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

Michael A Pacanowski, Issam Zineh, Haihong Li, B Delia Johnson, Rhonda M Cooper-DeHoff, Vera Bittner, Dennis M McNamara, Barry L Sharaf, C Noel Bairey Merz, Carl J Pepine, Julie A Johnson, Michael A Pacanowski, Issam Zineh, Haihong Li, B Delia Johnson, Rhonda M Cooper-DeHoff, Vera Bittner, Dennis M McNamara, Barry L Sharaf, C Noel Bairey Merz, Carl J Pepine, Julie A Johnson

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 alpha1A-, beta1-, beta2- and beta3-adrenergic receptors (ADRA1A, ADRB1, ADRB2, ADRB3, respectively), and their signaling proteins, G-protein beta 3 subunit (GNB3) and G-protein alpha 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, Pinteraction = 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 beta1- and beta3-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.

Figures

Figure 1
Figure 1
Kaplan-Meier plot for primary outcome by ADRB1 codon 389 genotype and CAD severity.
Figure 2
Figure 2
Kaplan-Meier plot for primary outcome by ADRB3 codon 64 genotype and CAD severity.
Figure 3
Figure 3
Test-set deviance for different size logic regression models. Test-set deviances from cross-validation analysis are shown for single logic regression trees containing 1 to 8 predictors. Lower test-scores represent the better-fitting model.

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