We submit here a proposal for renewal of the Pharmacogenomics of Arrhythmia Therapy (PAT) node of the PGRN. The studies we propose combine candidate, genome-wide, and targeting resequencing approaches to identify the genomic basis for arrhythmia drug response phenotypes of major public health importance. In addition, each Specific Aim includes a major focus on multi-institutional accumulation of large numbers of patients with well-defined drug response phenotypes. Studies In Specific Aim 1 further define the genomic basis underlying susceptibility to drug-induced long QT-related arrhythmias, a continuing challenge In clinical drug use and In drug development.
In Specific Aim 2, we build on previous work to prospectively assess the relationships among drug response, genotypes, and clinical endophenotypes in patients with atrial fibrillation (AF). While AF therapy often includes warfarin anticoagulation whose major complication is bleeding, pharmacogenomic studies of warfarin response to date have focused on determinants of dose.
In Specific Aim 3, we will identify a large set of cases of major warfarin-related bleeding in BioVU, our DNA repository linked to de-identified electronic medical records, and undertake a case-control study of the genomic determinants of this complication. We include here two proposals for network resources: (1) PGPop (PharmacoGenomic discovery and replication in very large patient Populations) that brings together multiple healthcare system-based nodes, including BioVU, that each Include extensive drug response phenotypes and extant or planned large DNA collections. PGPop will serve as a "real-world" platform for pharmacogenomic discovery;one initial project will be generation of a replication set for warfarin-related bleeding. (2) P-STAR (PGRN Statistical Analysis Resource), that will provide statistical support to PGRN sites and develop advanced methods in the field. These studies build on progress within our own site, across PGRN, and reach out beyond the network to develop expanded populations and new tools to enable application of pharmacogenetic knowledge to clinical care.
We build here on previous progress to understand the genomic basis of variability in drug response among patients with cardiac arrhythmias, a continuing public health problem. The methods we adopt have the potential not only to affect our understanding of arrhythmia pharmacogenomics but also to more generally refine and expand our approaches to the problem of variable drug responses.
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