Family Study of Carotid Atherosclerosis and Stroke Risk

项目摘要 中风是美国死亡和残疾的主要原因，并严重影响少数群体。 西班牙裔人中风的风险特别高;这种中风风险的增加可能是由特定的遗传因素造成的。 非遗传因素。多米尼加人是美国增长最快的加勒比海西班牙裔，但鲜为人知 关于中风和心血管疾病（CVD）的遗传和非遗传决定因素。过去15 多年来，我们的团队一直在研究多米尼加人的中风遗传风险因素。我们召集了一队人马 多米尼加家庭中风的高风险，并专注于中风前兆表型（SPPs），以减少 表型异质性和卒中病因的复杂性。我们调查了公认的SPP，包括 颈动脉内膜中层厚度、颈动脉斑块、左心室质量和左心房直径。我们有 利用高通量测序技术成功鉴定了与SPPs相关的数量性状基因座和DNA序列变异。 通量基因分型和下一代测序。这些发现只占了一小部分， SPPs的个体差异。在本申请中，我们建议将我们的研究扩展到进行甲基化- 广泛关联研究（MWAS）以鉴定与SPP相关的差异DNA甲基化区域（DMR）， 中风和CVD。甲基化是一种表观遗传过程，它在不改变DNA的情况下调节基因表达 顺序DNA甲基化已被证明是促进血管发生的关键过程。 疾病拟议的研究将为开发新的临床药物提供新的见解。 预防和治疗中风和心血管疾病的策略，因为我们的最终目标是减少中风风险和种族- 中风和CVD的种族差异。我们计划了4个目标：目标1：识别与卒中SPP相关的DMR;目标2： 2评估遗传和非遗传因素对SPP相关DMR的相对贡献;目标3 使用CRISPR-Cas9技术评估DNA序列变异和DMR的功能影响; 4检查SPP相关DMR对血管事件的预测作用。为了实现这些目标，我们将 利用家族研究中已收集的丰富数据，并添加新的数据收集以检测血管事件 （中风、心肌梗死、血管性死亡）。我们将在一个独立的样本中验证这些发现。 正在进行的纵向北方曼哈顿研究，家庭研究起源于此。两项研究都使用了 获得SPP、生活方式风险因素和全基因组的相同评估工具和收集工具 SNP数据。我们的建议的创新方面包括新发现的可修改的表观遗传位点， 中风和CVD，CRISPR-Cas9技术模拟特定的基因组编辑，多米尼加人的独特人群 和一个家庭的研究设计，和一个可用的独立人口的多米尼加验证研究。 我们的研究结果可能会导致最有前途的分子策略，用于危险分层，预防和治疗。 和中风的治疗。

Project Summary Stroke is the leading cause of death and disability in the US and disproportionally affects minority populations. Hispanics have a particularly high risk for stroke; this increased risk of stroke may be explained by specific genetic and non-genetic factors. Dominicans are the fastest growing Caribbean Hispanics in the US, and yet little is known about their genetic and non-genetic determinants of stroke and cardiovascular disease (CVD). For the past 15 years, our team has been investigating stroke genetic risk factors in Dominicans. We have assembled a cohort of Dominican families at high risk of stroke and focused on stroke precursor phenotypes (SPPs) to reduce phenotypic heterogeneity and complexity of stroke etiology. We investigated well-recognized SPPs including carotid intima-media thickness, carotid plaque, left ventricular mass, and left atrial diameter. We have successfully identified quantitative trait loci and DNA sequence variants associated with SPPs using high throughput genotyping and next generation sequencing. These findings account for a small portion of the inter- individual variation in SPPs. In this application, we propose to expand our investigations to conduct a methylome- wide-association-study (MWAS) to identify differential DNA methylation regions (DMRs) associated with SPPs, stroke and CVD. Methylation is an epigenetic process that regulates gene expression without changing DNA sequence. DNA methylation has been shown as a key process contributing to the development of vascular disease. The proposed investigations would provide new insights relevant to the development of novel clinical strategies for prevention and treatment of stroke and CVD, as our ultimate goal is to reduce stroke risk and race- ethnic disparities in stroke and CVD. We plan 4 aims: Aim 1 to identify DMRs associated with stroke SPPs; Aim 2 to assess the relative contribution of genetic and non-genetic factors to SPP-associated DMRs; Aim3 to evaluate the functional impact of DNA sequence variation and DMRs using CRISPR-Cas9 technology; and Aim 4 to examine the predictive effect of SPP-associated DMRs on vascular events. To achieve these aims we will leverage the rich data already collected in the Family Study and add new data collection to detect vascular events (stroke, myocardial infarction, vascular death). We will validate the findings in an independent sample from the ongoing longitudinal Northern Manhattan Study, from which the Family Study originated. Both studies have used the same assessment tools and collection instruments for obtaining SPPs, lifestyle risk factors and genome-wide SNP data. The innovative aspects of our proposal include novel discoveries of modifiable epigenetic sites for stroke and CVD, CRISPR-Cas9 technology to model specific genome-editing, a unique population of Dominicans and a family study design, and an available independent population of Dominicans for validation studies. Findings from our study may lead to the most promising molecular strategies for risk stratification, prevention and treatment of stroke.