Secondary Prevention of Subcortical Stroke Prevention Genetic Substudy

描述（由申请人提供）：小皮质下卒中的二级预防（SPS3）临床试验旨在确定有效的治疗方法，预防症状性小皮质下卒中（S3）患者的卒中复发和认知能力下降。2x2因子设计试验随机分配S3例患者阿司匹林加氯吡格雷组与阿司匹林单用组；正常（收缩压130-149 mmHg）和积极（收缩压< 130 mmHg）血压控制。主要结果是复发性中风，该试验预计将于2012年春季结束。这是SPS3基因样本收集的时间敏感子研究提案，用于测试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表明，CYP2C19*2等位基因功能丧失的患者预后较差，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。具体目标建立SPS3基因数据库，确定氯吡格雷治疗的CYP2C19*2基因型患者卒中复发率是否高于氯吡格雷治疗的CYP2C19*1*1基因型患者。正在进行的研究还指出，其他遗传变异可能影响氯吡格雷、阿司匹林和抗高血压药物的疗效，SPS3代表了一个很好的数据集，可以更广泛地推进我们对这些遗传决定因素的理解。具体目标2。确定先前与抗血小板或抗高血压药物药理反应相关的基因位点是否与SPS3参与者的复发性卒中以治疗特异性方式相关。SPS3的遗传队列也代表了推进脑卒中基因组学的绝佳机会，因为SPS3是世界上最大的S3病例集合之一。具体目标3。在SPS3中进行全基因组关联研究（GWAS），并进行GWAS荟萃分析，以检测与小皮质下卒中相关的新snp。此外，我们将确定皮层下卒中相关snp是否与S3患者复发性卒中相关。我们将与ninds支持的缺血性卒中遗传学联盟合作开展Aim 3研究，并确保SPS3基因组学数据最大限度地推进卒中基因组学领域。综上所述，我们建议建立SPS3 DNA库，检验CYP2C19基因型对SPS3主要结局影响的假设；进一步了解与抗血小板和降压药物疗效相关的基因变异；并发现原发性和继发性皮层下中风的新的遗传决定因素。

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.