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

项目摘要/摘要 缺血性心脏病(IHD)是全球最常见的死亡原因。在美国，女性比女性 比男性更有可能报告IHD的“非典型”症状，有误诊或未诊断的心脏病发作，以及 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。因此，女性 与重大不良心脏事件(MACE)相关的显著医疗差异，包括 心肌梗塞、中风和死亡。IHD和MACE在女性中的发病率最高 绝经后(MP后)阶段，超过年龄匹配的男性。已知的风险因素未能完全 解释这些基于性别的IHD差异。性别之间的基因变异被认为是一种主要的 症状和结局差异的原因，先于所有其他已知的心脏危险因素。它的机制， 然而，人们对此知之甚少。拥有非裔美国人(AA)血统的妇女和西班牙裔妇女在 不良结局的风险更大，但对其遗传风险因素知之甚少。 PI已经确定RAP1GAP2是女性IHD中性相关影响的强有力的候选基因 结果。她的初步研究表明：1)某些RAP1GAP2标记与IHD之间存在关联 女性而不是男性的病例状况和死亡率，祖先特有的等位基因存在差异；以及2) 性别、IHD和血小板活性的基因表达差异趋势。RAP1GAP2是主要贡献者 血小板被激活。血小板活性是心脏病的独立危险因素，凝血与IHD有关 发展。这项工作的下一个合乎逻辑的步骤是填充整个RAP1GAP2中缺失的基因标记数据 高危妇女的基因，确定与IHD结果的因果关系(又名，基因精细图谱)，而 解释了基因组祖先的变异。这将使我们的团队为机制和临床研究做好准备。 申请。 此R21的目的是确定指示女性相关的RAP1GAP2原因基因标记 心脏健康风险(目标1--首次发生重大心脏事件；目标2--出现“非典型”IHD症状) 和测试祖先-使用新的和严格的统计学方法调节基因对结果的影响(目标3) 遗传学方法。我们的研究团队将利用现有的来自三个全女性心脏的生物库数据 在美国国立卫生研究院性行为研究的指导下，对17,000多名女性进行了调查。 生物变量框架和症状科学模型，我们设计这项研究是为了解决经常被引用的 统计能力和多样性的研究局限。我们不是仅仅依赖种族的社会结构，而是 将结合基因组祖先标记来实现目标1和2。结果将填补证据方面的空白 女性IHD的遗传学基础。研究结果可能导致改善基于性别的IHD评估、治疗和 改善妇女的健康状况，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.