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

项目总结 遗传性TTR淀粉样变性(HATTR)患者诊断的艰辛通常持续数年，因为 症状和体征是非特异性的。同时，患者可能进展为晚期心脏病(心脏病 淀粉样变性)和神经疾病(多发性神经病)。一种影响非洲的常见致病TTR变异体 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， 但诊断延误使这些群体处于护理的边缘。新的治疗方法现在可以推迟 HATTR进展；然而，他们不能逆转这种疾病。出于这个原因，必须诊断 在可能的早期阶段，当这些治疗方法可能是最有益的时候。因为金子 HATTR相关心脏淀粉样变性的非侵入性诊断标准，核素扫描，包括 无症状患者暴露于电离辐射和敏感性尚不清楚，通过广泛筛查 这种方法还不合理。传统的表型优先研究已经识别出非心脏红旗征象和 预示未来心脏病的症状，但hAttr的完整表型谱和自然病史 尤其是在遗传风险较高的个体中，人们对此并不了解。到目前为止，大量不同的个人队列 与致病的Ttr变异体(Ttr+)尚未被广泛研究，以了解全面的临床 HAttr的特点。我们建议对主要是非洲裔美国人和西班牙裔/拉丁裔美国人进行基因分型研究。 来自纽约市与电子健康记录(EHR)相关联的生物群生物库的TTR+个人。首先，我们将 使用EHR进行回顾性深入的表型鉴定，以确定范围并制定心脏疾病的时间表 和非心脏特征，并估计年龄相关的外显率。我们将表演一场威力十足的 与其他生物库合作进行的全基因组关联研究，以确定相关的新健康特征 使用V142I。临床特征被发现在TTR+个体中丰富将累积成表型风险 评分，以帮助识别卫生系统中有hATTR风险的患者。此外，我们还将进行一次前瞻性的 为心脏成像监测的最佳模式和时间生成证据指南的研究 成年期的高危TTR+个体。我们将从生物圈招募100名TTR+个人进入多式联运 使用金标准和前沿实验成像方法进行心脏成像研究。通过这些 努力，我们将描绘一个时间表的预期系统和心脏成像信号独特的 有高遗传风险的个体。这一结果将使临床医生能够认识到这种疾病 最早的阶段，因此患者可以最大限度地从治疗中受益。我们假设，尽管hAttr目前总体上 在美国少数族裔患者中诊断不足，实际上可以通过发现先见之明更早地发现它 体征和症状，实施基于EHR的表型风险评分和适时的心脏成像。 这些方法将根除不同高危患者在护理上的差异。

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.