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Beta-Receptor Genetic Polymorphisms and Impact on Clinical Outcomes

Summary:

  • The most common genetic variants in humans are single nucleotide polymorphisms (SNPs). Although many SNPs have been discovered in beta-receptors, few are clinically relevant. There are 2 clinically relevant SNPs for beta 1-receptors (Ser49Gly and Arg389Gly), 4 for beta 2-receptors (Cys-19Arg, Arg16Gly, Gln27Glu, Thr164Ile), and 1 for beta 3-receptors (Trp64Arg)
  • Although SNPs may not directly cause disease, they appear to be risk factors for and modifiers of disease.  These SNPs also have the potential to alter response to medications when polymorphisms affect drug targets (e.g., beta-receptors), especially with regards to adrenergic agonists and antagonists.
  • Understanding the functional consequences of specific polymorphisms will lead to the individualization of drug therapy based on a patient's genetic makeup and could explain distinct inter-individual variability.  
  • There is great need for large, randomized, controlled trials to evaluate the conflicting data related to ß-receptor SNPs and related differences regarding disease and medications. These trials should by multinational and include a variety of ethnicities. Future evidence will promote the practice of personalized medicine.

Author: Adriane B. Marino, PharmD
Editor-in-Chief:
Anthony J. Busti, MD, PharmD, FNLA, FAHA
Content Editors: Donald S. Nuzum, PharmD, BCACP, BC-ADM, CDE, CPP and Sabrina W. Cole, PharmD, BCPS
Last Reviewed: August 2015

Explanation

  • Numerous genetic polymorphisms of adrenergic receptors have been identified. The most common genetic variants in humans are referred to as single nucleotide polymorphisms (SNPs). Although many SNPs have been discovered in beta-receptors, few are clinically relevant. There are 2 clinically relevant SNPs for the beta 1-receptors (Ser49Gly and Arg389Gly), 4 for the beta 2-receptors (Cys-19Arg, Arg16Gly, Gln27Glu, Thr164Ile), and 1 for the beta 3-receptors (Trp64Arg).1  Frequently, polymorphisms occur in certain combinations labeled haplotypes.  Results are controversial, but there is data to support a relationship between ß-receptor SNPs and outcomes.  Understanding the functional consequences of specific polymorphisms leads to the individualization of drug therapy based on a patient's genetic makeup and could explain distinct inter-individual variability.

    The table below summarizes clinically relevant ß-receptor polymorphisms, with an emphasis on the specific location of genetic mutations and the populations primarily affected.2-10

    ß1- receptor polymorphisms
    The most clinically relevant SNPs for ß1-receptors include Ser49Gly and Arg389Gly.  Ser49Gly leads to impaired down-regulation of the beta-1 receptor, and Arg389Gly leads to higher signal transduction.11, 12  Therefore, carriers of either variant have enhanced ß1-receptor activity and are more sensitive to beta-blocker therapy.  

    ß2-receptor polymorphisms

    The most clinically relevant SNPs for ß2-receptors include Arg16Gly, Gln27Glu, and Cys-19Arg.  Receptors with the Gly16 variant have enhanced down-regulation of the beta-2 receptor.  In contrast, receptors with the Glu27 variant appear resistant to down-regulation.3  Finally, the Cys-19 variant is associated with increased beta-2 receptor expression.8

     

    These polymorphisms of beta-receptors alter the sensitivity of patients to drug therapy, changing the pharmacodynamics of drug response.  Table 2 discusses clinical outcomes as they relate to each ß-receptor polymorphism.

     

    Although the known and studied polymorphisms of beta-receptors do not seem to produce disease, it is evident these genetic mutations can play a role in risk for disease and disease modification.  Moreover, the polymorphisms may change how a patient responds to drug therapy, specifically beta-agonist and antagonist therapies.  Such genotypic analysis can help guide drug selection and dosing. Although somewhat controversial, the evidence from research continues to improve understanding of beta-receptor signaling.  There is a great need for large, randomized, controlled trials to evaluate the conflicting data related to beta-receptor SNPs and related differences regarding disease and medications.  Recent studies suggest that analysis of haplotype may be more beneficial than analysis of individual polymorphisms in relation to drug response.  These trials should by multinational and include a variety of ethnicities.  Future pharmacogenetic evidence will promote the practice of personalized medicine.

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MESH Terms & Keywords

  • Beta receptor polymorphism, polymorphisms beta receptor, beta 1 receptor polymorphisms, beta 1 receptor SNP, beta 2 polymorphisms, beta 2 receptor SNP, beta receptor variants, beta 1 receptor variants, beta 2 receptor variants, Ser49Gly, Arg389Gly