Mapping genetic variants associated with beta-adrenergic responses in inbred mice.

Department of Medical Genetics, University of Lausanne, Lausanne, Switzerland.
PLoS ONE (Impact Factor: 3.53). 01/2012; 7(7):e41032. DOI: 10.1371/journal.pone.0041032
Source: PubMed

ABSTRACT β-blockers and β-agonists are primarily used to treat cardiovascular diseases. Inter-individual variability in response to both drug classes is well recognized, yet the identity and relative contribution of the genetic players involved are poorly understood. This work is the first genome-wide association study (GWAS) addressing the values and susceptibility of cardiovascular-related traits to a selective β(1)-blocker, Atenolol (ate), and a β-agonist, Isoproterenol (iso). The phenotypic dataset consisted of 27 highly heritable traits, each measured across 22 inbred mouse strains and four pharmacological conditions. The genotypic panel comprised 79922 informative SNPs of the mouse HapMap resource. Associations were mapped by Efficient Mixed Model Association (EMMA), a method that corrects for the population structure and genetic relatedness of the various strains. A total of 205 separate genome-wide scans were analyzed. The most significant hits include three candidate loci related to cardiac and body weight, three loci for electrocardiographic (ECG) values, two loci for the susceptibility of atrial weight index to iso, four loci for the susceptibility of systolic blood pressure (SBP) to perturbations of the β-adrenergic system, and one locus for the responsiveness of QTc (p<10(-8)). An additional 60 loci were suggestive for one or the other of the 27 traits, while 46 others were suggestive for one or the other drug effects (p<10(-6)). Most hits tagged unexpected regions, yet at least two loci for the susceptibility of SBP to β-adrenergic drugs pointed at members of the hypothalamic-pituitary-thyroid axis. Loci for cardiac-related traits were preferentially enriched in genes expressed in the heart, while 23% of the testable loci were replicated with datasets of the Mouse Phenome Database (MPD). Altogether these data and validation tests indicate that the mapped loci are relevant to the traits and responses studied.

  • [Show abstract] [Hide abstract]
    ABSTRACT: The beta-adrenergic blockade as a therapeutic approach first emerged in the 1950s. During the past five decades, the total number of indications that have been suggested, and the remarkable number approved by regulatory agencies, places beta-blockade far ahead of all competing treatments, not only in the cardiovascular area, but in all of therapeutics. Differentiation of beta-adrenergic blocking agents has been made on the basis of beta1 selectivity, duration of action, intrinsic sympathomimetic activity, lipophilicity, and whether or not the beta-adrenergic blocking action is accompanied by an alpha-adrenergic blocking action. With the development of nebivolol, a beta-adrenergic blocking agent that also activates nitric oxide synthase in blood vessels, comes a new therapeutic option. Endothelial dysfunction with loss of nitric oxide production is a common feature in many cardiovascular diseases. This fascinating class of drugs continues to provide us with new and important therapeutic opportunities.
    American Journal of Hypertension 01/2006; 18(12 Pt 2):165S-168S. · 3.67 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Many adult patients require temporary inotropic support after cardiac surgery. We reviewed the literature systematically to establish, present and classify the evidence regarding choice of inotropic drugs. The available evidence, while limited in quality and scope, supports the following observations; although all beta-agonists can increase cardiac output, the best studied beta-agonist and the one with the most favourable side-effect profile appears to be dobutamine. Dobutamine and phosphodiesterase inhibitors (PDIs) are efficacious inotropic drugs for management of the low cardiac output syndrome. Dobutamine is associated with a greater incidence of tachycardia and tachyarrhythmias, whereas PDIs often require the administration of vasoconstrictors. Other catecholamines have no clear advantages over dobutamine. PDIs increase the likelihood of successful weaning from cardiopulmonary bypass as compared with placebo. There is insufficient evidence that inotropic drugs should be selected for their effects on regional perfusion. PDIs also increase flow through arterial grafts, reduce mean pulmonary artery pressure and improve right heart performance in pulmonary hypertension. Insufficient data exist to allow selection of a specific inotropic agent in preference over another in adult cardiac surgery patients. Multicentre randomized controlled trials focusing on clinical rather than physiological outcomes are needed.
    Critical care (London, England) 07/2005; 9(3):266-79. · 4.72 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: This review examines the role of long-acting beta2-adrenergic agonists in the management of asthma, particularly focusing on recommendations in the newly revised Global Initiative for Asthma (GINA) and National Heart, Lung, and Blood Institute (NHLBI) asthma guidelines. GINA guidelines recommend increasing inhaled corticosteroid doses in all children with asthma not controlled on low-dose inhaled corticosteroids before adding a long-acting beta2-adrenergic agonist, whereas NHLBI guidelines have different age-based recommendations for children. In patients younger than 5 years, NHLBI guidelines recommend increasing the inhaled corticosteroid dose before adding a long-acting beta2-adrenergic agonist; in children aged 5-11 years, equal weight is given to increasing the inhaled corticosteroid dose or including add-on therapy to low-dose inhaled corticosteroids. In adults and adolescents aged 12 years and older, GINA recommends adding long-acting beta2-adrenergic agonists to low-dose inhaled corticosteroids over increasing the inhaled corticosteroid dose. NHLBI guidelines give equal weight to these choices, with alternative, although not preferred, therapies including the addition of theophylline, zileuton, or leukotriene receptor antagonists to low-dose inhaled corticosteroids. In the recently updated GINA and NHLBI asthma guidelines, long-acting beta2-adrenergic agonists are an important class of agents for the management of persistent asthma in patients whose asthma is not well controlled with inhaled corticosteroid monotherapy.
    Current opinion in pulmonary medicine 02/2008; 14(1):57-63. · 3.12 Impact Factor

Full-text (2 Sources)

Available from
May 21, 2014