Health Disparities and CVD: Admixture Mapping in the Jackson Heart Study

健康差异和 CVD：杰克逊心脏研究中的混合图谱

• 批准号: 7077078
• 负责人: James Graham Wilson
• 金额: $ 74.82万
• 依托单位: UNIVERSITY OF MISSISSIPPI MED CTR
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-05-22 至 2010-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7077078
• 关键词: African American; European; cardiovascular disorder epidemiology; clinical research; gene expression; genetic markers; genetic susceptibility; health disparity; health services research tag; human birth weight; human genetic material tag; human subject; hypertension; linkage mapping; lipid metabolism; single nucleotide polymorphism; ventricular hypertrophy

DESCRIPTION (provided by applicant): Genetic risk for complex processes like CVD appears to involve interactions among multiple genes of small effect. Association mapping is much more powerful than linkage mapping in identifying such genes, but requires 200-500 times as many markers to scan the genome. Admixture mapping can extract much of the power of association studies but requires genotyping only a few thousand markers genome-wide. This application partners Jackson Heart Study (JHS) investigators with two leaders in the field of admixture mapping, Drs. David Reich and Nick Patterson. The studies proposed will exploit the genotyping and analytic power of the Broad Institute to perform admixture mapping in the largest cohort ever assembled to study CVD in African Americans. Several factors contribute to the timeliness of this study and show the strength of the proposed research team: (a) Our group has published the first practical genetic resource for admixture mapping: 2,154 markers with large frequency differences between Africans and Europeans, and methods to analyze the data. (b) We have assembled a unique cohort for the largest-ever genome-wide admixture scan for CVD risk genes: 3,796 unrelated African Americans rigorously characterized for a large number of CVD phenotypes, including HTN, coronary artery disease, stroke, diabetes mellitus, and heart failure. (c) Admixture mapping has had its first empiric successes, localizing genes for hypertension and multiple sclerosis. Admixture mapping works in practice, making it critically important to apply it to seek CVD genes in the JHS cohort. We propose three specific aims: Specific Aim 1: Whole-genome admixture scanning for CVD related genes. We will type 3,072 admixture mapping markers in DMA of 3,796 unrelated African American participants from the JHS cohort. We will concentrate our analyses on phenotypes with known differences in prevalence between African Americans and Europeans: hypertension, serum lipid levels, left ventricular hypertrophy, and low birth weight. Specific Aim 2: Follow-up and fine-mapping of the two strongest peaks of association. We will genotype 2,535 additional SNPs/peak in 940 participants (470 at each extreme for the selected phenotype). Specific Aim 3: Acquire all recorded birth weights for JHS participants. Birth weight will be analyzed both as a covariate for CVD phenotypes and as an independent phenotype, by admixture mapping. Lav language description: Finding genes that affect the risk of disease can identify new targets for drug treatment and lead to the development of important medical tests. These studies will seek genes of African and European origin that cause heart and blood vessel diseases in African Americans.

描述（由申请人提供）：CVD等复杂过程的遗传风险似乎涉及多个影响较小的基因之间的相互作用。关联作图在识别这些基因方面比连锁作图强得多，但需要200-500倍的标记来扫描基因组。混合作图可以提取关联研究的大部分力量，但只需要几千个标记基因组范围内的基因分型。该应用程序将杰克逊心脏研究（JHS）研究人员与混合物标测领域的两位领导者大卫赖希博士和尼克帕特森博士合作。拟议的研究将利用Broad研究所的基因分型和分析能力，在有史以来最大的队列中进行混合作图，以研究非裔美国人的CVD。有几个因素促成了这项研究的及时性，并显示了拟议研究团队的实力：（a）我们的小组发表了第一个用于混合作图的实用遗传资源：非洲人和欧洲人之间频率差异较大的2，154个标记，以及分析方法数据。(b)我们已经为CVD风险基因的最大全基因组混合扫描组装了一个独特的队列：3，796名无关的非裔美国人严格表征了大量CVD表型，包括HTN，冠状动脉疾病，中风，糖尿病和心力衰竭。(c)混合物图谱已经取得了第一次经验性的成功，定位了高血压和多发性硬化症的基因。混合物定位在实践中起作用，因此将其应用于JHS队列中寻找CVD基因至关重要。我们提出了三个具体目标：具体目标1：全基因组混合扫描CVD相关基因。我们将在来自JHS队列的3，796名无关的非裔美国人参与者的DMA中对3，072个混合物作图标记进行分型。我们将集中分析非裔美国人和欧洲人之间患病率存在已知差异的表型：高血压、血脂水平、左心室肥大和低出生体重。具体目标2：跟踪和精细绘制两个最强关联峰。我们将在940名参与者中对2，535个额外的SNP/峰进行基因分型（对于所选表型，每个极端470个）。具体目标3：获取JHS参与者所有记录的出生体重。出生体重将作为CVD表型的协变量和作为独立表型通过混合作图进行分析。Lav语言描述：发现影响疾病风险的基因可以确定药物治疗的新靶点，并导致重要医学测试的发展。这些研究将寻找导致非裔美国人心脏和血管疾病的非洲和欧洲起源的基因。