The goal of this Pharmacogenetics Research Group is to identify common gene variants that contribute to interindividual differences in response to drugs used to reduce risk for cardiovascular disease (CVD). The Group comprises a multidisciplinary team of investigators with expertise in lipoprotein metabolism and blood pressure regulation; genomics and related computational methodology; clinical trials; human genetics and genetic epidemiology; transgenic mouse models, and database management and biostatistics. For the present study, the drugs chosen are atorvastatin, an HMG CoA reductase inhibitor that lowers plasma lipid levels, and ramipril, an ACE inhibitor that lowers blood pressure. Candidate genes are those with products in metabolic pathways that are potential targets of these drugs. DNA sequence variations in 50 genes will be determined in 24 Caucasians and 24 African-Americans, two ethnic groups with differing degrees of sequence diversity. Based on patterns of single nucleotide polymorphisms (SNPs), haplotypes will be constructed for each gene in both ethnic groups, and groups of SNP genotypes will be identified that are characteristic for the 2-4 most common haplotypes in each gene, present in at least 10 percent of the population. Haplotypes for genes related to atorvastatin effects (27 genes) will be determined in 600 individuals (300 from each ethnic group) who will receive 10 mg/day of this drug for 8 weeks. Haplotypes for genes related to ramipril effects (23 genes) will be determined in 600 individuals (300 from each ethnic group) who will receive 10 mg/day of this drug for 12 weeks. Detailed measurements of phenotypes related to lipoprotein and blood pressure regulation will be performed in the two respective cohorts, and associations will be sought with each of the respective candidate haplotypes. Functional effects of specific sequence variants will be tested in appropriate transgenic mouse models. Future studies will corroborate positive findings using samples from large ongoing clinical endpoint trials of atorvastatin and ACE inhibitor therapy. Data will be transmitted to the Pharmacogenetics Knowledge Base and other genomic databases. The findings will advance our fundamental understanding of the roles of specific genes and their variants in modulating biologic pathways of importance in the pathogenesis and management of CVD.
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