Predictors of Coronary Artery Calcification in an African-American Cohort

非洲裔美国人队列中冠状动脉钙化的预测因素

• 批准号: 7895688
• 负责人: Patricia Ann PEYSER
• 金额: $ 67.24万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-09-15 至 2013-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7895688
• 关键词: Adult; African American; American; Arterial Disorder; Arterial Fatty Streak; Atherosclerosis; Biology; Blood Pressure; Candidate Disease Gene; Clinical; Comorbidity; Coronary; Coronary Arteriosclerosis; Development; Disease; Disease susceptibility; Early identification; End stage renal failure; European; Event; Family; Future; Genes; Genetic; Genome; Health Services Accessibility; High Prevalence; Hypertension; Image; Individual; Knowledge; Lead; Left Ventricular Hypertrophy; Link; Lod Score; Measures; Methods; Mississippi; Nucleotides; Organ; Participant; Patients; Population; Relative (related person); Research Personnel; Resources; Risk; Risk Factors; Siblings; Susceptibility Gene; Tandem Repeat Sequences; Variant; Woman; X-Ray Computed Tomography; calcification; cohort; coronary artery calcification; disorder risk; ethnic minority population; follow-up; genetic epidemiology; genetic linkage analysis; genome-wide linkage; high risk; improved; insight; men; mortality; novel; novel therapeutic intervention; population based; programs; trait

DESCRIPTION (provided by applicant): Coronary artery disease (CAD) is the single largest killer of Americans. Relative to European Americans, African Americans have higher mortality rates from CAD, particularly in women and younger men. A high prevalence of risk factors (e.g., hypertension) and associated co-morbidities (e.g., end stage renal disease and left ventricular hypertrophy), poor risk factor control, and reduced access to care are likely contributors to some, but not all, ethnic disparities in CAD events. Atherosclerosis is the major cause of CAD and extent of coronary atherosclerosis is the most powerful predictor of subsequent clinical events. Non-invasive imaging of coronary artery calcification (CAC) has emerged as a useful method to assess CAD risk, especially in intermediate risk patients. Quantity of CAC measured by computed tomography correlates directly with quantity of coronary atherosclerotic plaque and CAC quantity in asymptomatic adults predicts risk for future clinical events. Asymptomatic African Americans with evidence of subclinical coronary atherosclerosis, as assessed by CAC quantity, are the highest risk ethnic minority population when European Whites are the reference group. Identification of CAD susceptibility genes in African Americans will provide insights into disease biology and suggested targets for novel therapeutic approaches. In this revised application, we propose to build upon the resources of the Genetic Epidemiology Network of Arteriopathy (GENOA) Study, part of the Family Blood Pressure Program. The GENOA Study is a population-based cohort of hypertensive sibships extensively characterized through two exams conducted between 1995 and 2004. GENOA has conducted studies to identify genes for hypertension and target-organ damage. We will extend those efforts by assessing CAC quantity in 900 African American siblings from the GENOA Field Center in Jackson, MS. 381 marker loci spanning the genome, already measured in GENOA will be used to localize genes influencing CAC quantity (for Aim 1). These same marker loci will then be used to localize genes with pleiotropic effects on CAC quantity and each of the CAD traditional and novel risk factors (Aim 2). We propose to follow-up the genome-wide linkage analysis for CAC quantity by localizing positional candidate genes under the most compelling LOD score peaks (from Aims 1 and 2) and evaluate the relationship of nucleotide variation in the identified candidate genes with CAC quantity. Genetic studies in African American populations will advance knowledge of mechanisms of subclinical atherosclerosis as well as lead to improved strategies for early identification of individuals at risk for CAD events, and development of new, more efficacious treatments tailored to those most likely to respond.

描述（由申请人提供）：冠状动脉疾病（CAD）是美国人最大的杀手。相对于欧洲人，非裔美国人的死亡率较高，尤其是在女性和年轻男性中。危险因素（例如高血压）和相关的合并症（例如，末期肾脏疾病和左心室肥大），危险因素控制差以及降低的护理机会可能是某些人，但不是全部，CAD事件中的种族差异可能是造成这种危险因素（例如，高血压）和相关的合并症（例如，末期肾脏疾病和左心室肥大），不良的危险因素和左心室肥大。动脉粥样硬化是CAD的主要原因，冠状动脉粥样硬化的程度是随后临床事件的最强大预测指标。冠状动脉钙化（CAC）的非侵入性成像已成为评估CAD风险的有用方法，尤其是在中级风险患者中。通过计算机断层扫描测量的CAC数量直接与无症状成年人中的冠状动脉粥样硬化斑块和CAC数量直接相关，可预测未来临床事件的风险。通过CAC数量评估的有亚临床冠状动脉粥样硬化的迹象的无症状非洲裔美国人是当欧洲白人是参考群体时，是最高风险的少数族裔人口。非洲裔美国人中CAD敏感性基因的鉴定将提供有关疾病生物学的见解，并提出了新型治疗方法的靶标。在此修订后的应用中，我们建议建立在遗传流行病学网络（Genoa）研究的资源基础上，这是家庭血压计划的一部分。热那亚研究是一项基于人群的高血压同胞的队列，该研究通过1995年至2004年之间进行的两次考试进行了广泛的特征。热那亚进行了研究，以鉴定高血压和靶向器官损伤的基因。我们将通过评估来自密西西比州杰克逊热那亚野战中心的900名非裔美国人兄弟姐妹的CAC数量来扩展这些努力。 381个跨越基因组的标记基因座，已在热那亚中测量的基因组将用于定位影响CAC数量的基因（对于AIM 1）。然后，这些相同的标记基因座将用于定位对CAC数量以及每个CAD传统和新型风险因素的基因（AIM 2）。我们建议通过将位置候选基因定位在最引人注目的LOD评分峰（来自AIM 1和2），并评估确定的候选基因与CAC量的核苷酸变异的关系，以跟进CAC数量的全基因组链接分析。非裔美国人人口中的遗传研究将提高对亚临床动脉粥样硬化的机制的了解，并导致改进的策略，以早日识别有CAD事件风险的个体，并开发出针对最有可能反应的人量身定制的新的，更有效的治疗方法。