The primary objective of this continuation grant is to determine if 18 prespecified genetic loci (polymorphisms)that code for proteins involved in coagulation-lipid-risk mechanisms contribute significant additive risk for the occurrence of time-dependent recurrent coronary events (unstable angina, non-fatal myocardial reinfarction, or coronary death) during long-term follow-up in an enriched population of post-myocardial infarction patients. The secondary objective is to determine if prespecified circulating lipid factors and lipid related genotypes are associated with increased hemostatic activation. The study population involves 1,045 post-infarction patents with 202 first recurrent cardiac events that occurred during an average 2-year follow-up. Genetic testing and additional coagulation and lipid tests will be performed on white blood cell samples, plasma, and serum that were collected and frozen at minus 70 Celsius during the prior enrollment of this cohort. Genotype identification will include 6 loci related to coagulation proteins, 3 related to adhesion molecules involved in thrombosis, and 9 involved in apolipoproteins and metabolism of triglyceride-rich lipoproteins. An innovative genetic carriership approach will be used in the primary analysis to determine if a pool of the 18 prespecified genotypes contributes additive susceptibility for time-dependent recurrent cardiac events in this well-defined cohort of unrelated patents. The identified genetic risk will be expressed as an average hazard ratio per number of risk loci present per individual, with appropriate adjustment for biologic, disease severity, and environmental covariates. The study has 90 percent power to detect a significantly increased average risk of 15percent or greater (hazard ratio greater than 1.15) per number or prespecified risk loci present (range 0 to 8 plus) per individual in this post-myocardial infarction cohort. Identification of an additive risk posed by a limited pool of risk genotypes in recurrent coronary events will be useful as a screening technique in the future identification and quantification of the role played by individual risk genotypes in this oligogenic disorder.
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