PARC Profile

Pharmacogenomics and Risk of Cardiovascular Disease

Abstract (June, 2008 Update)

Goals

The main goal of PARC is to both define and confirm the genetic contribution to the large inter-individual variability in the effects of statin drugs on cardiovascular disease risk. This objective is being carried out using multiple statin-treated population samples to test the reproducibility and generalizability of findings derived from both candidate gene and genome-wide searches for SNP associations with markers of statin efficacy as well as muscle toxicity.

Progress

Genome-wide analysis using an Illumina chip with 317,000 single nucleotide polymorphisms (SNPs) was performed in 975 Caucasian subjects from the first half of the combined populations from two statin trials: CAP (simvastatin 40 mg/day), and PRINCE (pravastatin 40 mg/day). A total of 13,680 of these SNPs were selected for genotyping in the second half of the combined study populations based primarily on the significance of their associations with statin-induced changes in lipoprotein and inflammatory markers, as well as with baseline values. For LDL cholesterol change, the primary endpoint, we have identified SNPs that satisfy the criteria of significance in both the first and second study subgroups, and in both CAP and PRINCE, with a false discovery rate of 5%. In addition, significant associations with baseline lipoprotein and CRP levels have been found that have been replicated in collaboration with other large cohort studies. In anticipation of the next test of replication and generalizability of our findings in a medical practice-based population, we have developed a quantitative phenotype for efficacy of LDL cholesterol lowering at multiple statin doses using electronic medical records of 3,710 atorvastatin-treated patients from the Marshfield Clinic in whom DNA is available.

Plans

We have embarked on a collaborative study with Pfizer, Inc. to increase our power to identify genotypes associated with statin efficacy by combining the genome-wide data from 975 subjects in PARC with those from 2,012 subjects treated with atorvastatin in Pfizer's TNT trial. Replication of significant associations will be carried out in the remaining ~3,000 subjects with available DNA in TNT as well as in the 3,710 atorvastatin-treated patients in the Marshfield Clinic as noted above.

In a second project, we will carry out both genome-wide and candidate gene association analyses in 225 Marshfield Clinic patients who developed documented myopathy on one of three statin drugs, and in an equal number of matched controls with comparable statin exposure.

Finally, we will use statin-exposed immortalized lymphocyte cell lines from PARC subjects to investigate alterations in gene expression and function associated with candidate SNPs.

PARC Team

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