Family Study of Carotid Atherosclerosis and Stroke Risk

颈动脉粥样硬化和中风风险的家庭研究

• 批准号: 10381545
• 负责人: SUSAN HALLORAN BLANTON
• 金额: $ 58.47万
• 依托单位: UNIVERSITY OF MIAMI SCHOOL OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-05-01 至 2024-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10381545
• 关键词: Affect; Alcohol consumption; Aorta; Apoptosis; Assessment tool; Atherosclerosis; Biological Markers; Biology; Blood; Blood Vessels; CRISPR/Cas technology; Caliber; Cardiovascular Diseases; Caribbean Hispanic; Carotid Artery Plaques; Carotid Atherosclerotic Disease; Cause of Death; Cessation of life; Clinical; Collection; DNA Methylation; DNA Sequence; Data; Data Collection; Data Set; Development; Dietary Practices; Dominican; Endothelial Cells; Epigenetic Process; Etiology; Evaluation; Event; Exposure to; Family; Family Study; Gene Expression; Genes; Genetic; Genetic study; Genotype; Goals; Heart Atrium; Heterogeneity; Hispanic Populations; Homeostasis; Human; Investigation; Knowledge; Lead; Left; Left Ventricular Mass; Life Style; Maps; Mediating; Methylation; Mexican Americans; Minority Groups; Modeling; Modification; Molecular; Myocardial Infarction; Participant; Pathway interactions; Permeability; Phenotype; Population; Population Heterogeneity; Prevention; Prevention strategy; Process; Public Health; Quantitative Trait Loci; Race; Research; Research Design; Risk Factors; Role; Sampling; Site; Smoking; Source; Stroke; Stroke prevention; System; Testing; Tissues; Unhealthy Diet; Variant; Vascular Diseases; atherosclerosis risk; carotid intima-media thickness; cohort; disability; epigenetic variation; epigenome editing; ethnic disparity; family structure; follow-up; genetic risk factor; genetic variant; genome editing; genome-wide; high risk; innovation; insight; instrument; inter-individual variation; lifestyle data; methylome; migration; multi-ethnic; next generation sequencing; non-genetic; novel; novel strategies; peripheral blood; physical inactivity; risk stratification; stroke incidence; stroke risk; stroke therapy; validation studies; vascular smooth muscle cell proliferation

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.

项目摘要 中风是美国死亡和残疾的主要原因，对少数群体人群产生了不成比例的影响。 西班牙裔中风的风险特别高；中风的风险增加可以通过特定的遗传来解释 和非遗传因素。多米尼加人是美国增长最快的加勒比西班牙裔美国人，但鲜为人知 关于它们中风和心血管疾病（CVD）的遗传和非遗传决定因素。过去15 多年来，我们的团队一直在调查多米尼加人的中风遗传危险因素。我们已经组装了一个队列 多米尼加家庭的中风风险高，专注于中风前体表型（SPP） 中风病因的表型异质性和复杂性。我们调查了公认的SPP 颈动脉内膜膜厚度，颈动脉斑块，左心室质量和左心房直径。我们有 成功识别了使用高的SPP相关的定量性状基因座和DNA序列变体 吞吐量基因分型和下一代测序。这些发现占了一小部分间 SPP的个体变异。在此应用中，我们建议扩大我们的研究以进行甲基 广泛协会研究（MWA），以识别与spps相关的差异DNA甲基化区（DMR） 中风和CVD。甲基化是一种表观遗传过程，可调节基因表达而不改变DNA 顺序。 DNA甲基化已显示为有助于血管发展的关键过程 疾病。拟议的调查将提供与新型临床发展有关的新见解 预防和治疗中风和CVD的策略是我们的最终目标是降低中风风险和种族 - 中风和CVD中的种族差异。我们计划4个目标：目标1来识别与中风spps相关的DMR；目的 2评估遗传和非遗传因素对与SPP相关的DMR的相对贡献；目标3 使用CRISPR-CAS9技术评估DNA序列变化和DMR的功能影响；和目标 4检查SPP相关的DMR对血管事件的预测效应。为了实现这些目标，我们将 利用家庭研究中已经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，心肌梗塞，血管死亡）。我们将验证从独立样本中的发现 曼哈顿北部正在进行的纵向研究，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。我们提案的创新方面包括可修改表观遗传站点的新发现 中风和CVD，CRISPR-CAS9技术，以建模特定的基因组编辑，这是多米尼加人独特的人群 以及家庭研究设计，以及多米尼加人可用的独立人群，用于验证研究。 我们研究的发现可能导致风险分层最有希望的分子策略 和中风的治疗。

项目成果

Association between variations in coagulation system genes and carotid plaque.

• DOI: 10.1016/j.jns.2012.08.020
• 发表时间: 2012-12-15
• 期刊: JOURNAL OF THE NEUROLOGICAL SCIENCES
• 影响因子: 4.4
• 作者: Della-Morte, David;Beecham, Ashley;Dong, Chuanhui;Wang, Liyong;McClendon, Mark S.;Gardener, Hannah;Blanton, Susan H.;Sacco, Ralph L.;Rundek, Tatjana
• 通讯作者: Rundek, Tatjana

Sirtuin/uncoupling protein gene variants and carotid plaque area and morphology.

• DOI: 10.1111/ijs.12623
• 发表时间: 2015-12
• 期刊: International journal of stroke : official journal of the International Stroke Society
• 作者: Dong C;Della-Morte D;Cabral D;Wang L;Blanton SH;Seemant C;Sacco RL;Rundek T
• 通讯作者: Rundek T

Genomewide linkage and peakwide association analyses of carotid plaque in Caribbean Hispanics.

• DOI: 10.1161/strokeaha.110.596981
• 发表时间: 2010-12
• 期刊: Stroke
• 影响因子: 8.3
• 作者: Dong C;Beecham A;Slifer S;Wang L;Blanton SH;Wright CB;Rundek T;Sacco RL
• 通讯作者: Sacco RL

Rare variants in previously identified linkage regions associated with carotid plaque in Dominican Republic families.

• DOI: 10.1371/journal.pone.0250799
• 发表时间: 2022
• 期刊: PloS one
• 影响因子: 3.7
• 作者: Dueker ND;Beecham A;Wang L;Dong C;Sacco RL;Blanton SH;Rundek T
• 通讯作者: Rundek T

Follow-up association study of linkage regions reveals multiple candidate genes for carotid plaque in Dominicans.

• DOI: 10.1016/j.atherosclerosis.2012.03.025
• 发表时间: 2012-07
• 期刊: ATHEROSCLEROSIS
• 影响因子: 5.3
• 作者: Dong, Chuanhui;Beecham, Ashley;Wang, Liyong;Blanton, Susan H.;Rundek, Tatjana;Sacco, Ralph L.
• 通讯作者: Sacco, Ralph L.