Myocardial infarction (MI) continues to be the number one cause of morbidity and mortality in the developed world with over a million MIs per year in the US alone, despite enormous progress in the diagnosis and aggressive treatment of conventional risk factors such as hypercholesterolemia, hypertension, and diabetes. The genetic contribution to MI is well established and development of diagnostic/prognostic tools and novel therapies based on unraveling these mechanisms should add substantially to the efforts of reducing conventional cardiovascular risk factors. The main objective of our study is to identify genetic variants that contribute to the risk of MI. To attain this goal we propose to conduct a broad-based and highly-powered strategy in a genome-wide association study using a high-yield and accurate tag-SNP array genotyping a total of 4500 MI patients and 7500 controls from US (Caucasians) and Iceland. Additionally, for cross-ethnic group testing of signals found in Caucasians, the study will include 600 MI patients and 600 controls of African-American ethnicity. The genome-wide association study will be carried out with a two-stage design which will lower the cost of genotyping while maintaining most of the power, thus allowing us to genotype more individuals resulting in a substantial increase in power to detect significant association. In the first stage approximately 35% of the total discovery group available is genotyped (1000 patients and 5000 controls) with the entire set of markers using 317K markers (Phase I genotyping). The most promising SNPs from the first stage will then be tested on the remaining 65% of the discovery group (2000 patients and 1000 controls), taking forward ~1% of the original SNPs (Phase II genotyping). The data from Phase I and Phase II will then be jointly analyzed to define markers that show significant association even after correcting for multiple testing. Significant SNPs from the joint analysis of the Phase I and II data will then be confirmed in an independent group of patients and controls (1500 patients and 1500 controls). Follow up genotyping of additional markers within the genes/regions showing association to MI will be done on the discovery cohort and also on the African-American case/control group. With the follow up genotyping we intend to identify additional Mi-associated markers that might correlate with the original signal and possibly show stronger association to the disease. The different populations will be analyzed (a) jointly, in order to identify risk variants common across the populations, and (2) separately to identify population specific risk variants and to explore ethnic effects. The project will use a high-yield and accurate array-based system from Illumina, Inc to genotype genome-wide tag-SNPs and a case/control single-point association analysis will be performed. Given that MI is a heterogeneous disorder that may depend on the impact of many genetic and environ- mental risk factors our study will also involve the analysis of interactions between genes (gene-gene) and between genetic and environmental factors (gene-environment) in both the discovery and confirmation groups. ? ? ? ?
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