Genomic Predictors of Arteriosclerosis in Hypertensives

高血压动脉硬化的基因组预测因子

• 批准号: 7642391
• 负责人: Sharon L Kardia
• 金额: $ 104.15万
• 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: 2007-04-21 至 2012-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7642391
• 关键词: African American; Age; Albuminuria; Alcohols; American Heart Association; Ankle; Arterial Disorder; Arteries; Arterioloscleroses; Arteriosclerosis; Arts; Atherosclerosis; Award; Blood Pressure; Brain; Caliber; Candidate Disease Gene; Cardiac; Cerebrum; Chronic; Chronic Kidney Failure; Classification; Clinical; Cohort Studies; Creatinine; Data; Dementia; Disease; Disease susceptibility; Education; End stage renal failure; Environment; Failure; Genes; Genetic; Genome; Genomics; Grant; Health Care Costs; Heart; Heart failure; Hypertension; Individual; Ischemic Brain Injury; Kidney; Measures; Methods; Myocardial Infarction; Not Hispanic or Latino; Obesity; Organ; Participant; Pathway interactions; Pattern Recognition; Peripheral; Peripheral arterial disease; Pharmaceutical Preparations; Phenotype; Physical activity; Plant Roots; Predisposition; Research Personnel; Risk; Risk Factors; Role; Sampling; Serum; Single Nucleotide Polymorphism; Smoking; Stroke; Structure; Testing; Trees; United States; Validation; Variant; Ventricular; abstracting; cerebral atrophy; claudication; clinical phenotype; clinically relevant; cohort; coronary artery calcification; familial hypertension; forest; genetic epidemiology; genetic linkage analysis; genome wide association study; indexing; predictive modeling; programs; sex; trait; white matter

DESCRIPTION (provided by applicant): Arteriosclerosis (i.e., atherosclerosis and arteriolosclerosis) of the cardiac, cerebral, renal, and peripheral arteries leads to target organ damage and clinical sequelae such as heart attack and failure, stroke and dementia, chronic kidney disease, and claudication. Because of multiple etiologic pathways, variations in a large number of genes are likely to influence susceptibility to target organ damage in hypertensive individuals. The Genetic Epidemiology Network of Arteriopathy (GENOA) was initiated in 1995 to study the genetics of hypertension and its target organ complications using linkage analysis in sibships. As part of the ongoing GENOA study, quantitative measures of Arteriosclerosis including both atherosclerotic/ macrovascular measures of coronary artery calcification, aortic root diameter, ankle-brachial BP index, and arteriolosclerotic /microvascular measures of ischemic brain injury (subcortical white matter hyperintensities, brain atrophy, and ventricular volume) and chronic kidney disease (serum creatinine and albuminuria) have been collected. In this application, we propose to conduct a genome-wide association study of these phenotypic measures of arteriosclerosis, utilizing 500,000 single nucleotide polymorphisms measured on 1418 African-Americans and 1095 non-Hispanic Whites from the GENOA cohort. With the following specific aims: Aim 1: To identify genomic regions containing evidence of disease susceptibility loci for quantitative measures of Arteriosclerosis in 1418 African-American and 1095 non-Hispanic white GENOA participants using 500,000 SNPs. We will perform genome-wide association analysis in these two samples using state-of-the-art univariate and multivariate approaches to identify trait-specific loci, as well as genetic loci with pleiotropic effects on multiple genetically correlated measures of arteriosclerosis. Capitalizing on the hypertensive sibpair structure of our data, we will create two replicate sets of hypertensives (one sib in unrelated Set 1, second sib in unrelated Set 2) to perform replicate genome-wide associations. SNP associations will be adjusted for multiple testing, assessed for their predictive utility using cross-validation, and compared for replicate evidence to reduce false positives. Aim 2: To investigate the role of context dependent genetic effects on the distribution of target organ disease in these cohorts, we will test for effects of SNP-covariate interactions (age, sex, smoking, obesity, alcohol, physical activity, education, blood pressure drug treatment) and SNP-SNP interactions on the same quantitative measures of Arteriosclerosis investigated in Aim 1. SNP associations will be adjusted for multiple testing, assessed for their predictive utility using cross-validation, and compared for replicate evidence to reduce false positives. We will also use supervised pattern recognition methods (classification and regression trees, random forests, genomic identity-by-state methods) to build predictive models of these clinical phenotypes to identify at-risk individuals. (End of Abstract)

描述（由申请人提供）： 心脏、脑、肾和外周动脉的动脉硬化（即动脉粥样硬化和小动脉硬化）导致靶器官损伤和临床后遗症，例如心脏病发作和衰竭、中风和痴呆、慢性肾病和跛行。由于多种病因途径，大量基因的变异可能会影响高血压个体对靶器官损伤的易感性。动脉病遗传流行病学网络 (GENOA) 于 1995 年启动，旨在利用同胞连锁分析来研究高血压及其靶器官并发症的遗传学。作为正在进行的 GENOA 研究的一部分，动脉硬化的定量测量包括冠状动脉钙化、主动脉根直径、踝臂血压指数的动脉粥样硬化/大血管测量，以及缺血性脑损伤（皮质下白质高信号、脑萎缩和心室容积）和慢性肾脏疾病的动脉粥样硬化/微血管测量 （血清肌酐和蛋白尿）已被收集。在本申请中，我们建议利用对来自 GENOA 队列的 1418 名非裔美国人和 1095 名非西班牙裔白人测量的 500,000 个单核苷酸多态性，对这些动脉硬化的表型测量进行全基因组关联研究。具有以下具体目标： 目标 1：使用 500,000 个 SNP 确定包含疾病易感性位点证据的基因组区域，用于对 1418 名非裔美国人和 1095 名非西班牙裔白人 GENOA 参与者的动脉硬化进行定量测量。我们将使用最先进的单变量和多变量方法对这两个样本进行全基因组关联分析，以确定性状特异性基因座，以及对动脉硬化的多种遗传相关指标具有多效性影响的基因位点。利用我们数据的高血压同胞对结构，我们将创建两个高血压患者复制集（一个同胞在不相关的第 1 组中，第二个同胞在不相关的第 2 组中）来执行复制全基因组关联。 SNP 关联将针对多重测试进行调整，使用交叉验证评估其预测效用，并比较重复证据以减少误报。目标 2：为了研究背景依赖性遗传效应对这些队列中靶器官疾病分布的作用，我们将测试 SNP 协变量相互作用（年龄、性别、吸烟、肥胖、酒精、体力活动、教育、血压药物治疗）的影响以及 SNP-SNP 相互作用对目标 1 中研究的动脉硬化的相同定量测量的影响。SNP 关联将针对多重测试进行调整，并使用以下方法评估其预测效用 交叉验证，并比较重复证据以减少误报。我们还将使用监督模式识别方法（分类和回归树、随机森林、按状态进行基因组识别的方法）来构建这些临床表型的预测模型，以识别高危个体。 （摘要完）

项目成果

Software comparison for evaluating genomic copy number variation for Affymetrix 6.0 SNP array platform.

• DOI: 10.1186/1471-2105-12-220
• 发表时间: 2011-05-31
• 期刊: BMC bioinformatics
• 影响因子: 3
• 作者: Eckel-Passow JE;Atkinson EJ;Maharjan S;Kardia SL;de Andrade M
• 通讯作者: de Andrade M

Genome-wide association study of gene by smoking interactions in coronary artery calcification.

• DOI: 10.1371/journal.pone.0074642
• 发表时间: 2013
• 期刊: PloS one
• 影响因子: 3.7
• 作者: Polfus LM;Smith JA;Shimmin LC;Bielak LF;Morrison AC;Kardia SL;Peyser PA;Hixson JE
• 通讯作者: Hixson JE

Association between SLC2A9 transporter gene variants and uric acid phenotypes in African American and white families.

非裔美国人和白人家庭中 SLC2A9 转运蛋白基因变异与尿酸表型之间的关联。

• DOI: 10.1093/rheumatology/keq425
• 发表时间: 2011
• 期刊: Rheumatology (Oxford, England)
• 作者: Rule,AndrewD;deAndrade,Mariza;Matsumoto,Martha;Mosley,TomH;Kardia,Sharon;Turner,StephenT
• 通讯作者: Turner,StephenT