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

建立用于发现和评估遗传及其他生物资源的生物资源

• 批准号: 7893707
• 负责人: John Navid Danesh
• 金额: $ 10.69万
• 依托单位: UNIVERSITY OF CAMBRIDGE
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-07-15 至 2011-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7893707
• 关键词: 1p13.3; 9p21.3; Agar Gel Electrophoresis; Apolipoprotein E; Applications Grants; Area; Asia; Award; Blood; Blood specimen; Brain Diseases; Case-Control Studies; Cessation of life; Characteristics; Collection; Control Groups; Coronary heart disease; DNA; Development; Diabetes Mellitus; Ethnic Origin; European; Evaluation; Event; Funding; Genetic; Genetic Determinism; Genotype; Goals; Grant; Habits; Image; Individual; Institutes; Institution; Joints; Laboratories; Life Style; Link; Maryland; Methods; Morbidity - disease rate; Myocardial Infarction; Other Genetics; Pakistan; Participant; Patients; Pennsylvania; Pilot Projects; Plasma; Population; Population Genetics; Preparation; Prevention strategy; Procedures; Process; Public Health; Quality Control; Questionnaires; Recording of previous events; Recruitment Activity; Risk; Risk Assessment; Risk Factors; Sampling; Scheme; Scientist; Signal Transduction; Smoking; Socioeconomic Status; South Asian; Stroke; Tobacco; Transport Process; Trust; Universities; Validation; Whole Blood; cardiovascular risk factor; case control; cerebrovascular; cost; disability; disorder risk; experience; genetic variant; genome wide association study; high risk; insight; lifestyle factors; mortality; non-genetic; novel; public health relevance

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.

描述（由申请人提供）：种族（脑血管事件的风险评估）研究是巴基斯坦新生的生物库，旨在研究南亚中风的遗传和其他决定因素。当前R21赠款申请的支持将启用：（i）扩大种族，包括2500张成像确认的中风案件和2500个对照，这将是南亚中风的最大可用生物库； （ii）在欧洲人口中，二十个最强关联信号（p <10-7）的种族样本评估，这些信号（p <10-7）将从欧洲人口中的中风全基因组协会研究（GWAS）中出现； （iii）对20个SNP的种族样本评估，先前与冠状动脉疾病风险和/或心血管危险因素相关联（例如ApoE，Chr 9p21.3，Chr 1p13.3）； （iv）南亚中风中的几种优先级非基因因素（例如，吸烟习惯，糖尿病史）直接评估； （v）加强巴基斯坦涉及我们和英国科学家的科学能力建设计划。在本申请中描述的计划的完成还将启用支持将种族扩展到病例对照研究的申请，涉及20,000个符合特征良好的中风案件和20,000个控件。我们已经通过以下方式证明了扩大种族扩展的可行性：血浆和全血样品以-700C的形式存储在当地实验室，并从Buffy Coat提取DNA，并通过基因分型和琼脂糖凝胶电泳来检查质量控制； （ii）建立招聘程序，这些程序已经招募了300多个成像，确认的中风病例和300个对照案件； 2008年5月； （iii）证明了我们在确定巴基斯坦心肌梗塞研究风险（PROMIS）方面的记录，这项病例对照研究已招募了3500例确认的有史以来第一次心肌梗塞的病例，并于2008年5月招募了3500个对照（最终目标是20,000 MI病例和20,000个控制）。 Promis和Race涉及类似的科学方法和合作者的重叠网络。惠康信托基金（Wellcome Trust）最近获得的140万英镑赠款提供了进一步的科学和金融协同作用，该授予在前5000 MI案件中支持GWAS和Promis中的5000个控件。使用该公共对照组的5000个个体将在2008/9进行GWA，将对巴基斯坦中风的遗传决定因素进行成本效益的研究，这些遗传决定因素参与种族招募参与者（通过类似于Wellcome Trust Case Concontrols Concontrols的方法）。公共卫生相关性：不知道为什么南亚人遇到中风的风险特别高，这是全球死亡和残疾的主要原因（1-4）。寻求支持以扩大近10倍的现有特征良好的研究，对300例中风和300例对照患者，并评估了巴基斯坦中风的几个高优先级遗传和非遗传因素。这项研究的发现应提供见解，以增强对中风的原因和/或制定针对南亚人量身定制的预防策略的理解，并将提供宝贵的经验，以便进一步将本生物库扩展到20,000个中风案例和20,000个控制的最终目标大小。