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

描述：（由申请人提供）：每年有超过75万美国人中风。其中，近16万人死亡，数十万人致残。鉴于每年有1100万次亚临床中风导致认知能力下降和痴呆，公共卫生的负担甚至更大。缺血性中风占所有中风的85%。既定的中风危险因素在确定人群水平的中风危险中起主要作用，但对个体风险的预测仍未实现。确定使个体处于缺血性中风危险的因素是制定治疗性预防策略的核心。维生素干预脑卒中预防（VISP）试验是美国国立卫生研究院资助的一项多中心、双盲、随机对照临床试验，旨在确定每日摄入高剂量叶酸、维生素B6和B12是否能减少复发性脑梗死和联合血管终点。补充b族维生素的益处与风险的问题仍然是一个有争议的话题。考虑到这些干预措施可能会产生可测量的风险，需要明确哪些人可能受益，哪些人可能会受到这些治疗的伤害，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，在维生素治疗的背景下，存在与复发性缺血性中风风险显著相关的遗传变异。该建议的具体目的是：1)确定对维生素治疗影响卒中复发或合并血管终点风险的遗传变异；2)确定基因变异与卒中复发、心肌梗死或死亡风险之间的关联是否通过饮食、炎症和/或凝血介导；3)建立结合遗传和临床信息的预测模型，用于未来的临床试验设计；4)与其他UOl获奖者和NHGRI合作，开发药物基因组学临床试验设计范例。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

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.