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

J Transl Med. 2008 Mar 10;6:11. doi: 10.1186/1479-5876-6-11.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aged
  • Cardiovascular Diseases / genetics*
  • Cardiovascular Diseases / mortality*
  • Chromogranins
  • Clinical Trials as Topic
  • Continental Population Groups
  • Female
  • Follow-Up Studies
  • GTP-Binding Protein alpha Subunits, Gs / genetics
  • Gene Frequency
  • Genotype
  • Heterotrimeric GTP-Binding Proteins / genetics
  • Humans
  • Kaplan-Meier Estimate
  • Logistic Models
  • Membrane Proteins / genetics*
  • Middle Aged
  • Myocardial Ischemia / genetics
  • Myocardial Ischemia / mortality
  • Polymorphism, Single Nucleotide*
  • Proportional Hazards Models
  • Receptors, Adrenergic / genetics*
  • Receptors, Adrenergic, beta-1 / genetics
  • Receptors, Adrenergic, beta-3 / genetics
  • Risk Factors

Substances

  • Chromogranins
  • G-protein beta3 subunit
  • Membrane Proteins
  • Receptors, Adrenergic
  • Receptors, Adrenergic, beta-1
  • Receptors, Adrenergic, beta-3
  • GNAS protein, human
  • GTP-Binding Protein alpha Subunits, Gs
  • Heterotrimeric GTP-Binding Proteins

Associated data

  • ClinicalTrials.gov/NCT00000554