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 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.


CONCLUSIONS
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.


BACKGROUND
ClinicalTrials.gov NCT00000554.
Pacanowski
Michael A
MA
Department of Pharmacy Practice and Center for Pharmacogenomics, University of Florida College of Pharmacy, Gainesville, FL, USA. pacanow@cop.ufl.edu
Zineh
Issam
I
Li
Haihong
H
Johnson
B Delia
BD
Cooper-DeHoff
Rhonda M
RM
Bittner
Vera
V
McNamara
Dennis M
DM
Sharaf
Barry L
BL
Merz
C Noel Bairey
CN
Pepine
Carl J
CJ
Johnson
Julie A
JA
D000368:Aged; D002318:Cardiovascular Diseases / Q000235:genetics* / Q000401:mortality*; D002864:Chromogranins; D002986:Clinical Trials as Topic; D005260:Female; D005500:Follow-Up Studies; D019205:GTP-Binding Protein alpha Subunits, Gs / Q000235:genetics; D005787:Gene Frequency; D005838:Genotype; D020962:Heterotrimeric GTP-Binding Proteins / Q000235:genetics; D006801:Humans; D053208:Kaplan-Meier Estimate; D016015:Logistic Models; D008565:Membrane Proteins / Q000235:genetics*; D008875:Middle Aged; D017202:Myocardial Ischemia / Q000235:genetics / Q000401:mortality; D020641:Polymorphism, Single Nucleotide; D016016:Proportional Hazards Models; D044469:Racial Groups; D011941:Receptors, Adrenergic / Q000235:genetics*; D018342:Receptors, Adrenergic, beta-1 / Q000235:genetics; D022702:Receptors, Adrenergic, beta-3 / Q000235:genetics; D012307:Risk Factors
D002864:Chromogranins; C454420:G-protein beta3 subunit; D008565:Membrane Proteins; D011941:Receptors, Adrenergic; D018342:Receptors, Adrenergic, beta-1; D022702:Receptors, Adrenergic, beta-3; C406732:GNAS protein, human; D019205:GTP-Binding Protein alpha Subunits, Gs; D020962:Heterotrimeric GTP-Binding Proteins