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.

Project Narrative 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.