rs1042713 — ADRB2 Arg16Gly
Beta-2 adrenergic receptor variant affecting receptor downregulation, exercise capacity, beta-agonist drug response, and cardiovascular function
Details
- Gene
- ADRB2
- Chromosome
- 5
- Risk allele
- A
- Protein change
- p.Gly16Arg
- Consequence
- Missense
- Inheritance
- Codominant
- Clinical
- Risk Factor
- Evidence
- Strong
- Chip coverage
- v3 v4 v5
Population Frequency
Ancestry Frequencies
Category
Fitness & BodyADRB2 Arg16Gly — Your Fight-or-Flight Receptor
The ADRB2 gene encodes the beta-2 adrenergic receptor11 beta-2 adrenergic receptor
A G-protein-coupled receptor on the surface of cells in the lungs, heart, blood vessels, and fat tissue that binds adrenaline and noradrenaline, one of the body's
primary mediators of the fight-or-flight response. When adrenaline binds this
receptor, it triggers bronchodilation (opening of airways), vasodilation
(relaxation of blood vessels), increased heart rate, and lipolysis (fat
breakdown). The Arg16Gly variant is a single nucleotide change (G to A) at
codon 16 that swaps glycine for arginine, altering how quickly the receptor
desensitizes after repeated stimulation.
This is not a rare disease variant — approximately 48% of people worldwide carry at least one A allele (Arg16). The variant's importance lies not in causing disease but in modulating exercise capacity, asthma medication response, and cardiovascular outcomes.
The Mechanism
The beta-2 receptor sits on the cell surface and is activated by
catecholamines22 catecholamines
Adrenaline (epinephrine) and noradrenaline (norepinephrine) — the hormones released during stress and exercise.
After repeated stimulation, the receptor undergoes
downregulation33 downregulation
A process where the cell reduces the number of receptors on its surface, dampening the response to continued stimulation —
the cell pulls receptors off its surface to dampen the signal.
The Gly16 form (G allele, reference allele) shows
enhanced agonist-promoted downregulation44 enhanced agonist-promoted downregulation
Green et al. demonstrated this in airway smooth muscle cells: Gly16 receptors are internalized faster after agonist exposure
compared to Arg16 (A allele). This means Gly16 carriers lose receptor
availability faster during sustained catecholamine exposure — such as
prolonged exercise or chronic beta-agonist medication use. Paradoxically,
Gly16 carriers may have higher baseline receptor density (before
desensitization begins), which explains why they can show both
enhanced initial responses and faster decline with sustained stimulation.
The Arg16 form maintains receptor density more effectively under chronic
stimulation but may show a different coupling pattern to downstream
G-protein signaling55 G-protein signaling
The receptor signals through both Gs (stimulatory) and Gi (inhibitory) G-proteins; the Arg16 variant may alter the balance between these pathways,
particularly relevant in cardiac tissue.
The Evidence
Exercise and Cardiovascular Function:
A controlled study of 64 healthy adults66 controlled study of 64 healthy adults
Snyder EM et al. Arg16Gly polymorphism of the beta2-adrenergic receptor is associated with differences in cardiovascular function at rest and during exercise. J Physiol, 2006
found that Arg16 homozygotes (AA) had significantly lower cardiac output
(5.7 vs 6.7 L/min, p < 0.01), stroke volume (68 vs 89 mL/beat, p < 0.01),
and higher resting heart rate (86 vs 80 bpm, p < 0.01) compared to Gly16
homozygotes (GG). These differences persisted during both light and heavy
exercise.
A Korean study of elite athletes77 Korean study of elite athletes
Kim J et al. Genetic association between ADRB2 rs1042713 and elite athletic performances in the Korean population. Gene, 2023
found the Gly16 allele significantly overrepresented among elite athletes,
with a notable gender-specific effect in women. However, findings across
populations have been inconsistent — a
Spanish study88 Spanish study
Santiago C et al. Adrenergic beta-2 receptor polymorphism and athletic performance. J Hum Genet, 2010
found no significant differences among world-class athletes.
Asthma and Beta-Agonist Response:
The strongest pharmacogenomic evidence comes from asthma treatment. A
meta-analysis of 4,226 children99 meta-analysis of 4,226 children
Turner S et al. Childhood asthma exacerbations and the Arg16 beta2-receptor polymorphism: a meta-analysis stratified by treatment. J Allergy Clin Immunol, 2016
found that each copy of the Arg16 (A) allele increased asthma exacerbation
risk by 52% (OR 1.52, 95% CI 1.17-1.99, p = 0.002) in children using
long-acting beta-agonists (LABA) plus inhaled corticosteroids. This
association was absent in children on corticosteroids alone or with
leukotriene receptor antagonists (LTRA) added.
Heart Failure:
In a study of 2,403 heart failure patients1010 study of 2,403 heart failure patients
Kang S et al. ADRB2 polymorphism Arg16Gly modifies the natural outcome of heart failure and dictates therapeutic response to beta-blockers. Cell Discovery, 2018,
Gly16 carriers (AG and GG) had a 50% higher risk of cardiovascular death
or heart transplantation (HR 1.49, p < 0.001) compared to Arg16 homozygotes.
However, the same Gly16 carriers showed dramatically better response to
beta-blocker therapy: 36% risk reduction in AG patients (p = 0.03) and
62% in GG patients (p < 0.001), while AA patients showed no significant
benefit.
Practical Implications
For AA (Arg/Arg) individuals: your beta-2 receptors resist downregulation, maintaining responsiveness under chronic stimulation. However, your baseline cardiovascular function metrics may be lower than Gly16 carriers. If you have asthma and use a LABA, discuss with your physician whether genotype-guided therapy could reduce exacerbation risk.
For GG (Gly/Gly) individuals: your receptors downregulate faster under sustained catecholamine exposure, which affects exercise recovery and medication response patterns. You may have higher baseline cardiac output and stroke volume. If you develop heart failure, beta-blocker therapy may be particularly beneficial for you.
For AG (Arg/Gly) individuals: you have an intermediate receptor profile. In heart failure contexts, you still derive meaningful benefit from beta-blocker therapy.
Interactions
ADRB2 Arg16Gly is commonly studied alongside rs1042714 (Gln27Glu), the other major coding variant in the same gene. The Gly16/Glu27 haplotype has been associated with protection against asthma development, while the Arg16/Gln27 haplotype may confer better treatment response. Women homozygous for the Gly16/Gln27 haplotype showed the highest body fat percentage and impaired glucose tolerance in one study.
Drug Interactions
Genotype Interpretations
What each possible genotype means for this variant:
Standard beta-2 receptor function with enhanced agonist-mediated downregulation
The Gly16 form of the beta-2 receptor displays enhanced agonist-promoted downregulation in cell studies — meaning the receptor is pulled off the cell surface more rapidly during sustained adrenaline exposure. Despite this, baseline receptor density can actually be higher in Gly16 homozygotes, which may explain the higher resting cardiac output observed in the Snyder et al. study (2006).
In heart failure patients (Kang et al. 2018), Gly/Gly individuals had the highest baseline cardiovascular risk (HR 1.71 for CV death/transplant vs Arg/Arg) but also the most dramatic response to beta-blocker therapy (62% risk reduction, p < 0.001). This suggests that the enhanced downregulation can be therapeutically targeted.
In the asthma context, the Gly/Gly genotype is not associated with increased exacerbation risk on LABA therapy — the risk is specifically tied to the A (Arg) allele.
One Arg16 allele — intermediate receptor function with mixed cardiovascular profile
As a heterozygote, your cells produce both Arg16 and Gly16 receptor variants. The net effect on receptor dynamics is intermediate. In the Snyder et al. cardiovascular study, AG individuals showed cardiac output (6.1 L/min) and stroke volume (82 mL/beat) between the two homozygous groups.
For asthma pharmacogenomics, carrying one A allele confers some increased exacerbation risk on LABA therapy (OR 1.52 per allele copy in the Turner et al. meta-analysis of 4,226 children). This is meaningful because approximately 48% of the population carries this genotype.
The heart failure data (Kang et al. 2018) showed AG individuals had an intermediate risk profile (HR 1.42 for CV death/transplant vs AA) and significant beta-blocker benefit (36% risk reduction, p = 0.03).
Homozygous Arg16 — reduced baseline cardiovascular function with altered beta-agonist response
The Arg16 receptor variant resists agonist-promoted internalization, meaning receptor numbers remain relatively stable under chronic catecholamine exposure. However, Snyder et al. (2006) found that Arg/Arg individuals had notably lower cardiovascular function at rest: cardiac output of 5.7 L/min (vs 6.7 for Gly/Gly, p < 0.01), stroke volume of 68 mL/beat (vs 89, p < 0.01), and paradoxically higher resting heart rate (86 vs 80 bpm, p < 0.01). These differences persisted during exercise.
In the asthma context, the Arg/Arg genotype carries the strongest pharmacogenomic signal. In children receiving ICS + LABA, two copies of the A allele approximately double exacerbation risk (the per-allele OR 1.52 compounds multiplicatively). Palmer et al. (2009) found that regular beta2-agonist use was specifically deleterious in Arg16 homozygotes.
In heart failure, Arg/Arg individuals actually had the lowest baseline cardiovascular risk (14.0% event rate vs 22.8% for Gly/Gly) but derived no significant benefit from beta-blocker therapy (HR 0.70, p = 0.121).
Key References
Turner et al. 2016 — Meta-analysis of 4,226 children: Arg16 allele increases asthma exacerbation risk on LABA therapy (OR 1.52)
Kang et al. 2018 — 2,403 heart failure patients: Gly16 carriers have 50% higher CV death risk but 36-62% greater beta-blocker benefit
Snyder et al. 2006 — 64 healthy subjects: Arg16 homozygotes have lower cardiac output and stroke volume at rest and during exercise
Zhang et al. 2014 — Meta-analysis of 10 studies (7,322 subjects): no significant association between Arg16Gly and obesity risk
Kim et al. 2023 — Korean elite athletes: Gly16 allele associated with elite athletic performance, especially in women
Palmer et al. 2009 — Arg16 genotype predisposes to exacerbations in asthmatic patients using regular beta2-agonists
Basu et al. 2018 — Systematic review of ADRB2 pharmacogenetics: rs1042713 most consistently linked to LABA response in children