Genetic Associations of Ischemic Heart Disease and Symptoms Among Diverse Postmenopausal Women

项目总结/摘要 缺血性心脏病（IHD）是全球死亡率最常见的原因。在美国， 比男性更可能报告IHD的"非典型"症状，有误诊或未确诊的心脏病发作， 延迟心脏治疗。目前的筛查、诊断和干预方案都是基于研究 主要关注欧洲血统男性的症状和生理特征。所以女人 经历与主要心脏不良事件（MACE）相关的显著医疗差异，包括 心肌梗塞中风和死亡女性IHD和MACE的发生率在2010年期间最高， 绝经后（后MP）阶段，当它超过年龄匹配的男性。已知的风险因素不能完全 解释这些基于性别的IHD差异。两性之间的遗传变异被认为是 症状和结果差异的原因，先于所有其他已知的心脏风险因素。其机制， 然而，人们对此知之甚少。非裔美国人（AA）血统的妇女和西班牙裔妇女在 结果不佳的风险更大，但对他们的遗传风险因素知之甚少。 PI已将RAP 1GAP 2确定为与女性IHD性别相关影响的强有力候选基因 结果。她的初步研究表明：1）某些RAP 1GAP 2标记物与IHD之间的关联 女性而非男性的病例状况和死亡率，以及祖先特异性等位基因的变化;以及2） 性别、IHD和血小板活性的基因表达差异趋势。RAP1GAP 2是一个主要的贡献者， 血小板活化血小板活性是心脏病的独立危险因素，将凝血与IHD联系起来 发展这项工作的下一个合乎逻辑的步骤是填补整个RAP 1GAP 2中缺失的基因标记数据。 基因在高危女性中，确定与IHD结果的因果关系（又名，基因精细定位）， 解释基因组祖先变异。这将使我们的团队能够进行机制和临床研究 应用程序. 该R21的目的是确定指示女性相关性乳腺癌的RAP1GAP 2致病基因标记物。 心脏健康风险（目标1-至首次发生MACE的时间;目标2-存在"非典型" IHD症状） 并使用新的和严格的统计方法来测试基因对结果的影响（目标3） 遗传学方法我们的研究团队将利用现有的生物储存库数据，从三个全女性心脏 在美国国立卫生研究院的性别指导下， 生物变量框架和症状科学模型，我们设计了这项研究，以解决经常被引用的 统计能力和多样性的研究局限性。而不是仅仅依赖于种族的社会结构，我们 将纳入基因组祖先标记，以实现目标1和2。调查结果将填补 遗传学是女性IHD的基础。研究结果可能会导致改善基于性别的IHD评估，治疗， 为女性提供更好的结果，从而减少心脏健康差距。

Project Summary/Abstract Ischemic heart disease (IHD) is the most common cause of global mortality. Women in the U.S. are more likely than men to report “atypical” symptoms of IHD, have a mis- or undiagnosed heart attack, and experience delayed cardiac treatment. Current screening, diagnostic, and intervention protocols are based on research focused primarily on symptoms and physiologic profiles in men of European ancestry. As a result, women experience significant healthcare disparities related to major adverse cardiac events (MACE), including myocardial infarction, stroke, and death. The incidence of IHD and MACE in women is highest during the postmenopausal (post-MP) phase, when it surpasses that of age-matched men. Known risk factors fail to fully explain these sex-based IHD disparities. Genetic variation between the sexes has been implicated as a major reason for symptom and outcome differences, preceding all other known cardiac risk factors. Its mechanisms, however, are poorly understood. Women with African American (AA) ancestry and Hispanic women are at greater risk of poor outcomes, yet even less is known about their genetic risk factors. The PI has identified RAP1GAP2 as a strong candidate gene for sex-associated effects on women’s IHD outcomes. Her preliminary studies demonstrate 1) associations between certain RAP1GAP2 markers and IHD case status and mortality among women but not men, with variations in ancestry-specific alleles; and 2) trends in gene-expression differences by sex, IHD, and platelet activity. RAP1GAP2 is a major contributor to platelet activation. Platelet activity is an independent risk factor for heart disease, linking clotting with IHD development. The next logical step in this work is to fill in missing gene marker data across the full RAP1GAP2 gene in high-risk women, identifying causal associations with IHD outcomes (aka, gene fine-mapping) while accounting for genomic ancestry variation. This will poise our team for studies of mechanism and clinical application. The purpose of this R21 is to determine RAP1GAP2 causal gene markers indicative of female-associated cardiac health risks (Aim 1—time to first MACE occurrence; Aim 2—presence of “atypical” IHD symptoms) and test ancestry-moderation of gene effects on outcomes (Aim 3) using novel and rigorous statistical genetics methods. Our research team will harness existing biorepository data from three all-female cardiac studies that examined more than 17,000 post-MP women in the U.S. Guided by the NIH’s sex-as-a- biological-variable framework and symptom science model, we designed this study to address often-cited research limitations of statistical power and diversity. Rather than relying solely on social constructs of race, we will incorporate genomic ancestry markers to achieve Aims 1 and 2. Results will fill evidentiary gaps in the genetics underlying women’s IHD. Findings could lead to improved sex-based IHD evaluation, treatment, and outcomes for women, thereby reducing cardiac health disparities.