Secondary Prevention of Subcortical Stroke Prevention Genetic Substudy

皮质下中风预防的二级预防基因亚组研究

• 批准号: 8239529
• 负责人: OSCAR R BENAVENTE
• 金额: $ 67.19万
• 依托单位: UNIVERSITY OF FLORIDA
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-03-15 至 2014-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8239529
• 关键词: Accounting; Alleles; Antihypertensive Agents; Antiplatelet Drugs; Asians; Aspirin; Blood Pressure; Boxing; Cardiovascular system; Caucasians; Caucasoid Race; Clinical Trials; Clinical Trials Design; Collection; Cytochromes; DNA; DNA Library; Data; Data Set; Disease; Enrollment; European; Event; Genes; Genetic; Genetic Databases; Genetic Determinism; Genetic Polymorphism; Genomics; Genotype; Heart Diseases; Heritability; Hypotension; Impaired cognition; Individual; Ischemic Stroke; Label; Letters; Medicine; Meta-Analysis; National Institute of Neurological Disorders and Stroke; Outcome; Participant; Patients; Pharmaceutical Preparations; Pharmacogenetics; Pharmacogenomics; Platelet aggregation; Plavix; Predisposition; Prevention; Prodrugs; Proteins; Publishing; Recurrence; Reporting; Research; Risk; Sample Size; Sampling; Secondary Prevention; Stroke; Stroke prevention; Testing; Therapeutic; Time; Update; Variant; Vascular Dementia; Vascular Diseases; base; blood pressure regulation; clopidogrel; cohort; design; drug efficacy; follow-up; genetic variant; genome wide association study; genome-wide; loss of function; novel; prevent; primary outcome; public health relevance; response; sample collection

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. PUBLIC HEALTH RELEVANCE: Small subcortical strokes (S3) are a common stroke subtype and contribute importantly to vascular dementia. The SPS3 trial seeks to define optimal treatment approaches with antiplatelet and antihypertensive medications to prevent recurrent stroke in S3 patients. We will collect genetic samples from SPS3 participants and conduct studies to help define if there are genetic factors that influence responses to antiplatelet and antihypertensive medications. We will also conduct a study to identify genetic variants that increase the risk for subcortical stroke.

描述（由申请人提供）：小皮质下中风二级预防（SPS3）临床试验旨在确定治疗性预防有症状的小皮质下中风（S3）患者中风复发和认知能力下降的有效方法。 2x2 析因设计试验将 S3 患者随机分配至阿司匹林加氯吡格雷组与单用阿司匹林组；以及常规（SBP 130-149 mmHg）与积极（SBP < 130 mmHg）血压控制。主要结果是复发性中风，试验预计于 2012 年春季结束。这是针对 SPS3 的一项时间敏感的子研究提案，用于收集遗传样本，用于测试药物基因组学和基因组假设。最近对接受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，这一发现的解释是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 患者中也会观察到氯吡格雷疗效的类似下降。具体目标 1. 建立 SPS3 遗传学数据库，并确定接受氯吡格雷治疗的 CYP2C19*2 携带者是否比接受氯吡格雷治疗的 CYP2C19*1*1 基因型个体具有更高的卒中复发率。正在进行的研究还指出可能影响氯吡格雷、阿司匹林和抗高血压药物疗效的其他遗传变异，SPS3 代表了一个极好的数据集，可以更广泛地增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的药理反应相关的基因位点是否与 SPS3 参与者中以治疗特定方式复发性中风相关。 SPS3 中的遗传队列也代表了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 (GWAS) 以及 GWAS 荟萃分析，以检测与小型皮质下中风相关的新 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 支持的缺血性中风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动中风基因组学领域的发展。总之，我们建议建立一个SPS3 DNA库来检验CYP2C19基因型对SPS3主要结局影响的假设；促进对抗血小板和抗高血压药物疗效重要的基因变异的了解；并发现原发性和继发性皮质下中风的新遗传决定因素。 公共卫生相关性：小型皮质下中风 (S3) 是一种常见的中风亚型，对血管性痴呆有重要影响。 SPS3 试验旨在确定抗血小板和抗高血压药物的最佳治疗方法，以预防 S3 患者复发中风。我们将从 SPS3 参与者收集遗传样本并进行研究，以帮助确定是否存在影响抗血小板和抗高血压药物反应的遗传因素。我们还将开展一项研究，以确定增加皮质下中风风险的基因变异。