Secondary Prevention of Subcortical Stroke Prevention Genetic Substudy

描述(申请人提供)：皮质下小中风二级预防(SPS3)临床试验旨在确定有效的治疗方法，预防有症状的皮质下小中风(S3)患者中风复发和认知能力下降。2x2析因设计试验将S3患者随机分配到阿司匹林加氯吡格雷与单用阿司匹林，以及常规(SBP 130-149 mm Hg)与高强度(SBP&lt；130 mm Hg)血压控制组。主要结果是复发性中风，试验预计将于2012年春季结束。这是一个对SPS3进行遗传样本收集的时间敏感的子研究建议，用于测试药物基因组学和基因组假说。最近对接受氯吡格雷治疗的心脏病患者的研究表明，那些丧失功能的CYP2C19*2等位基因患者的预后较差，这一发现可以解释为这些人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。具体目的1.建立SPS3遗传学数据库，确定接受氯吡格雷治疗的CYP2C19*2携带者是否比携带CYP2C19*1*1基因的携带者有更高的卒中复发发生率。正在进行的研究还指出了可能影响氯吡格雷、阿司匹林和降压药疗效的其他遗传变异，SPS3为更广泛地促进我们对这些遗传决定因素的理解提供了一个极好的数据集。特定目的2.确定先前与抗血小板或抗高血压药物的药理反应相关的遗传位点是否与SPS3参与者中的复发中风以一种特定的治疗方式相关。SPS3中的遗传队列也代表着推进中风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(GWA3)，同时进行GWAMeta分析，以检测与皮质下小卒中相关的新SNP。此外，我们还将确定皮质下卒中相关SNPs是否与S3患者的复发卒中有关。我们将与NINDS支持的缺血性中风遗传学联盟合作，进行AIM 3研究，并确保SPS3基因组数据最大限度地推动中风基因组学领域的发展。综上所述，我们建议建立一个SPS3DNA文库，以检验关于CYP2C19基因对SPS3主要结局的影响的假说；促进对抗血小板和抗高血压药物疗效重要的遗传变异的理解；并发现原发和继发性皮质下卒中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.