DESCRIPTION (provided by applicant): The overall objective of the Center "Pharmacogenomics of Statin Therapy" (POST) is to apply genomic, transcriptomic, and metabolomic analyses, together with studies in cellular and animal models, and innovative informatic tools, to identify and validate biomarkers for efficacy of statin drugs in reducing riskof cardiovascular disease (CVD), and for adverse effects of statins, specifically myopathy and type 2 diabetes. This multidisciplinary approach is enabled by a team of investigators with expertise in genomics (human, mouse, and molecular), statistics and informatics, and clinical medicine and pharmacology. The Center is comprised of three Projects, two Research Cores, and an Administrative Core. A major aim of Project 1 is the identification of cellular transcriptomic and metabolomic markers for clinical efficacy and adverse effects of statins. This will be accomplished by analyses in statin-exposed lymphoblast cell lines derived from patients with major adverse coronary events, or onset of myopathy or type 2 diabetes on statin treatment, compared with unaffected statin- treated controls. In addition, using genome wide genotypes from these patients, DNA variants will be identified that are associated with statin-induced changes in the transcripts and metabolites that most strongly discriminate affected patients and controls. Project 2 will use a unique, well-characterized panel of 100 inbred mouse strains to discover genetic variation associated with statin-induced myopathy and dysglycemia. Mechanisms underlying these effects will be investigated, with emphasis on the role of dysregulation of autophagy by statin treatment. Projects 1 and 2 will also use relevant cellular and mouse models, respectively, to perform functional studies to validate effects of genes identified in all POST projects as strong candidates for modulating statin efficacy or adverse effects. In Project 3, information derived from genome-wide genotypes, electronic health records, and pharmacy data in a very large and diverse population-based patient cohort will be leveraged to identify and replicate genetic associations with statin efficacy (lipid lowering and CVD event reduction) and adverse effects (myopathy and type 2 diabetes), as well as to assess the overall heritability of these responses. The Clinical Core, based in Kaiser Permanente of Northern California, will provide the clinical information and biologic materials for both Projects1 and 3. Investigators in the Informatics Core will optimize data analysis and integration of results across all projects. The Administrative Core will provide scientific leadership and management of the Center, and foster scientific interactions and training opportunities. Overall, the research program of this Center provides an innovative model for a "systems" approach to pharmacogenomics that incorporates complementary investigative tools to discover and validate genetically influenced determinants of drug response. Moreover, the findings have the potential for guiding more effective use of statins for reducing CVD risk and minimizing adverse effects, and identifying biomarkers of pathways that modulate the multiple actions of this widely used class of drugs.

PUBLIC HEALTH RELEVANCE: Coronary heart disease and stroke are the leading causes of death and disability in the United States, and statins are the most widely prescribed class of drugs to prevent these conditions. There is however, considerable interindividual variation in efficacy of statins for reducing disease risk, as well as in susceptibility to the most common adverse statin effects, myopathy and type 2 diabetes. The goal of the Center "Pharmacogenomics of Statin Therapy" (POST) is to apply complementary investigative approaches and multidisciplinary expertise for discovering and validating the genetic and metabolic factors responsible for this variability. This information has the potential for optimizig use of statins in clinical practice, and for identifying new pathways that underlie the diverse biologic actions of this drug class.