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
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
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.
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
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.
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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