Myocardial infarction (Ml) and peripheral arterial disease (PAD) pose an enormous public health burden and there is an urgent need to develop new strategies for their prevention and treatment. Both are manifestations of atherosclerotic vascular disease yet differ in risk factor profiles and clinical presentation. A major aim of this proposal is to identify novel genetic determinants of atherosclerotic vascular disease. Discovering such determinants will lead to new strategies for identifying high-risk subjects who would benefit from aggressive intervention to prevent Ml and PAD and uncover novel etiologic pathways that may serve as targets for new therapies. We will leverage a biorepository of blood samples in 750 Ml and 750 PAD cases and corresponding controls, genotyping performed by NHGRI, and phenotypes and environmental exposures extracted from Mayo's EMR and mapped to standard data formats such as HL7 and CHI standard vocabularies such as SNOMED and RxNorm; we will validate this process against humanly curated phenotype data on both cohorts. We will also serialize this data to facilitate conventional row-oriented analyses tools such as SAS or R. Since genomic data cannot be meaningfully de-identified or anonymized, we will engage extensively with research participants and the community regarding best practices to weigh the future benefits of genomic research to patients, families, and the society, against the potential risks. A systematic examination of patient consenting practices and patient understanding will inform our ethical conduct of research and foster community engagement with the genomic research agenda. We will develop and refine our consenting procedures in collaboration with Mayo's IRB on the basis of our findings, through an """"""""Ethics Incubator"""""""" developed as part of Mayo's Clinical and Translational Science Award (CTSA). A combination of in-depth patient interviews, consenting """"""""experiments"""""""", and community engagement using Deliberative Democracy methods will be employed. We will make anonymized phenotype annotations for consenting patients available for scientific access through methods to be defined by the NHGRI Cooperative Agreement steering committee. We will analyze whether genotypes at -500,000 SNP loci across the genome, supplied by NHGRI, are associated with two distinct phenotypes of atherosclerotic vascular disease: Ml and PAD. Further, we will investigate how environmental and lifestyle measures (e.g., smoking), identified from the Mayo EMR, modify the observed relationship between genotype and the atherosclerotic vascular disease phenotypes (i.e., gene-environment interactions). We will also investigate whether gene-gene interactions influence susceptibility to Ml and PAD. ? ? ?
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