Pharmacogenomic studies in VISP: results & implications for clinical trial design

VISP 中的药物基因组学研究：结果

基本信息

批准号：
8298859
负责人：
MICHELE M SALE
金额：
$ 14.63万
依托单位：
UNIVERSITY OF VIRGINIA
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-09-29 至 2014-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8298859
关键词：
Accounting Address Adverse effects American Atherosclerosis Bioethics Biological Markers Blood Vessels Cerebral Infarction Cerebrovascular Disorders Cessation of life Clinical Clinical Trials Clinical Trials Design Coagulation Process Collaborations Collection Consent Country Cox Proportional Hazards Models DNA Data Data Set Dementia Diet Direct Costs Disabled Persons Dose Double-Blind Method Electronics Endothelium Environmental Exposure Event Facilities and Administrative Costs Fibrinogen Fibrinolysis Folate Folic Acid Functional disorder Funding Future Gene Frequency Genes Genetic Genetic Materials Genetic Predisposition to Disease Genetic Risk Genomics Genotype Goals Guidelines Health Health Sciences Homocysteine Homocystine Human Hyperlipidemia Impaired cognition Individual Inflammation Institutes Intake International Intervention Ischemic Stroke Letters Marketing Measurable Measures Mediating Medical Records Medical Research Methodology Methods Mind Minor Modeling National Human Genome Research Institute National Institute of Neurological Disorders and Stroke Neurologic Neurology Outcome Paper Participant Patients Pharmacogenomics Play Population Predisposition Prevention Principal Investigator Privacy Public Health Randomized Randomized Clinical Trials Randomized Controlled Clinical Trials Recurrence Research Research Personnel Resources Risk Risk Assessment Risk Factors Role Sales Sampling Stroke Stroke prevention Supplementation Survival Analysis Technology Testing Therapeutic Intervention Time United States National Institutes of Health Universities VWF gene Validation Variant Virginia Vitamin B 12 Vitamin B Complex Vitamin B6 Vitamins Work base cofactor cohort cost data management design diabetes control experience follow-up genetic risk factor genetic variant genome wide association study genome-wide genome-wide analysis improved inflammatory marker innovation insight member novel predictive modeling prevent repository response therapeutic development treatment effect vitamin therapy

项目摘要

DESCRIPTION: (provided by applicant): More than 750,000 Americans suffer stroke each year. Of these, nearly 160,000 die and hundreds of thousands are disabled. The burden on the public health is even greater given that 11 million subclinical strokes per year contribute to cognitive decline and dementia. Ischemic stroke accounts for 85% of all strokes. Established stroke risk factors play major roles in defining stroke risk at a population level, but prediction of individual risk remains unrealized. Identification of factors that place individuals at risk for ischemic stroke is central to the development of therapeutic preventative strategies. The Vitamin Intervention for Stroke Prevention (VISP) trial, an NIH-funded, multicenter, double-blind, randomized, controlled clinical trial, was designed to determine whether the daily intake of high dose folic acid, vitamins B6 and B12 reduced recurrent cerebral infarction and a combined vascular endpoint. The question of benefit versus risk for B-vitamin supplementation remains a controversial topic. Concern that such interventions may incur measurable risk heightens the need to clarify who might benefit and who might be harmed by such therapies, particularly given population-level folate supplementation efforts. Our central hypothesis is that there are genetic variants that significantly correlate with risk of recurrent ischemic stroke in the setting of vitamin therapy. The specific aims of this proposal are to: 1) Identify genetic variants that influence the risk of recurrent stroke or combined vascular endpoints in response to vitamin therapy; 2) Determine whether the association between genetic variants and risk of recurrent stroke, MI or death is mediated via diet, inflammation, and/or coagulation; 3) Develop predictive models, incorporating genetic and clinical information, that can be applied to future clinical trial design; 4) Work collaboratively with other UOl awardees and the NHGRI to develop a paradigm for pharmacogenomic clinical trial design. The VISP trial provides a unique data set and a wealth of analytic opportunities. These analyses are expected generate testable models predictive of stroke risk, impart insights into pathophysiologies underlying susceptibility to ischemic stroke, and be instructive in providing a framework to develop guidelines for genome-wide studies on future clinical trials; PUBLIC HEALTH RELEVANCE: More than 750,000 Americans suffer stroke each year. Of these, nearly 160,000 die and hundreds of thousands are disabled. The burden on the public health is even greater given that 11 million subclinical strokes per year contribute to cognitive decline and dementia. Beyond the human cost, the direct and indirect costs of ischemic stroke in the U.S. are projected to exceed $2.2 trillion in 2050.

描述：（由申请人提供）：每年有75万美国人中风。其中，将近160,000人死亡，数十万残疾。鉴于每年有1100万个亚临床中风会导致认知能力下降和痴呆症，因此对公共卫生的负担更大。缺血性中风占所有中风的85％。既定的中风风险因素在定义人群水平上定义中风风险方面起着重要作用，但对个人风险的预测仍然未实现。识别将个人处于缺血性中风风险的因素是治疗预防策略的发展至关重要的。旨在确定高剂量叶酸，维生素B6和B12的每日摄入是否是否每天摄入高剂量的大脑梗死和血管界点的血管结合点，用于预防中风预防（VISP）试验的维生素干预旨在确定每日摄入高剂量叶酸，维生素B6和B12是否减少了每日摄入高剂量的叶酸，维生素B6和B12。补充B-Vitamin的利益与风险的问题仍然是一个有争议的话题。担心这种干预措施可能会产生可衡量的风险，这会增加澄清谁可能受益并可能受到这种疗法伤害的人的需求，特别是考虑到人口水平的补充工作。我们的中心假设是，在维生素治疗的情况下，有一些遗传变异与复发性缺血性中风的风险显着相关。该提案的具体目的是：1）确定影响复发性中风的风险或响应维生素治疗的血管终点的风险； 2）确定遗传变异与复发性中风，MI或死亡风险之间的关联是否是通过饮食，炎症和/或凝结介导的； 3）开发预测模型，结合了遗传和临床信息，可以应用于将来的临床试验设计； 4）与其他UOL获奖者和NHGRI合作开发了用于药物基因组临床试验设计范式。 VISP试验提供了独特的数据集和大量的分析机会。这些分析是预期产生可预测中风风险的可检验模型，赋予对缺血性中风易感性的病理生理的见解，并在提供一个框架以制定针对全基因组研究的指南方面具有启发性；公共卫生相关性：每年有75万美国人中风。其中，将近160,000人死亡，数十万残疾。鉴于每年有1100万个亚临床中风会导致认知能力下降和痴呆症，因此对公共卫生的负担更大。除人类成本外，美国缺血性中风的直接和间接成本预计在2050年将超过2.2万亿美元。