? ? The Programs in Gene-Environment Interaction (PROGENI) represents a network of family studies designed to discover novel interactions between genes and environment. The goal at Johns Hopkins has been to discover genes that modify the response of platelets to low dose aspirin (ASA). The study, known as GeneSTAR (Genetic Study of Aspirin Responsiveness), is being conducted in over 3000 people characterized for platelet function at baseline and after low dose ASA. The study population represents 609 2-generational families with premature coronary disease. We are analyzing results from the first 1600 participants of i) a 550-short tandem repeat (STR) marker genome scan and 2) single nucleotide polymorphism (SNP) genotyping of 3000 SNPs in 191 candidate genes selected for their role in platelet function, cell signaling, inflammation, and vascular structure and function. Preliminary analyses have identified some genetic loci and candidate genes with significant linkage and/or association with platelet phenotypes. In this continuation of our work, our fist aim is to perform linkage analysis of STR markers to identify genomic loci that are linked to important platelet phenotypes followed by fine mapping using additional STR markers to achieve a density of 1cM and/or 2) appropriate SNP clusters. We will prioritize the loci for fine mapping on the basis of the presence of both a significant linkage peak and a significant association of a candidate gene in the linkage region with a phenotype of interest. Secondly, we will perform family based association analysis to determine whether candidate genes are associated with important platelet phenotypes. The genotyping results from the second half of the study sample will be used as a replication sample for the results from the first 1600 participants. Analyses will also be performed to discover haplotypes of candidate genes associated with baseline and post-ASA phenotypes. We plan a further replication of our results for collagen-induced platelet aggregation in whole blood in the HAPI Heart Study (a PROGENI study in the Old Order Amish). Finally, we will work with novel statistical models using conditional logic regression analysis to discover whether gene-gene and/or gene-environment interactions may affect important baseline and post-ASA platelet phenotypes. ? ? ?
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