Pharmacogenetics and Cardiovascular Events

BACKGROUND:

This complex study will collect additional genetic data for 3 ongoing case-control observational studies of drug-gene interactions in myocardial infarction, stroke, and new-onset atrial fibrillation. This study will add single nucleotide polymorphism (SNP) discovery for 16 of 36 candidate genes involving the renin-angiotensin system, sodium transport, adrenergic receptors, and G-proteins, and allow analysis of haplotype data.

The study was initiated in response to RFA HL-03-001, Ancillary Studies in Pharmacogenetics.

DESIGN NARRATIVE:

The primary aim of this study is to assess interactions between selected cardiovascular medications and the major candidate-gene variants or haplotypes on the incidence of myocardial infarction (MI), stroke and atrial fibrillation (AF). The candidate-gene sets-selected on the basis of biology, pharmacology, and information from genome-wide scans-include: (1) 10 genes in the renin-angiotensin system; (2) 10 genes involved in renal sodium transport; (3) 8 genes encoding alpha and beta adrenergic receptors; (4) 8 other genes, including G-proteins, estrogen receptors, and the alpha-1C subunit of the L-type calcium channel. The products of these genes represent the sites of action for many cardiovascular drugs: angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, all classes of diuretics, alpha blockers, beta-blockers, central alpha agonists, calcium antagonists, and estrogens. Both hypothesis-testing and hypothesis-generating analyses are planned. For selected single nucleotide polymorphisms (SNPs) studied in vitro or in small clinical populations, several specific drug-gene interactions are plausible, and these associations will be evaluated in an hypothesis-testing manner.