Adrenergic gene polymorphisms and cardiovascular risk in the NHLBI-sponsored Women's Ischemia Syndrome Evaluation

BACKGROUND: Adrenergic gene polymorphisms are associated with cardiovascular and metabolic phenotypes. We investigated the influence of adrenergic gene polymorphisms on cardiovascular risk in women with suspected myocardial ischemia. METHODS: We genotyped 628 women referred for coronary angiography for eight polymorphisms in the α(1A)-, β(1)-, β(2)- and β(3)-adrenergic receptors (ADRA1A, ADRB1, ADRB2, ADRB3, respectively), and their signaling proteins, G-protein β 3 subunit (GNB3) and G-protein α subunit (GNAS). We compared the incidence of death, myocardial infarction, stroke, or heart failure between genotype groups in all women and women without obstructive coronary stenoses. RESULTS: After a median of 5.8 years of follow-up, 115 women had an event. Patients with the ADRB1 Gly389 polymorphism were at higher risk for the composite outcome due to higher rates of myocardial infarction (adjusted hazard ratio [HR] 3.63, 95% confidence interval [95%CI] 1.17–11.28; Gly/Gly vs. Arg/Arg HR 4.14, 95%CI 0.88–19.6). The risk associated with ADRB1 Gly389 was limited to those without obstructive CAD (n = 400, P(interaction )= 0.03), albeit marginally significant in this subset (HR 1.71, 95%CI 0.91–3.19). Additionally, women without obstructive CAD carrying the ADRB3 Arg64 variant were at higher risk for the composite endpoint (HR 2.10, 95%CI 1.05–4.24) due to subtle increases in risk for all of the individual endpoints. No genetic associations were present in women with obstructive CAD. CONCLUSION: In this exploratory analysis, common coding polymorphisms in the β(1)- and β(3)-adrenergic receptors increased cardiovascular risk in women referred for diagnostic angiography, and could improve risk assessment, particularly for women without evidence of obstructive CAD. TRIAL REGISTRATION: ClinicalTrials.gov NCT00000554.