Beta-Adrenergic Receptors and Beta Blocker Response Notes

Beta-adrenergic receptors are typically bound by norepinephrine and epinephrine.
Beta-blockers function as antagonists, blocking signaling through the β-adrenoceptors.
There exist three β-adrenoceptor subtypes: β1, β2, and β3.
These receptors are G-protein coupled receptors.
β1 receptors increase cardiac rate and force.
β2 receptors facilitate bronchodilation and vasodilation.
Beta-blockade can be specific (β1) or non-specific (β1 and β2).

Two common variants exist in ADBR1:
- p.Arg389Gly (rs1801253)
  - The Arg 389 allele exhibits increased function in vitro compared to Gly389 receptors, demonstrating higher basal levels of adenylyl cyclase activity.
  - The minor allele Gly389 decreases both basal and agonist-promoted receptor activity.
- p.Ser49Gly (rs1801252)
  - The minor allele Gly49 showed altered glycosylation and increases agonist-promoted receptor downregulation
Minor alleles Gly389 and Gly49 are associated with:
- Decreased heart rate at rest and in response to exercise.
- Decreased risk of developing hypertension.

In healthy individuals:
- Carriers of p.Arg389Gly and p.Ser49Gly are less responsive to β-blockade than wild type.
In individuals with high blood pressure:
- Some studies show the p.Arg389Gly and p.Ser49Gly have no significant change in blood pressure after β-blockade.
Not all studies find an effect of the ADBR1 genotype and response to β-blockers.
- Other clinical variables may play a role.
- Other candidate genes may be involved.

Studied the interaction between ADRB1 Arg389Gly polymorphism and β-blockers in heart failure (HF) patients with reduced ejection fraction.
Retrospective analysis of DNA substudies from BEST (B-Blocker Evaluation of Survival Trial) and HF-ACTION (Heart Failure: A Controlled Trial Investigating Outcomes of Exercise Training).
Defined β-blocker dose as no/low dose or high dose based on total daily dose of bucindolol (BEST) or other β-blockers (HF-ACTION) standardized to carvedilol equivalents.
All-cause mortality was the main outcome.
CV mortality/HF hospitalization was a secondary outcome.
Results:
- Subjects with ADRB1 Arg389Arg had less all-cause mortality with high- versus no/low-dose β-blocker.
- High-dose bucindolol with ADRB1 Arg389Arg had a differential favorable treatment effect compared to Gly carriers.
- HF-ACTION Arg389Arg genotype subjects taking no/low-dose β-blocker had greater all-cause mortality compared with 389Gly carriers.
Conclusions:
- The enhanced HF efficacy of bucindolol in the ADRB1 Arg389Arg versus 389Gly carrier genotypes occurs at high dose.
- Other β-blockers taken at low dose have reduced efficacy for Arg389Arg genotype subjects compared with 389Gly carriers.
- Supports using high, clinical trial target doses of all β-blockers to treat HF with reduced ejection fraction.

Studied the association of genetic polymorphisms in ADRB2 and ADRB1 with differential survival in heart failure patients taking β-blockers.
Assessed associations and interactions between β-blocker dose, SNP genotype, and mortality using a Cox proportional hazard model.
Two SNPs, ADRB1 Arg389Gly and ADRB2 Glu27Gln, displayed significant interactions with β-blocker dose and their association with mortality.
Suggests that ADRB2 27Glu and ADRB1 389Arg may confer a larger survival benefit with higher β-blocker doses in patients with HF.

There is inter-individual variability in response to beta-blockers.
Variation in the genes that encode beta-adrenergic receptors has been shown to have an effect on the function of the receptor in vitro.
Identifying those individuals who don’t respond well to beta-blockers could be clinically valuable.
Even after 20 years of research, there are still conflicting results.
Recent studies suggest that at high dosage of beta-blockers, there is a relationship between genotype and clinical outcome.
There is still hope for personalized medicine in this area.