rs1801253 — ADRB1 Arg389Gly

ADRB1 Arg389Gly — Your Heart's Throttle Response

The ADRB1 gene encodes the beta-1 adrenergic receptor¹¹ beta-1 adrenergic receptor
The primary receptor on cardiac muscle cells that binds adrenaline and noradrenaline, controlling heart rate, contractile force, and cardiac output in response to stress and exercise, the principal mediator of sympathetic nervous system control over the heart. When adrenaline and noradrenaline flood the bloodstream during exercise, stress, or danger, they bind this receptor and accelerate the heart. The Arg389Gly variant determines just how powerfully that signal is received.

At codon 389, most people carry the C allele (Arg389), which produces a receptor with higher basal coupling efficiency and stronger response to catecholamines. About 54% of Europeans are homozygous for this high-activity form; only 7% carry two copies of the reference G allele (Gly389). This makes Arg389 simultaneously the "variant" allele in name and the dominant allele in practice. The variant's importance lies not in rarity but in its influence on exercise heart rate response, beta-blocker pharmacogenomics, and myocardial infarction risk.

The Mechanism

At position 389 in the intracellular C-terminal tail of the receptor, the amino acid change from glycine (G allele) to arginine (C allele) alters the geometry of the region that couples to Gs protein²² Gs protein
The stimulatory G-protein that activates adenylyl cyclase when bound by a ligand-occupied receptor, generating cAMP as the intracellular second messenger. The Arg389 form has enhanced basal cAMP³³ cAMP
Cyclic adenosine monophosphate — the intracellular messenger that triggers protein kinase A activity, ultimately increasing heart rate and contractile force production even without catecholamine stimulation, and generates a larger cAMP surge when adrenaline binds compared to the Gly389 form.

This is not merely a quantitative difference. A 2008 cardiac gene expression study⁴⁴ 2008 cardiac gene expression study
Swift SM et al. Differential coupling of Arg- and Gly389 polymorphic forms of the beta1-adrenergic receptor leads to pathogenic cardiac gene regulatory programs. Physiol Genomics, 2008 using human heart tissue found that Arg389 receptor activation uniquely upregulates genes involved in inflammation, programmed cell death, and extracellular matrix remodeling — signaling programs not activated by the Gly389 form. This divergence in downstream gene regulation may explain why the genotype predicts differential cardiovascular outcomes and drug responses.

The Evidence

Exercise Heart Rate Response: The pharmacogenomic signature of this variant is most directly demonstrated in exercise contexts. A controlled study of 27 healthy adults⁵⁵ controlled study of 27 healthy adults
Muszkat M et al. The common Arg389gly ADRB1 polymorphism affects heart rate response to the ultra-short-acting β(1) adrenergic receptor antagonist esmolol in healthy individuals. Pharmacogenet Genomics, 2013 administered intravenous esmolol (an ultra-short-acting beta-1 blocker) during exercise. The inhibition of exercise-induced heart rate increase was 0.78 bpm in Gly389 homozygotes, 5.11 bpm in heterozygotes, and 10.22 bpm in Arg389 homozygotes — a 13-fold difference (p = 0.014). This dose-dependent genotype effect confirms that Arg389 carriers have a stronger adrenergic drive on exercise heart rate, and a correspondingly stronger response to blockade.

A study of 35 healthy subjects⁶⁶ study of 35 healthy subjects
Yogev D et al. Effects of sex and the common ADRB1 389 genetic polymorphism on the hemodynamic response to dobutamine. Pharmacogenet Genomics, 2015 using dobutamine infusion (a synthetic catecholamine) found that Arg389Arg homozygotes showed a 4.7-fold greater resting heart rate increase (12.95 vs 2.75 bpm) and a 3.9-fold greater renin response than Gly389Gly individuals. Heterozygotes showed intermediate responses. Genotype was the primary determinant in multivariate analysis (p = 0.011).

Beta-Blocker Response in Heart Failure: The most clinically impactful finding concerns beta-blocker dose optimization in heart failure. A pooled analysis of the BEST and HF-ACTION trials⁷⁷ pooled analysis of the BEST and HF-ACTION trials
Parikh KS et al. Dose Response of β-Blockers in Adrenergic Receptor Polymorphism Genotypes. Circ Genom Precis Med, 2018 (combined N = 1,997 patients) found that Arg389Arg homozygotes on high-dose beta-blocker therapy had a 60% reduction in all-cause mortality (HR 0.40, p = 0.002), compared to no significant benefit in Gly allele carriers (p > 0.2). Critically, at low doses, Arg389Arg individuals actually showed increased mortality (HR 1.83, p = 0.015) — suggesting that underdosing may be harmful in this genotype. A 2022 pharmacogenomics study⁸⁸ 2022 pharmacogenomics study
Guerra LA et al. Genetic polymorphisms in ADRB2 and ADRB1 are associated with differential survival in heart failure patients taking β-blockers. Pharmacogenomics J, 2022 confirmed this interaction: Arg389 carriers derived greater survival benefit at higher beta-blocker doses (p_interaction = 0.043).

Acute MI and Cardioprotection: In a Japanese case-control study⁹⁹ Japanese case-control study
Iwai C et al. Arg389Gly polymorphism of the human beta1-adrenergic receptor in patients with nonfatal acute myocardial infarction. Am Heart J, 2003 of 354 AMI patients versus 354 matched controls, Arg389 homozygotes had an odds ratio of 2.86 (95% CI 1.92–4.26, p = 0.0001) for nonfatal MI, independent of classical risk factors. This risk likely reflects the enhanced sympathetic activation of the Arg389 receptor, which can drive adverse myocardial remodeling. Consistent with this, a 2025 clinical trial analysis¹⁰¹⁰ 2025 clinical trial analysis
Clemente-Moragón A et al. Pharmacogenomics and chronotherapy of drug-induced cardioprotection in acute myocardial infarction. Nat Commun, 2025 found that metoprolol reduced infarct size exclusively in Arg389 homozygotes; Gly389 carriers received no cardioprotective benefit, with in-silico modeling showing unstable metoprolol binding to the Gly389 variant.

Blood Pressure Response: A Chinese study of 87 hypertensives¹¹¹¹ Chinese study of 87 hypertensives
Si D et al. Association of common polymorphisms in β1-adrenergic receptor with antihypertensive response to carvedilol. J Cardiovasc Pharmacol, 2014 found that Arg389 homozygotes had a 4-fold greater diastolic blood pressure reduction on carvedilol (10.61 vs 2.62 mmHg, p = 0.013), suggesting that genotype-guided prescribing could optimize antihypertensive therapy.

Practical Implications

For Arg389Arg (CC) individuals: your beta-1 receptors have higher basal activity and generate a stronger heart rate and blood pressure response to sympathetic stimulation. In heart failure or post-MI contexts, high-dose beta-blocker therapy is particularly important and effective for you. Inform your cardiologist of this genotype if you have cardiovascular disease.

For Gly389Gly (GG) individuals: your receptors have lower basal coupling efficiency, resulting in blunted catecholamine response. Beta-blocker response is weaker and may not confer the same survival benefits in heart failure. In acute MI, metoprolol-based cardioprotection may not apply to your genotype.

For heterozygotes (CG): your response profile is intermediate, tracking dose-dependently with the number of Arg389 alleles.

Interactions

ADRB1 Arg389Gly interacts with the ADRB1 Ser49Gly variant (rs1801252) to form functionally distinct haplotypes. The Ser49/Arg389 haplotype (the more active combination) has been associated with greater beta-blocker benefit in several studies. Petersen et al. (2011) found that Arg389 homozygotes combined with the ADRB2 Gln27 (rs1042714) variant had doubled mortality on carvedilol but not on metoprolol, suggesting that beta-blocker choice may matter when multiple adrenergic receptor variants are present.