PARC Abstract, 2005

Abstract (July, 2005 Update)

The main objective of PARC is to both define and confirm the genetic contribution to the large inter-individual variability in the effects statin drugs on cardiovascular disease risk. To address this objective, we have assembled a multidisciplinary team with expertise in genomics, statistical genetics and informatics, clinical pharmacology and cardiology, laboratory measurements of cardiovascular risk factors, and epidemiology.

Progress

To date PARC has focused on identifying associations of statin responsiveness with single nucleotide polymorphisms (SNPs) in candidate genes involved in pathways mediating effects of statin treatment on cardiovascular risk, as well as systems modulating statin pharmacokinetics. The analyses have been based on measurements of lipoproteins and other cardiovascular risk markers in a cohort of 944 Caucasians and African-Americans who were treated with simvastatin 40 mg/day in a carefully supervised six-week trial. Linkage disequilibrium analysis of SNPs identified in a total of 78 genes was used to determine 891 tag sites that were genotyped in the first half of the cohort. Confirmation of the positive associations as well as testing of additional candidate genes is now being carried out in the second half of the cohort (>700 sites in 60 genes). In addition, we have completed pilot studies of pharmacogenetics of blood pressure response to ACE inhibitors in two study cohorts. In total, these studies will result in deposits in the PharmGKB database of nearly 800,000 individual genotypes as well as the measured phenotypes from both the statin and ACE inhibitor trials.

Experimental Plans

In the next phase of PARC we will extend our investigation of statin pharmacogenetics to a series of analyses based on a genome-wide approach for identifying SNPs that are associated with clinically relevant laboratory measurements of statin response. These measures include LDL and HDL subfractions, indices of cholesterol synthesis and absorption, and inflammatory markers. Critical elements of this effort will be to test associations of SNPs with responses to several of the most widely used statins in both African-Americans and Caucasians, to test for significant pair-wise genotype associations, to replicate results in multiple cohorts, including a large clinical practice population, and ultimately to test associations of the most informative SNPs with clinical cardiac endpoints in several of the largest statin trials. Initial analyses in 1,000 Caucasian subjects from trials of simvastatin (PARC) or pravastatin (PRINCE) will be based on a panel of 250,000 genome-wide SNPs (Aim 1). Confirmatory analyses in the remaining 1,000 subjects in PARC and PRINCE, as well as additional cohorts treated with rosuvastatin (Aim 2) and atorvastatin (Aim 3), involving a total of ~10,000 subjects, will yield a panel of 1,100 SNPs most consistently associated with variation in statin response of LDL cholesterol and other phenotypes. 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 statin-induced 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 systematic and sequential multicohort design provides both adequate statistical power and the critical ability to minimize false positive results, features that are essential for a successful genome-wide association study.

In summary, this program presents a comprehensive approach for determining effects of specific genotypes on clinically meaningful variations in responsiveness to the class of drugs most widely used to prevent cardiovascular disease.