Next Steps in Gene Discovery: Building upon GWAS." Comprehensive biomarker study to capitalize on existing GWAS in 10K South Asians The NHLBI portfolio of genome-wide association studies (GWAS) is large but does not currently include South Asians, even though the burden of coronary heart disease (CHD) among South Asians (who comprise ~1 million people living in the US and 1.5 billion worldwide) is high and rapidly increasing. Conduct of studies in South Asians is a strategic priority, both for scientific discovery, for comparison with other racial and ethnic groups, and for disease control purposes. This Grand Opportunity proposal provides the NHLBI with the opportunity to capitalize on an existing large South Asian myocardial infarction (MI) case-control study in which subjects have already been genome-wide genotyped. By funding additional biomarker studies, NHLBI can bring this unique study into the NHLBI GWAS portfolio. The Pakistan Risk of Myocardial Infarction Study (PROMIS) is internationally unique because in a South Asian population it has already: (1) recruited >5000 confirmed cases of acute myocardial infarction (MI) and >5000 controls (goal is 10,000 cases and 10,000 controls by end of 2009);(2) recorded several hundred clinical and lifestyle characteristics;(3) completed a genome-wide association scan (Illumina 660K Quad) in 10,000 participants (and assayed the IBC 50K "cardiochip" gene array in 4000 participants) and (4) assayed standard lipids, glucose and HbA1c. We seek support to add a comprehensive biochemical dimension to PROMIS by assaying plasma biomarkers potentially relevant to atherogenesis, plaque rupture and/or thrombosis. To facilitate comparisons with our South Asian sample, we will assay analytes previously studied in GWAS of other ethnic groups, including in the existing NHLBI cohorts. To study markers of particular relevance to South Asians, we will also assay some novel analytes not previously reported in previous GWAS. We will assay markers of: (1) lipids and lipoproteins (apoA-I, apoA-II, apoB, apoC-III, apoE, lipoprotein(a), lipoprotein subclasses, oxidized phospholipids, authoantibodies to oxLDL, LpPLA2, sPLA2, myeloperoxidase);(2) insulin resistance and adiposity (insulin, C-peptide, adiponectin, leptin, resistin, liver function enzymes);(3) renal function (creatinine, cystatin C, ADMA, uric acid, 25(OH)vitamin D, parathyroid hormone);and (4) inflammation and hemostasis (hsCRP, MCP-1, IL-6, sTNFRII, sVCAM-1, sICAM-1, serum amyloid A, MMP-9, E-selectin, P-selectin, CD40 ligand, fibrinogen, von Willebrand factor, and D-dimer). This proposal will advance understanding of etiological pathways for MI in South Asians and will expand the scope of NHLBI GWAS studies focused on the genetic basis of cardiovascular risk and disease. Public Health Relevance Statement: The NHLBI portfolio of genetic association studies does not currently include a large, wellcharacterized study of South Asians, even though the burden of coronary heart disease (CHD) among South Asians is high and rapidly increasing. We propose that the the Pakistan Risk of Myocardial Infarction Study (PROMIS) will be a highly cost-effective addition to the NHLBI GWAS portfolio. We seek support for additional blood markers to PROMIS by assaying plasma biomarkers potentially relevant to atherogenesis, plaque rupture and/or thrombosis.