The overall objective of this grant is to both define and confirm the genetic contribution to the large inter-individual variability in clinical response to treatment with statin drugs. The multidisciplinary research team has expertise in genomics, statistical genetics and informatics, clinical pharmacology and cardiology, laboratory measurements of cardiovascular risk factors, and epidemiology. In a sequential design, using samples from a total of 10,000 subjects treated with various statins, we will use a genome wide association approach to identify SNPs (single nucleotide polymorphisms) that are associated with laboratory measurements of statin response, including LDL and HDL subfractions, markers of cholesterol absorption and synthesis, and the inflammatory marker hs-CRP. Initial analyses in 1,000 Caucasian subjects from trials of simvastatin or pravastatin will be based on a panel of 250,000 genome-wide SNPs (Aim 1). Confirmatory analyses in cohorts treated with rosuvastatin (Aim 2) and atorvastatin (Aim 3) will yield a panel of 1,100 SNPs most consistently associated with variation in statin response of LDL cholesterol and other phenotypes in Caucasians and African-Americans. In addition, the genome-wide SNP panel along with candidate gene SNPs will be used to identify those associated with statin-related myopathy in 150 cases vs. 300 matched controls. Genomic resequencing of the 50 genes most strongly associated in Aims 2 and 3 with statininduced reductions in LDL cholesterol and other informative phenotypes will identify allelic variants in a total of 48 Caucasians and 48 African-American randomly selected from the highest and lowest 5% of the distributions of these phenotypes in the respective ethnic groups (Aim 4). Finally, these SNPs will be tested for associations with both laboratory phenotypes and clinical cardiovascular outcomes (Aim 5). This program presents a comprehensive approach for determining effects of specific genotypes on clinically meaningful variations in responsiveness to a class of drugs widely used to prevent cardiovascular disease.
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