Common diseases, such as heart failure, have a complex genetic and environmental etiology that require sophisticated statistical genetics analytical approaches to untangle. The objective of Core C is to provide high quality, high throughput statistical genetic analysis to the investigators of this SCCOR in order to test for clinical significance of polymorphisms identified in genes that are involved in the adrenergic and Ca2 cycling features of heart failure risk, cardiac function and response to treatment and exercise challenges. A wide range of clinically important genetic studies have been proposed in Projects 1, 2, and 3. Core C will work closely with these investigators to design, implement, and analyze the data from these studies. There are five main statistical genetic objectives for Core C so that Projects 1-3 can achieve their Specific Aims: 1) To determine the allelic architecture of heart failure susceptibility and modification genes in 4,000 cases and 4,000 controls (includes non-Latino Whites, African-Americans, and Latinos), 2) To perform allelic, genotypic, and haplotypic association studies in this case-control cohort, as well as case-only studies of time to death/transplantation and age of onset, 3) To test gene-gene interactions to identify combinations of genetic variations that are associated with high risk of hear failure, 4) To statistically assess the functional significance of specific genetic variations from intensive hemodynamic and exercise tolerance test, and 5) To evaluate the influence of drug treatment on indicators of hear failure severity and risk of death/transplantation in two potentially clinically important genetic classes. We have implemented permutation routines to adjust p-values for multiple testing and will utilize cross-validation methods to more accurately estimate the predictive capacity of the genetic variants investigated in this proposal.
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