TempO-Vseq Screen for Genomic Risk of CAD Using Blood from a Finger Prick

摘要：在这个第一阶段的计划中，我们将演示一种检测方法的可行性，以确定哪些受试者 冠状动脉疾病(CAD)的高遗传风险以及心绞痛、心肌梗死、心力衰竭的后遗症 和猝死使用一滴全血斑点在滤纸(WBsf)上，并在没有 用高通量TEMPO-SEQ®DNA变异体靶向测序技术分离DNA Vseq.由TEMPO-VSEQ分析确定的变异呼叫和遗传风险分数(GRS)将被作为基准 针对Infinium®基因分型呼叫和GRS，以建立性能。年三分之一的死亡是由CAD造成的 美国和世界范围内。基于多基因GRS的冠心病遗传易感性已被证明是 不受包括年龄在内的常规风险因素的影响。已经进行了大规模的基因分型研究， 已经表明，多基因GRS可以预测发生CAD事件的风险，而预防性治疗 他汀类药物或坚持健康的生活方式可以降低高危人群的发病率。这些研究已经 确定了可作为目标以提供GRS的变体。基于以下因素的筛查试验的临床原理 GRS是，它可以在任何年龄进行，但如果在40岁之前的任何时间进行，在临床风险之前 因素通常是显而易见的，它可以识别风险并为早期治疗性预防性使用提供机会 他汀类药物和/或追求健康的生活方式。两者都能降低冠心病的发生率，如果他汀类药物 给高危GRS受试者开处方，每治疗13人，就能防止1人死亡。在确定了变种 对于确定GRS的CAD屏幕，需要成本最低的平台来提供以下性能 目前的基因分型阵列，并提供最佳的健康经济的样本收集、运输、存储和 化验。Tempo-Vseq屏幕的优势预计是成本降低2倍或更多，没有专利 需要购买硬件，从指尖获取更简单的样品(或者如果在第二阶段发现更好的， 口腔拭子或唾液)，更简单的运输和存储滤纸，而不是冰冻的血液，全自动 处理和数据分析，变种呼叫错误率低于排序，每周吞吐量 &gt；11,000个样品的测序仪。用其他变体增强的同一屏幕可以用来识别 房颤(缺血性中风的主要原因)、2型糖尿病和其他导致冠心病的因素的高风险。

Summary: In this Phase I program we will demonstrate the feasibility of an assay to identify subjects who have a high genetic risk of coronary artery disease (CAD) and sequelae of angina, myocardial infarction, heart failure and sudden death using a drop of whole blood spotted on filter paper (WBsf) and assayed directly without isolation of the DNA using a high throughput TempO-Seq® DNA variant targeted sequencing assay, TempO- Vseq. The variant calls and genetic risk score (GRS) determined by the TempO-Vseq assay will be benchmarked against Infinium® genotyping calls and GRS to establish performance. CAD is responsible for 1/3 of deaths in the US and world-wide. Genetic predisposition for CAD based on a polygenic GRS has been shown to be independent of conventional risk factors, including age. Large genotyping studies have been carried out that have shown that a polygenic GRS can predict risk of incident CAD events, and that prophylactic treatment with statin or adherence to a healthy lifestyle reduces incidence in subjects who are high risk. These studies have identified the variants that can be targeted to provide a GRS. The clinical rationale for a screening test based on GRS is that it can be carried out at any age, but if carried out any time before the age of 40, before clinical risk factors are typically evident, it can identify risk and afford the opportunity for early therapeutic prophylactic use of statins and/or pursuit of a healthy lifestyle. Both reduce the incidence of CAD, and if statin were to be prescribed to high-risk GRS subjects, would prevent 1 death for every 13 treated. Having identified the variants for a CAD screen to determine GRS, the need is for the lowest cost platform that provides the performance of current genotyping arrays and provides the best health economics of sample collection, shipping, storage, and assay. Advantages of the TempO-Vseq screen are expected to be 2x or greater reduction in cost, no proprietary hardware purchase required, simpler sample acquisition from a finger-prick (or if found superior in Phase II, buccal swab, or spit), simpler shipping and storage of filter paper rather than frozen blood, fully automated processing and data analysis, lower variant calling error rate than sequencing, and a weekly throughput per sequencer of >11,000 samples. The same screen augmented with additional variants could be used to identify high risk for atrial fibrillation (a leading cause of ischemic stroke), type 2 diabetes, and other contributors to CAD.