Thrombosis Genetics, MI and Stroke in Older Adults

老年人的血栓形成遗传学、心肌梗死和中风

• 批准号: 8288363
• 负责人: ALEXANDER P REINER
• 金额: $ 53.6万
• 依托单位: UNIVERSITY OF WASHINGTON
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-07-01 至 2015-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8288363
• 关键词: Accounting; Acute myocardial infarction; Address; African American; Age; Anti-Inflammatory Agents; Anti-inflammatory; Anticoagulation; Architecture; Atherosclerosis; Biochemical Markers; Bioinformatics; Biological Markers; Biology; Blood Coagulation Factor VII; C-reactive protein; Candidate Disease Gene; Cardiovascular Diseases; Cardiovascular system; Clinical; Coagulation Process; Complex; Computer Simulation; Contracts; Coronary heart disease; Data; Development; Disease; Elderly; Environment; Etiology; Event; Fibrinogen; Floods; Funding; Gene Expression; Genes; Genetic; Genetic Determinism; Genetic Markers; Genome; Genotype; Grant; Haplotypes; Health; Heart; Human; In Vitro; Individual; Inflammation; Inflammatory; Link; Measurement; Measures; Methods; Molecular; Myocardial Infarction; National Heart, Lung, and Blood Institute; North Carolina; Nucleotides; Oral; Pathway interactions; Patients; Pattern; Pharmaceutical Preparations; Phenotype; Plasma; Population; Predisposition; Prevention; Procedures; Proteins; Public Health; Randomized; Research Personnel; Resources; Risk; Risk Factors; Role; Screening procedure; Smoking; Stratification; Stroke; Systematic Bias; Testing; Therapeutic; Thrombosis; Tissue Sample; Universities; Validation; Variant; Vermont; Washington; Women' s Health; analytical method; base; cardiovascular disorder risk; cardiovascular risk factor; cohort; disability; disease phenotype; flexibility; functional genomics; gene environment interaction; gene interaction; genetic association; genetic risk factor; genetic variant; genome wide association study; human tissue; innovation; interest; novel; programs; response; trait; vascular inflammation

DESCRIPTION (provided by applicant): This project represents a collaborative effort among investigators of the University of Washington, the University of Vermont, University of North Carolina, and Johns Hopkins. While the therapeutic benefits of anti-thrombotic and anti-inflammatory therapies suggest a major role for clotting and inflammation in the etiology of myocardial infarction (MI) and stroke, the genetic determinants of the pro-thrombotic and pro-inflammatory components of cardiovascular disease (CVD) risk remain poorly characterized. By building on candidate gene-CVD clinical and intermediate phenotype association results from our first grant cycle, the proposed renewal application links biologic advances in thrombosis and vascular inflammation pathways, functional genomics, population and statistical genetics, with the unique resources of Cardiovascular Health Study (CHS), a large, biracial cohort of older adults. Through the CHS main contract, 5,888 older adults have been followed for over 15 years, with the accrual of large number (>2,000) of clinical CVD events. Data on baseline traditional risk factors, subclinical disease, and several important inflammation/thrombosis biomarkers (fibrinogen, C-reactive protein, factor VII, and others) are also available. Through the proposed renewal, we plan to perform additional measurements of 8 plasma thrombosis biomarkers, selected on basis of our preliminary findings and rigorously defined biologic criteria, which will be utilized as intermediate phenotypes to strengthen evidence for CVD event-candidate gene association. By integrating existing candidate gene genotype data from the first cycle with >2,000 candidate genes from the NHLBI-supported CARE study and existing CHS genome-wide data (Illumina Human Hap 370CNV), we propose to evaluate thoroughly the association of thrombosis/inflammation genes with intermediate phenotypes and incident MI and stroke. Additional strengths of the application include excellent candidate gene SNP coverage in whites and African-Americans, and a flexible analytic approach that includes assessment of single- and multi-locus genotypes, haplotypes, gene-environment and gene-gene interaction. Validation of findings will occur through replication genotyping in additional cohorts with large numbers of CVD events (ARIC, Honolulu Heart Program, Women's Health Initiative), as well as in vitro and bioinformatics assessment of associated SNPs. PUBLIC HEALTH RELEVANCE: While the therapeutic benefits of anti-thrombotic therapies suggest a major role for clotting and inflammation in the etiology of coronary disease and stroke, the specific genetic determinants that underlie the predisposition toward vascular inflammation and thrombosis associated with cardiovascular risk remains largely unknown in older adults. Understanding the molecular background of these common but complex atherothrombotic disorders may help identify older individuals at high cardiovascular risk because of genetic or environmental differences in the inflammatory or thrombotic response to advanced atherosclerosis and may provide new directions for prevention and treatment of MI and stroke.

描述(申请人提供)：这个项目代表了华盛顿大学、佛蒙特大学、北卡罗来纳大学和约翰霍普金斯大学的研究人员之间的合作努力。虽然抗血栓和抗炎治疗的疗效表明凝血和炎症在心肌梗死(MI)和中风的病因中发挥了重要作用，但心血管疾病(CVD)风险的血栓前和促炎成分的遗传决定因素仍然缺乏特征。通过建立在我们第一个赠款周期的候选基因-心血管疾病临床和中间表型关联结果的基础上，拟议的更新应用将血栓形成和血管炎症途径、功能基因组学、人口和统计遗传学方面的生物学进展与心血管健康研究(CHS)的独特资源联系起来，CHS是一个大型的老年人混血队列。通过CHS主合同，5888名老年人已经被跟踪超过15年，并积累了大量(&gt；2,000)临床心血管事件。关于基线传统危险因素、亚临床疾病和几个重要的炎症/血栓形成生物标志物(纤维蛋白原、C-反应蛋白、因子VII等)的数据也是可用的。通过拟议的更新，我们计划对根据我们的初步发现和严格定义的生物学标准选择的8个血浆血栓形成生物标志物进行额外的测量，这些生物标志物将被用作中间表型，以加强CVD事件候选基因关联的证据。通过将第一个周期的现有候选基因基因型数据与NHLBI支持的CARE研究中的2,000个候选基因和现有的CHS全基因组数据(Illumina Human Hap 370CNV)相结合，我们建议彻底评估血栓形成/炎症基因与中间表型、心肌梗死和中风事件的关联。该应用程序的其他优势包括在白人和非裔美国人中出色的候选基因SNP覆盖率，以及一种灵活的分析方法，包括评估单基因和多基因座基因类型、单倍型、基因-环境和基因-基因相互作用。研究结果的验证将通过在发生大量心血管疾病事件(ARIC、火奴鲁鲁心脏计划、妇女健康倡议)的其他队列中进行复制基因分型以及相关SNP的体外和生物信息学评估来进行。公共卫生相关性：虽然抗血栓治疗的疗效表明凝血和炎症在冠心病和中风的病因中发挥了重要作用，但在老年人中，与心血管风险相关的血管炎症和血栓形成的易感性背后的特定基因决定因素仍然很大程度上是未知的。了解这些常见但复杂的动脉粥样硬化血栓形成疾病的分子背景可能有助于识别因遗传或环境差异而对晚期动脉粥样硬化的炎症或血栓反应具有高心血管风险的老年人，并可能为预防和治疗心肌梗死和中风提供新的方向。

项目成果

Genetic association analysis highlights new loci that modulate hematological trait variation in Caucasians and African Americans.

• DOI: 10.1007/s00439-010-0925-1
• 发表时间: 2011-03
• 期刊: Human genetics
• 影响因子: 5.3
• 作者: Lo KS;Wilson JG;Lange LA;Folsom AR;Galarneau G;Ganesh SK;Grant SF;Keating BJ;McCarroll SA;Mohler ER 3rd;O'Donnell CJ;Palmas W;Tang W;Tracy RP;Reiner AP;Lettre G
• 通讯作者: Lettre G

Recent findings in the genetics of blood pressure and hypertension traits.

• DOI: 10.1038/ajh.2010.218
• 发表时间: 2011-04
• 期刊: AMERICAN JOURNAL OF HYPERTENSION
• 影响因子: 3.2
• 作者: Franceschini, Nora;Reiner, Alexander P.;Heiss, Gerardo
• 通讯作者: Heiss, Gerardo