Secondary Prevention of Subcortical Stroke Prevention Genetic Substudy

描述（由申请方提供）：小型皮质下卒中二级预防（SPS 3）临床试验旨在确定治疗预防症状性小型皮质下卒中（S3）患者卒中复发和认知功能下降的有效方法。2x2析因设计试验将S3患者随机分配至阿司匹林+氯吡格雷组与阿司匹林单药组;以及常规（SBP 130-149 mmHg）与积极（SBP < 130 mmHg）血压控制组。主要结局是复发性卒中，预计试验将于2012年春季结束。这是一项针对遗传样本采集的SPS 3的时间敏感子研究提案，用于检测药物基因组学和基因组学假设。最近对氯吡格雷治疗的心脏病患者的研究显示，CYP 2C 19 *2等位基因功能丧失的患者结局较差，这一发现可以解释为这些患者无法将氯吡格雷转化为其活性代谢产物。我们假设在S3患者中也会观察到类似的氯吡格雷疗效下降。具体目标1。建立一个SPS 3遗传学数据库，并确定接受氯吡格雷治疗的CYP 2C 19 *2携带者是否比接受氯吡格雷治疗的CYP 2C 19 *1*1基因型个体有更高的卒中复发率。正在进行的研究还指出了可能影响氯吡格雷，阿司匹林和抗高血压药物疗效的其他遗传变异，SPS 3代表了更广泛地促进我们对这些遗传决定因素的理解的优秀数据集。具体目标2。在SPS 3受试者中，以治疗特异性方式确定先前与抗血小板或抗高血压药物药理学反应相关的遗传位点是否与复发性卒中相关。SPS 3中的遗传队列也代表了推进卒中基因组学的绝佳机会，因为SPS 3是世界上最大的S3病例集合之一。具体目标3。在SPS 3中进行全基因组关联研究（GWAS），沿着GWAS荟萃分析，以检测与皮质下小卒中相关的新SNP。此外，我们将确定皮层下卒中相关的SNP是否与S3患者的复发性卒中相关。我们将与NINDS支持的缺血性卒中遗传学联盟合作，进行Aim 3研究，并确保SPS 3基因组学数据尽可能地推进卒中基因组学领域。总之，我们建议建立一个SPS 3 DNA库，以检验CYP 2C 19基因型对SPS 3主要结局影响的假设;进一步了解对抗血小板和抗高血压药物疗效重要的遗传变异;并发现原发性和继发性皮质下卒中的新遗传决定因素。

DESCRIPTION (provided by applicant): The Secondary Prevention of Small Subcortical Strokes (SPS3) clinical trial aims to define efficacious approaches for therapeutic prevention of stroke recurrence and cognitive decline in patients with symptomatic small subcortical stroke (S3). The 2x2 factorial design trial randomly allocates S3 patients to aspirin plus clopidogrel versus aspirin alone; and to usual (SBP 130-149 mmHg) vs. aggressive (SBP < 130 mmHg) blood pressure control. The primary outcome is recurrent stroke and the trial is projected to close in spring 2012. This is a time-sensitive substudy proposal to SPS3 for genetic sample collection, to be used for testing pharmacogenomic and genomic hypotheses. Recent studies of clopidogrel-treated patients with heart disease have shown poorer outcomes in those with the loss of function CYP2C19*2 allele, a finding explained by the inability of these individuals to convert clopidogrel to its active metabolite. We hypothesize that similar decrements in clopidogrel efficacy will be observed in S3 patients. Specific Aim 1. Build an SPS3 genetics database and determine if CYP2C19*2 carriers treated with clopidogrel have higher rates of recurrent stroke than clopidogrel-treated individuals with the CYP2C19*1*1 genotype. Ongoing research also points to additional genetic variants that may influence efficacy of clopidogrel, aspirin, and antihypertensive drugs and SPS3 represents an excellent dataset for more broadly advancing our understanding of these genetic determinants. Specific Aim 2. Determine if genetic loci previously associated with pharmacologic response to antiplatelet or antihypertensive medications are associated with recurrent stroke in a treatment specific manner in SPS3 participants. A genetic cohort in SPS3 also represents an excellent opportunity for advancing stroke genomics, since SPS3 is among the largest collections of S3 cases in the world. Specific Aim 3. Conduct a genome wide association study (GWAS) in SPS3 along with a GWAS meta-analysis to detect novel SNPs associated with small subcortical stroke. Additionally we will determine if subcortical stroke- associated SNPs are associated with recurrent stroke in S3 patients. We will partner with the NINDS-supported Ischemic Stroke Genetics Consortium to conduct Aim 3 studies and to insure that SPS3 genomics data advance the stroke genomics field to the full extent possible. In summary, we propose to build an SPS3 DNA bank to test hypotheses on the influence of CYP2C19 genotype on the SPS3 primary outcome; to advance understanding of the genetic variants important to antiplatelet and antihypertensive drug efficacy; and to discover novel genetic determinants of primary and secondary subcortical stroke.