Establishment of a bioresource for discovery and evaluation of genetic and other

描述（由申请人提供）：RACE（脑血管事件风险评估）研究是巴基斯坦的一项新生生物资源，旨在研究南亚中风的遗传和其他决定因素。对当前R21拨款申请的支持将使：（i）扩大RACE，纳入2500例经影像学证实的卒中病例和2500例对照，这将是南亚最大的卒中生物资源;（ii）在RACE样本中评估20个最强关联信号（P < 10-7），这将出现在欧洲人群中风的单独资助的全基因组关联研究（GWAS）中;（iii）在RACE样本中评估先前与冠状动脉疾病风险和/或心血管风险因素相关的20个SNP（如，载脂蛋白E，chr 9p21.3，chr 1p13.3）;（iv）直接评估南亚中风的几个优先非遗传因素（如，吸烟习惯，糖尿病史）;（v）加强巴基斯坦的科学能力建设倡议，包括美国和英国科学家。完成本申请中所述的计划还将能够准备申请，以支持将RACE扩展到涉及20，000例特征明确的卒中病例和20，000例对照的病例对照研究。我们通过以下方式证明了扩大种族竞争方案的可行性：（i）在2007年期间完成验证和试点研究。这涉及开发一个预先试点的、当地验证的300项问卷，内容涉及种族、烟草、社会经济地位和其他生活方式暴露等特征，以及开发从每位参与者采集、处理、运输和储存30 ml非空腹血液的程序（血清、血浆和全血样本储存在当地实验室，温度为-70 ℃），从血沉棕黄层提取DNA，通过基因分型和琼脂糖凝胶电泳检查质量控制; ㈡建立招募程序，到2008年5月，已经招募了300多名经影像学证实的中风病例和300名对照病例;（iii）展示我们在建立巴基斯坦心肌梗塞风险研究（PROMIS）方面的往绩，一项病例对照研究，截至2008年5月招募了3500例首次心肌梗死确诊病例和3500例对照（最终目标是20，000例MI病例和20，000例对照）。PROMIS和RACE涉及类似的科学方法和重叠的合作者网络。惠康信托基金会最近提供了140万英镑的赠款，用于支持全球WAS在PROMIS中的前5000例MI病例和5000例控制中的进一步科学和财政协同作用。在2008/09年将进行GWAS的5000名个体的共同对照组的使用将使涉及参与者的巴基斯坦卒中遗传决定因素的成本效益研究在RACE中招募（通过与Wellcome Trust病例对照联盟的方法类比）。公共卫生相关性：目前尚不清楚为什么南亚人中风的风险特别高，中风是全球死亡和残疾的主要原因（1-4）。寻求支持，扩大近10倍现有的300名中风患者和300名对照的良好表征的研究，并评估几个高度优先的遗传和非遗传因素中风在巴基斯坦。这项研究的结果应该提供的见解，将提高对中风的原因和/或预防策略的发展为南亚人量身定制的理解，并将提供宝贵的经验，以进一步扩大这一生物资源的最终目标规模20,000中风病例和20,000对照。

DESCRIPTION (provided by applicant): The RACE (Risk Assessment of Cerebrovascular Events) Study is a nascent bioresource in Pakistan that aims to study of the genetic and other determinants of stroke in South Asia. Support of the current R21 grant application will enable: (i) expansion of RACE to include 2500 imaging confirmed stroke cases and 2500 controls, which will be the largest available bioresource for stroke in South Asia; (ii) evaluation in RACE samples of the twenty strongest association signals (P < 10-7) that will emerge from separately funded genomewide association studies (GWAS) of stroke in European populations; (iii) evaluation in RACE samples of 20 SNPs previously linked with coronary disease risk and/or cardiovascular risk factors (eg, APOE, chr 9p21.3, chr 1p13.3); (iv) direct evaluation of several priority non-genetic factors (eg, smoking habits, history of diabetes) in stroke in South Asia; and (v) enhancement of scientific capacity-building initiatives in Pakistan involving US and UK scientists. Completion of the plan described in this application will also enable preparation of an application for support for expansion of RACE to a case-control study involving 20,000 well-characterised stroke cases and 20,000 controls. We have demonstrated the feasibility of expanding RACE by: (i) completion of validation and pilot studies during 2007. This has involved development of a pre-piloted, locally validated 300-item questionnaire on characteristics such as ethnicity, tobacco, socioeconomic status, and other life-style exposures as well as the development of procedures to collect, process, transport and store 30 ml of non-fasting blood from each participant (serum, plasma and whole blood samples are stored at the local laboratory at -700C) and to extract DNA from buffy coat and to check for quality control through genotyping and agarose gel electrophoresis; (ii) establishment of recruitment procedures that have already enabled recruitment of over 300 imaging confirmed cases of stroke and 300 controls by May 2008; (iii) demonstration of our track record in establishing the Pakistan Risk of Myocardial Infarction Study (PROMIS), a case-control study that has recruited 3500 confirmed cases of first-ever myocardial infarction and 3500 controls by May 2008 (the final target is 20,000 MI cases and 20,000 controls). PROMIS and RACE involve similar scientific approaches and overlapping networks of collaborators. Further scientific and financial synergy is provided by the Wellcome Trust's recent award of a pound1.4M grant to support a GWAS in the first 5000 MI cases and 5000 controls in PROMIS. The use of this common control group of 5000 individuals in whom a GWAS will be conducted in 2008/9 will enable cost-effective study of the genetic determinants of stroke in Pakistan involving participants to be recruited in RACE (by analogy with the approach of the Wellcome Trust Case-Control Consortium). PUBLIC HEALTH RELEVANCE: It not known why South Asians are at particularly high risk of stroke, a leading cause of global death and disability (1-4). Support is sought to expand by almost 10-fold an existing well-characterized study of 300 patients with strokes and 300 controls and to evaluate several high priority genetic and non-genetic factors for stroke in Pakistan. Findings from this study should provide insights that will enhance understanding of the causes of stroke and/or development of preventive strategies tailored to South Asians, and will provide valuable experience in order to expand further this bioresource to a final target size of 20,000 stroke cases and 20,000 controls.