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.

The study used data from previously funded case-control studies which are expected to produce 1053 MI cases, 565 stroke cases and 800 atrial fibrillation cases and 3249 matching controls from the enrollees of Group Health Cooperative. These patients will already have had chart abstractions, pharmacy database searches, telephone interviews and phlebotomy with specimen storage.