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

Michael A Pacanowski¹ , Issam Zineh¹ , Haihong Li² , B Delia Johnson³ , Rhonda M Cooper-DeHoff⁴ , Vera Bittner⁵ , Dennis M McNamara⁶ , Barry L Sharaf⁷ , C Noel Bairey Merz⁸ , Carl J Pepine⁴ and Julie A Johnson¹

¹Department of Pharmacy Practice and Center for Pharmacogenomics, University of Florida College of Pharmacy, Gainesville, FL, USA

²Department of Epidemiology and Health Policy Research, University of Florida College of Medicine, Gainesville, FL, USA

³Department of Epidemiology, University of Pittsburgh Graduate School of Public Health, Pittsburgh, PA, USA

⁴Department of Medicine, University of Florida College of Medicine, Gainesville, FL, USA

⁵Department of Medicine, University of Alabama Birmingham, Birmingham, AL, USA

⁶Department of Medicine, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA

⁷Department of Medicine, Rhode Island Hospital, Providence, RI, USA

⁸Department of Medicine and Cedars-Sinai Research Institute, Cedars-Sinai Medical Center, Los Angeles, CA, USA

author email corresponding author email

Journal of Translational Medicine 2008, 6:11doi:10.1186/1479-5876-6-11


Published:	10 March 2008

Abstract

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-, β₁-, β₂- and β₃-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 β₁- and β₃-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.