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

描述：(申请人提供)：每年有超过75万美国人罹患中风。其中，近16万人死亡，数十万人残疾。公共卫生的负担甚至更大，因为每年有1100万亚临床中风导致认知能力下降和痴呆症。缺血性中风占所有中风的85%。已建立的卒中风险因素在人群水平上定义卒中风险方面发挥了主要作用，但对个体风险的预测仍未实现。确定将个体置于缺血性中风风险中的因素是制定治疗预防策略的核心。预防中风的维生素干预试验是一项由美国国立卫生研究院资助的、多中心、双盲、随机、对照的临床试验，旨在确定每天摄入高剂量叶酸、维生素B6和B12是否可以减少复发的脑梗塞和复合血管终点。补充维生素B的益处和风险的问题仍然是一个有争议的话题。由于担心这种干预措施可能会招致可衡量的风险，更有必要澄清哪些人可能受益于这些疗法，哪些人可能受到伤害，特别是考虑到人群水平的叶酸补充努力。我们的中心假设是，在维生素治疗的环境中，存在与复发缺血性中风风险显著相关的基因变异。该建议的具体目的是：1)确定影响中风复发风险或联合血管终点的基因变异，以应对维生素治疗；2)确定基因变异与中风复发、心肌梗死或死亡风险之间的关联是否通过饮食、炎症和/或凝血调节；3)开发包含遗传和临床信息的预测模型，可应用于未来的临床试验设计；4)与其他UOL获奖者和NHGRI合作，为药物基因组临床试验设计开发一个范例。VISP试验提供了独特的数据集和丰富的分析机会。这些分析是 预期将产生可预测中风风险的可测试模型，为缺血性中风的易感性提供见解，并在为未来临床试验的全基因组研究提供指导方针方面提供指导框架；公共卫生相关性：每年有超过75万美国人患有中风。其中，近16万人死亡，数十万人残疾。公共卫生的负担甚至更大，因为每年有1100万亚临床中风导致认知能力下降和痴呆症。除人力成本外，美国缺血性中风的直接和间接成本预计将在2050年超过2.2万亿美元。

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.