ADRB2 Genotype Research Articles

Genotype-driven asthma prescribing of inhaled corticosteroids and long-acting β2-agonist: A cost-effectiveness analysis.

Predicting response to inhaled corticosteroids (ICSs) + long-acting β2-agonist (LABA) by previously detecting the presence of Arg16Gly ADRB2 genotype is a strategy that could reduce and optimize the management of asthmatic patients. There is a need for economic evaluations to facilitate the implementation of such tests. This research aims to evaluate the cost-effectiveness of Arg16Gly ADRB2 screening in children with asthma in Colombia. From the perspective of a third-party payer, we conducted a cost-effectiveness analysis to determine the cost and quality-adjusted life-years (QALYs) of genotype-driven asthma prescribing based on the Arg16Gly ADRB2 genotype versus current treatment based on no genetic testing. Using four state-transition models, we estimate cost and QALYs employing micro-simulation modeling with a time horizon of 10 years and a cycle length of 1 week. Cost-effectiveness was assessed at a willingness-to-pay (WTP) value of US$5180. The mean incremental cost of strategy genetic testing versus no genetic testing is US$ -6809. The mean incremental benefit of strategy genetic testing is 16 QALYs. The incremental net monetary benefit of strategic genetic testing versus no genetic testing is US$ 88,893. Genetic testing is the strategy with the highest expected net benefit. The outcomes derived from our primary analysis remained robust when subjected to variations in all underlying assumptions and parameter values. Genetic testing of Arg16Gly ADRB2 is a cost-effective strategy to address asthma management in asthmatic children requiring ICS+LABA. This result should encourage the generation of more evidence and the incorporation of such evidence into clinical practice guidelines for pediatric asthma.

Impact of pharmacotherapy with tiotropium/olodaterol on the pulmonary function in COPD patients depending on the Arg16Gly polymorphism of ADRB2 gene

BACKGROUND. Chronic obstructive pulmonary disease (COPD) is a widespread chronic disease, that can be prevented and treated. Internal or genetic factors play a significant role in the COPD development.
 OBJECTIVE. To investigate a response to the tiotropium/olodaterol treatment in patients with different ADRB2 gene polymorphism.
 MATERIALS AND METHODS. 100 patients with the diagnosis of COPD were included into the study. Pulmonary function testing was performed during all study visits. All patients received treatment according to GOLD 2019, which included a combination of long-acting b2-agonists and long-acting muscarinic antagonists. According to the results of genetic testing all patients were divided into three groups: Arg16Arg – 23 patients (23 %), Arg16Gly – 39 (39 %), Gly16Gly – 38 (38 %).
 RESULTS. Groups did not differ by sex, age, part of smokers, COPD duration. There was a significant difference in force vital capacity (FVC), which was 66.92±4.33 % in Arg16Arg group, 79.75±3.51 % in Arg16Gly group and 76.59±2.73 % in Gly16Gly group (p=0.05). There was a weak negative correlation between Arg16Arg genotype and FVC (r=-0.204; p=0.043). In regression analysis Arg16Arg genotype was associated with 10.52 % lower FVC on average (odds ratio -10.523; 95 % confidence interval from -20.502 to -0.544; p=0.039). A statistically significant improvement of forced expiratory volume in the first second (FEV1) and FVC was observed in all groups during the study (p<0.001).
 CONCLUSIONS. Arg16Arg genotype was associated with the lowest FVC values during all study visits. Combination of tiotropium/olodaterol was effective in improving pulmonary function in patients with different ADRB2 genotypes, which was demonstrated by a significant improvement of FEV1 and FVC in study groups during the study.

Impact of Polymorphism in the β2-Receptor Gene on Metabolic Responses to Repeated Hypoglycemia in Healthy Humans.

The Arg16 variant in the β2-receptor gene is associated with increased risk of severe hypoglycemia in subjects with type 1 diabetes mellitus. We hypothesized that the Arg16 variant is associated with decreased metabolic and symptomatic responses to recurrent hypoglycemia. Twenty-five healthy male subjects selected according to ADRB2 genotype and being homozygous for either Arg16 (AA; n = 13) or Gly16 (GG; n = 12) participated in 2 consecutive trial days with 3 periods of hypoglycemia (H1-H3) induced by a hyperinsulinemic hypoglycemic clamp. The main outcome measure was mean glucose infusion rate (GIR) during H1-H3. During H1-H3, there was no difference between AA or GG subjects in GIR, counter-regulatory hormones (glucagon, epinephrine, cortisol, growth hormone), or substrate levels of lactate, glycerol, and free fatty acids (FFAs), and no differences in symptom response score or cognitive performance (trail making test, Stroop test). At H3, lactate response was reduced in both genotype groups, but AA subjects had decreased response (mean ± standard error of the mean of area under the curve) of glycerol (-13.1 ± 3.8 μmol L-1 hours; P = .0052), FFA (-30.2 ± 11.1 μmol L-1 hours; P = .021), and β-hydroxybutyrate (-0.008 ± 0.003 mmol L-1 hour; P = .027), while in GG subjects alanine response was increased (negative response values) (-53.9 ± 20.6 μmol L-1 hour; P = .024). There was no difference in GIR between genotype groups, but secondary outcomes suggest a downregulation of the lipolytic and β-hydroxybutyrate responses to recurrent hypoglycemia in AA subjects, in contrast to the responses in GG subjects.

Influence of β2 adrenergic receptor genotype on longitudinal measures of forced vital capacity in patients with Duchenne muscular dystrophy

The progression of decline in forced vital capacity as percent predicated (FVC%p) is a strong indicator of worsening prognosis in patients with Duchenne muscular dystrophy (DMD). Evidence suggests that ß2 adrenergic (ADRB2) receptors may play a role in determining respiratory function, whereby more functional ADRB2 genotype variants (e.g., Gly16) are associated with improved pulmonary function. The purpose of this study was to determine the influence of ADRB2 genotype on longitudinal measures of FVC%p as a function of age in DMD patients. Data from the CINRG Duchenne Natural History Study including 169 DMD patients (5–25 yrs) were analyzed. A generalized additive mixed effects model was used to examine differences in the nonlinear trend of FVC%p across patient ages between genotype groups after controlling for patient demographics, corticosteroid-use, and ambulatory status. Both genotype groups displayed a progressive, maturational decline in FVC%p. Notwithstanding this decline, patients expressing the Gly16 polymorphism demonstrated systematically lower FVC%p values at any given age compared with patients expressing the Arg16 polymorphism (P < 0.01). Therefore, expressing the Gly16 polymorphism may prove detrimental to respiratory function in DMD patients. These data suggest maybe ADRB2 genotyping should be considered in the clinical management of DMD patients.

β1-receptor polymorphisms and junctional ectopic tachycardia in children after cardiac surgery.

Junctional ectopic tachycardia (JET) is a potentially life‐threatening postoperative arrhythmia in children with specific congenital heart defects and can contribute significantly to postoperative morbidity for at‐risk populations. In adults, β1‐adrenergic receptor (ADRB1) and β2‐adrenergic receptor (ADRB2) genotypes have been associated with increased risk for arrhythmias. However, their association with arrhythmia risk in children is unknown. We aimed to test associations between ADRB1 and ADRB2 genotypes and postoperative JET in patients with congenital heart defects. Children who underwent cardiac surgery were genotyped for the ADRB1 p.Ser49Gly (rs1801252; c.145A>G), p.Arg389Gly (rs1801253; c.1165C>G), ADRB2 p.Arg16Gly (rs1042713; c.46A>G), and p.Glu27Gln (rs1042714; c.79G>C) polymorphisms. The occurrence of postoperative JET was assessed via cardiologist‐interpreted electrocardiograms. Genotype associations with JET were analyzed via logistic regression, adjusted for clinical variables associated with JET, with separate analysis in patients not on a β‐blocker. Of the 343 children included (median age 8 months, 53% boys, 69% European ancestry), 45 (13%) developed JET. The Arg389Arg genotype was not significantly associated with JET in the overall population (odds ratio [OR] = 1.96, 95% confidence interval [CI] = 0.96–4.03, p = 0.064), but was nominally associated in patients not taking a β‐blocker (n = 324, OR = 2.25, 95% CI = 1.05–4.80. p = 0.034). None of the other variants were associated with JET. These data suggest that the ADRB1 Arg389Arg genotype may predict risk for JET following cardiac surgery in pediatric patients in the absence of β‐blockade. Whether treatment with a β‐blocker ameliorates this association requires further research.

HUBUNGAN GENOTIPE rs 1042713 (Arg16Gly) DENGAN EFEKTIVITAS 2-AGONIS PADA PENDERITA ASMA

ABSTRACT&#x0D; &#x0D; To produce an effect, the agonist drug 2 will bind to the ADRB2 receptor. The effect of agonist 2&#x0D; shows variation between individuals due to the presence of encoding gene polymorphisms. There are&#x0D; 80 ADRB2 polymorphisms, including Arg16Gly in amino acids 16. The innate ADRB2 genotype is&#x0D; called wildtype, whereas mutated ones is called mutant. The purpose of this study was to determine&#x0D; whether there was a relationship between genotype rs 1042713 (Arg16Gly) and the effectiveness of&#x0D; β2-agonist drugs in asthma sufferers. This study was an observational study with a cross sectional&#x0D; design and prospective data collection. Examination of the presence of gene polymorphisms and&#x0D; assessment of effe A total of 101 asthma patients who met the inclusion criteria were sorted by&#x0D; genome type by pharmacogenomic examination uses the Asthma Control Test (ACT) questionnaire.&#x0D; The results of the statistical test with chi square to determine the relationship of genome type and&#x0D; asthma control obtained p value 0.131. The comparison of the effectiveness of the wildtype genome&#x0D; is more effective than the mutant of 1.887x, and heterozygote is more effective 1,667x greater than&#x0D; the mutant. There is no significant relation between genotypes rs 1042713 (Arg16Gly) with&#x0D; effectiveness, but the possibility of clinical effectiveness is different.&#x0D; &#x0D; Keywords: Asthma, β2-agonist, ADRB2, genotype, effectiveness.

Workplace bullying increases the risk of anxiety through a stress-induced \u03b22-adrenergic receptor mechanism: a multisource study employing an animal model, cell culture experiments and human data

ObjectivesSeveral studies show that severe social stressors, e.g., in the form of exposure to workplace bullying in humans, is associated with negative mental health effects such as depression and anxiety among those targeted. However, the understanding of the underlying biological mechanisms that may explain the relationship between exposure to bullying and such negative health outcomes is scarce. The analyses presented here focus on understanding the role of the β2-adrenergic receptors (ADRB2) on this association.MethodsFirst, a resident-intruder paradigm was used to investigate changes in circulating norepinephrine (NE) in rat serum induced by repeated social defeat and its relationship with subsequent social behavior. Second, the direct effects of the stress-hormones NE and cortisol, i.e., synthetic dexamethasone (DEX), on the ADRB2 expression (qPCR) and monocyte chemoattractant protein-1 (MCP-1) release (immunoassay) was examined in cultured EL-1 cells. Third, in a probability sample of 1052 Norwegian employees, the 9-item short version of the Negative Acts Questionnaire—Revised (S-NAQ) inventory, Hopkins Symptom Checklist and genotyping (SNP TaqMan assay) were used to examine the association between social stress in the form of workplace bullying and anxiety moderated by the ADRB2 genotype (rs1042714) in humans.ResultsThe present study showed a clear association between reduced social interaction and increased level of circulating NE in rats previously exposed to repeated social defeat. Parallel cell culture work, which was performed to examine the direct effects of NE and DEX on ADRB2, demonstrated ADRB2 downregulation and MCP-1 upregulation in cultured EL-1 cells. Genotyping with regard to the ADRB2 genotype; rs1042714 CC vs CG/GG, on human saliva samples, showed that individuals with CC reported more anxiety following exposure to bullying behaviors as compared to the G carriers.ConclusionWe conclude that workplace bullying promotes anxiety and threaten well-being through an ADRB2 associated mechanism.

Exposure-Response and Clinical Outcome Modeling of Inhaled Budesonide/Formoterol Combination in Asthma Patients.

Exposure-response and clinical outcome (CO) model for inhaled budesonide/formoterol was developed to quantify the relationship among pharmacokinetics (PK), pharmacodynamics (PD) and CO of the drugs and evaluate the covariate effect on model parameters. Sputum eosinophils cationic proteins (ECP) and forced expiratory volume (FEV1) were selected as PD markers and asthma control score was used as a clinical outcome. One- and two-compartment models were used to describe the PK of budesonide and formoterol, respectively. The indirect response model (IDR) was used to describe the PD effect for ECP and FEV1. In addition, the symptomatic effect on the disease progression model for CO was connected with IDR on each PD response. The slope for the effect of ECP and FEV1 to disease progression were estimated as 0.00008 and 0.644, respectively. Total five covariates (ex. ADRB2 genotype etc.) were searched using a stepwise covariate modeling method, however, there was no significant covariate effect. The results from the simulation study were showed that a 1 puff b.i.d. had a comparable effect of asthma control with a 2 puff b.i.d. As a result, the 1 puff b.i.d. of combination drug could be suggested as a standardized dose to minimize the side effects and obtain desired control of disease compared to the 2 puff b.i.d.

Influence of \u03b22 adrenergic receptor genotype on risk of nocturnal ventilation in patients with Duchenne muscular dystrophy

Duchenne muscular dystrophy (DMD) is a progressive neuromuscular disease resulting in severe respiratory derangements. As such, DMD patients are at a high risk of nocturnal hypoventilation, thereby requiring nocturnal ventilation (NV). To this end, NV is an important clinical milestone in the management of DMD. Emerging evidence suggests that ß2 adrenergic receptors (ADRB2) may play a role in determining respiratory function, whereby more functional ADRB2 genotype variants (e.g., Gly16) are associated with improved pulmonary function and respiratory muscle strength. These findings suggest that the more functional ADRB2 genotype may help to preserve respiratory function in patients with DMD. The purpose of this study was to identify the influence of ADRB2 genotype on the risk of NV use in DMD. Data from the CINRG Duchenne Natural History Study including 175 DMD patients (3–25 yrs) were analyzed focusing on ADRB2 genotype variants. Time-to-event analyses were used to examine differences in the age at prescription of full-time NV use between genotypes. There were no differences between genotype groups in age, height, weight, corticosteroid use, proportion of ambulatory patients, or age at loss of ambulation. DMD patients expressing the Gly16 polymorphism had a significantly (P < 0.05) lower mean age at NV prescription compared with those patients expressing the Arg16 polymorphism (21.80 ± 0.59 yrs. vs 25.91 ± 1.31 yrs., respectively). In addition, a covariate-adjusted Cox model revealed that the Gly16 variant group possessed a 6.52-fold higher risk of full-time NV use at any given age compared with the Arg16 polymorphism group. These data suggest that genetic variations in the ADRB2 gene may influence the age at which DMD patients are first prescribed NV, whereby patients with the Gly16 polymorphism are more likely to require NV assistance at an earlier age than their Arg16 counterparts.

Influence of Beta‐2 Adrenergic Receptor Genotype on Age of Nocturnal Ventilation in Patients with Duchenne Muscular Dystrophy

Duchenne muscular dystrophy (DMD) is an inheritable disease that presents itself in diminished respiratory function and is the main contributor to mortality in these patients. The main respiratory concerns in DMD are reduced diaphragmatic function, reduced mucocilliary clearance, increased muscle proteolysis, and increased inflammation. The Gly16 variant of the β2‐adrenergic receptor (ADRB2) has been identified as providing a protective effect for respiratory weakness. The aim of this study was to identify the influence of ADRB2 genotype on the age of use for nocturnal ventilatory assistance in DMD. Data from CINRG‐DNHS including 175 DMD patients (ages 3–25 years) with up to 9.7 years follow‐up were analyzed focusing on ADRB2 functional variants. We performed Cox proportional hazard and Kaplan‐Meier time to event analyses for the age of nocturnal ventilation use. There were no differences between genotype groups in age, height, weight, corticosteroid use, number of ambulatory patients, or age of loss of ambulation. The genotype groups differed significantly in the age at which nocturnal ventilation use was prescribed with the Gly16 demonstrating a 2.77‐fold increased risk of using nocturnal ventilation at any given age. These data suggest that genetic variations in the ADRB2 gene may influence the age of nocturnal ventilation use in DMD. Specifically, the Gly16 polymorphism of the ADRB2 may have a deleterious effect on age of nocturnal ventilation use in DMD.This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

Impact of Genetic Polymorphism in the β2-Receptor Gene on Risk of Severe Hypoglycemia in Patients With Type 1 Diabetes.

Severe hypoglycemic events are unevenly distributed in people with type 1 diabetes, making a genetic influence probable. Of the common adrenoceptor β-2 receptor gene (ADRB2) polymorphisms, the Arg16 allele is associated with receptor downregulation and reduced agonist-mediated endogenous glucose production. We tested the hypothesis that the Arg16 variant is associated with severe hypoglycemia. A cohort of 311 patients with type 1 diabetes reported severe hypoglycemic events retrospectively in a validated questionnaire. The patients were characterized by diabetes history, state of hypoglycemia awareness, C-peptide status, HbA1c, and ADRB2 genotype. The ADRB2 Gly16Arg genotype distribution was in Hardy-Weinberg equilibrium. The rate of severe hypoglycemia differed among all genotypes (P = 0.01). Patients homozygous for the Arg16 genotype (AA; n = 60) had a relative rate (RR) of severe hypoglycemia of 2.2 (95% CI, 1.3 to 3.6) compared with patients homozygous for the Gly16 genotype (GG; n = 116; P = 0.002). Among patients with impaired awareness or unawareness (n = 175), those with the AA genotype (n = 33) had an RR of severe hypoglycemia of 3.2 (95% CI, 1.7 to 6.0) compared with patients with the GG genotype (n = 58; P < 0.000). Genotype was not associated with state of hypoglycemia awareness per se, as assessed by any of three classification methods. The difference was not explained by other risk factors. Genetic polymorphism in ADRB2 is associated with risk of severe hypoglycemia in individuals with type 1 diabetes, especially in those with impaired hypoglycemia awareness.

ADRB2 gene polymorphism and emphysema heterogeneity can modulate bronchodilator response in patients with emphysema

BackgroundGenetic variation in the β2-adrenergic receptor (ADRB2) gene has been thought to have an important role in the differential response to β2-agonist therapy for asthma. However, previous studies have shown little evidence for an association between these ADRB2 variants and the bronchial dilator response (BDR) in chronic obstructive pulmonary disease (COPD) patients. This discrepancy could be explained by differences in the distribution and heterogeneity of pulmonary emphysema in COPD patients, since emphysema distribution and heterogeneity are thought to have a role in pulmonary function in COPD patients. We hypothesized that differences in emphysema distribution and heterogeneity may have masked significant alterations of the bronchodilator response among ADRB2 genotypes in COPD patients in previous studies. MethodsThe BDR (induced by 20 μg of procaterol) was measured in 211 patients who had a smoking history of more than 10 pack/years and had undergone chest high resolution computed tomography examination. A low attenuations area (<960 Hounsfield Units) was identified and the emphysema heterogeneity index (EHI%) was calculated with a range in value from −100% to 100%. ADRB2 Arg16Gly genotyping was performed using polymerase chain reaction-restriction fragment length polymorphism analysis. ResultsThe BDR was augmented in patients with homogenous emphysema compared with those with upper-dominant emphysema. In patients carrying the AA genotype of ADRB2, the BDR was significantly increased in patients with upper-dominant emphysema, but not in patients with lower-dominant emphysema. ConclusionCombination analysis of ADRB2 Arg16Gly polymorphism and EHI% may predict the effectiveness of β2-adrenergic receptor agonist treatment in patients with COPD and emphysema.

Beta-2 Adrenergic Receptor Genotype Influences Power Output in Healthy Subjects.

Kelley, EF, Johnson, BD, and Snyder, EM. Beta-2 adrenergic receptor genotype influences power output in healthy subjects. J Strength Cond Res 31(8): 2053-2059, 2017-The purpose of this study was to determine the effects of ADRB2 genotypes on muscle function (absolute power and relative power) in healthy subjects. We performed genotyping of the ADRB2 (amino acid 16) and high-intensity, steady-state exercise on 77 healthy subjects (AA = 18, AG = 25, GG = 34). There were no differences between genotype groups in age, height, weight, or body mass index (BMI) (age = 28.9 ± 5.7 years, 27.9 ± 5.7 years, 29.2 ± 5.9 years, height = 170.7 ± 8.6 cm, 174.9 ± 8.7 cm, 173.4 ± 9.6 cm, weight = 68.5 ± 13.0 kg, 75.0 ± 12.9 kg, 74.4 ± 12.9 kg, and BMI = 23.4 ± 3.9, 24.4 ± 2.9, 24.7 ± 3.4, for AA, AG, and GG, respectively). The genotype groups differed significantly in watts, and watts/V[Combining Dot Above]O2 with heavy exercise (watts = 186.3 ± 54.6, 237.8 ± 54.4, 219.4 ± 79.5, watts/V[Combining Dot Above]O2 = 0.08 ± 0.006, 0.09 ± 0.005, 0.08 ± 0.006). There was a trend toward significance (p = 0.058) for W·kg (2.7 ± 0.4, 3.2 ± 0.5, 2.9 ± 0.8, for AA, AG, and GG, respectively). These data suggest that genetic variation of the ADRB2 may influence relative strength in healthy subjects and may become an important genetic determinant of muscular strength and functional capacity in patients with diseases that result in a loss of muscle strength.

Association Between ADRB2 Genetic Polymorphisms and the Risk of Chronic Obstructive Pulmonary Disease: A Case-Control Study in a Chinese Population.

This study was designed to investigate the association between single nucleotide polymorphisms (SNPs) of the β2-adrenergic receptor (ADRB2) gene and the risk of chronic obstructive pulmonary disease (COPD) in a Chinese population. From January 2010 to October 2014, 261 COPD patients were selected as the case group and 239 healthy subjects were selected as the control group. Pulmonary function tests were performed to detect forced vital capacity (FVC), 1-s forced expiratory volume (FEV1), and FEV1/FVC (%). rs1042711, rs1042714, and rs1042718 were selected as tagSNPs of the ADRB2 gene from the HapMap database in accordance with previous studies. The ADRB2 genotypes were established by real-time polymerase chain reaction assays using TaqMan-labeled probes. The relationships between the ADRB2 polymorphisms and COPD risk were estimated using logistic regression analyses. The frequency of the genotypes and alleles of rs1042711 in ADRB2 showed a significant difference between the COPD and control groups (p < 0.05); compared with the CC genotype, the non-CC genotypes showed an increased COPD risk (p = 0.002). Compared with the CC haplotype, the TG haplotype increased COPD risk, while the CG haplotype reduced COPD risk for normal individuals. Compared with the CC genotype, the TT genotype showed significantly lower FEV1 and FEV1/FVC (p = 0.022, p = 0.0191, respectively). Both the TC and TG haplotypes showed lower FEV1 and FEV1/FVC in comparison with the CC haplotype (both p < 0.05). The results of logistic regression analysis showed that rs1042711 of ADRB2 and smoking history were associated with COPD risk (both p < 0.05). It is indicated that the TT genotype of rs1042711 and smoking pack years are both risk factors for COPD.

In the Wrong Place with the Wrong SNP: The Association Between Stressful Neighborhoods and Cardiac Arrest Within Beta-2-adrenergic Receptor Variants.

Sudden cardiac arrest has been linked independently both to stressful neighborhood conditions and to polymorphisms in the ADRB2 gene. The ADRB2 gene mediates sympathetic activation in response to stress. Therefore, if neighborhood conditions cause cardiac arrest through the stress pathway, the ADRB2 variant may modify the association between neighborhood conditions, such as socioeconomic deprivation and incidence of cardiac arrest. The Cardiac Arrest Blood Study Repository is a population-based repository of specimens and other data from adult cardiac arrest patients residing in King County, Washington. Cases (n = 1,539) were 25- to 100-year-old individuals of European descent who experienced out-of-hospital cardiac arrest from 1988 to 2004. Interactions between neighborhood conditions and the ADRB2 genotype on cardiac arrest risk were assessed in a case-only study design. Gene-environment independence was assessed in blood samples obtained from King County residents initially contacted by random-digit dialing. Fewer than 4% of study subjects resided in socioeconomically deprived neighborhoods. Nonetheless, the case-only analysis indicated the presence of supramultiplicative interaction of socioeconomic deprivation and the homozygous Gln27Glu variant (case-only odds ratio: 1.8 [95% confidence interval: 1.0, 2.9]). Interactions between population density and the homozygous Gln27Glu variant were weaker (case-only odds ratio: 1.2 [95% confidence interval: 0.97, 1.5]). Findings support a supramultiplicative interaction between the Gln27Glu ADRB2 variant and socioeconomic deprivation among individuals of European descent. This result is consistent with the hypothesis that the elevation in cardiac arrest risk associated with socioeconomic deprivation operates through the stress pathway.

Genetic Variation Of The Beta-2 Adrenergic Receptor Influences Power Output In Healthy Subjects

BACKGROUND: Muscular strength and power are important in health, disease, and with aging. With age and disease, a decrease in muscular strength and power are primary contributors to a drop in functional capacity. The beta-2 adrenergic receptors (ADRB2) are important in muscle growth and power output through increased size and glucogenolysis. In disease models, the ADRB2 have been shown to be important in Ca+ homeostasis and cAMP accumulation in cells, both of which are important in attenuating the deterioration of muscle cell function. PURPOSE: The purpose of this study was to determine the effects of ADRB2 genotypes on muscle function (absolute power and relative power) in healthy subjects. METHODS: To determine this, we performed genotyping of the ADRB2 (amino acid 16) and maximal exercise on 77 healthy subjects (AA = 18, AG = 25, GG = 34). RESULTS: There were no differences between genotype groups in age, height, weight, or BMI (age = 28.9 ± 5.7yrs, 27.9 ± 5.7yrs, 29.2 ± 5.9yrs, height = 170.7 ± 8.6cm, 174.9 ± 8.7cm, 173.4 ± 9.6cm, weight = 68.5 ± 13.0kg, 75.0 ± 12.9kg, 74.4 ± 12.9kg, and BMI = 23.4 ± 3.9, 24.4 ± 2.9, 24.7 ± 3.4, for AA, AG, and GG, respectively). The genotype groups differed significantly in watts, and watts/VO2 at peak exercise with a trend towards significance (p=0.058) for watts/kg (watts = 186.3± 54.6, 237.8 ± 54.4, 219.4 ± 79.5, watts/VO2 = 0.08 ± 0.006, 0.09 ± 0.005, 0.08 ± 0.006, and watts/kg = 2.7 ± 0.4, 3.2 ± 0.5, 2.9 ± 0.8, for AA, AG, and GG, respectively). CONCLUSION: These data suggest that genetic variation of the ADRB2 may influence relative strength in healthy subjects and may become an important genetic determinant of muscular strength and functional capacity in patients with diseases that result in a loss of muscle strength.

ADRB2 Polymorphism and Salbutamol Responsiveness in Northern Indian Children with Mild to Moderate Exacerbation of Asthma.

The primary objective was to determine the association between beta-2 adrenergic receptor (ADRB2) gene polymorphism (rs1042713, c.46A>G, p.Arg16Gly) and the response to inhaled salbutamol in North Indian children aged 5 to 15 years, with mild to moderate exacerbation of asthma. This cross-sectional study was done at a tertiary-care hospital in Northern India from June 2011 to May 2013. 120 children with asthma with mild to moderate exacerbation underwent spirometry at baseline and after administration of three doses of salbutamol. An increase in FEV1 =15% was considered as positive response. Blood samples from these children were analysed for ADRB2 polymorphism (p.Arg16Gly). 94 non-asthmatic adult controls were also studied to determine the prevalence of ADRB2 polymorphism. In asthmatic children, the frequency of AA, GG, AG genotypes were 24.2%, 24.2% and 51.7% compared to 20.2%, 20.2% and 59.6%, respectively in the non-asthmatic adults. Salbutamol responsiveness showed no correlation with the studied ADRB2 polymorphism (p= 0.55). A trend towards greater bronchodilator responsiveness amongst AA genotype, compared to GG genotype was observed (Median change in percent predicted FEV1 14.5% and 7.5%, respectively). No correlation was found between salbutamol responsiveness and ADRB2 genotype in Northern Indian children with asthma with mild-to moderate exacerbation.

β2-Adrenergic receptor promoter haplotype influences the severity of acute viral respiratory tract infection during infancy: a prospective cohort study.

BackgroundDespite the significant interest in β2-Adrenergic receptor (ADRB2) polymorphisms related to asthma, whether ADRB2 genetic variants are similarly associated with acute respiratory tract infections have not been studied. We hypothesized that genetic variants in ADRB2 associated with a response to asthma therapy during an asthma exacerbation were also associated with severity of acute respiratory tract infections.MethodsTo test this hypothesis, we genotyped 5 common polymorphisms in the promoter region and coding block of the ADRB2 gene (loci -2387, -2274, -1343, +46, and +79) from 374 Caucasian and African American term infants who were enrolled at the time of acute respiratory illness over four respiratory viral seasons. Severity of respiratory tract infections was measured using a bronchiolitis severity score (BSS; range = 0-12, clinically significant difference = 0.5) with a higher score indicating more severe disease. We assigned the promoter, coding and combined promoter and coding haplotypes to the unphased genotype data. The associations between each of these five single-nucleotide polymorphisms (SNPs) as well as the haplotypes and infant BSS were analyzed using nonparametric univariate analysis and multivariable proportional odds model separately in Caucasians and African Americans.ResultsThere was no significant association between infant BSS and each of the SNPs in both Caucasians and African Americans. However, promoter haplotype CCA was associated with a decreased BSS in African Americans in a dose dependent manner. The median (interquartile range) BSS of infants with no copies of the CCA haplotype, one copy, and two copies of the CCA haplotype were 5.5 (2.0, 8.0), 4.0 (1.0, 7.5), and 3.0 (1.0, 4.0), respectively. This dose dependent relationship persisted after adjusting for infant age, gender, daycare exposure, secondhand smoke exposure, prior history of breastfeeding, siblings at home, and enrollment season (adjusted odds ratio: 0.59, 95 % confidence interval: 0.36, 0.98). There was no similar protective relationship of haplotype CCA on severity of respiratory tract infections identified in Caucasians.ConclusionsADRB2 genotype may be predictive of severity of acute respiratory tract infections in African Americans, and potentially identify a subset of infants who may respond to beta-agonist therapy.Electronic supplementary materialThe online version of this article (doi:10.1186/s12881-015-0229-3) contains supplementary material, which is available to authorized users.

The Effect of β2-Adrenoceptor Genotype on Phenylephrine Dose Administered During Spinal Anesthesia for Cesarean Delivery.

The β2-adrenoceptor (ADRB2 gene) possesses several polymorphic sites that have physiologic and/or pharmacologic significance. Previous work has demonstrated that the ADRB2 genotype affects the amount of ephedrine administered to maintain blood pressure during cesarean delivery with spinal anesthesia. This study investigated whether the ADRB2 genotype affected phenylephrine dose requirements during cesarean delivery. Our hypothesis was that the ADRB2 genotype altered the ephedrine dose-response and that we would not see this effect if phenylephrine was the vasopressor used to maintain blood pressure because phenylephrine does not act via the β2-adrenoceptor. Women undergoing elective cesarean delivery were studied. Baseline systolic blood pressure (SBP) was determined, and spinal anesthesia was initiated with hyperbaric bupivacaine 12 mg, fentanyl 20 μg, and morphine 200 μg. Hypotension was treated with a phenylephrine infusion using a standardized algorithm (50 μg/min if SBP was 90%-99% of baseline, 100 μg/min for SBP 80%-89% baseline, and 200 μg/min plus boluses for SBP <80% baseline) for 15 minutes after the administration of spinal anesthesia. ADRB2 genotype at codons 16 and 27 was determined. The effect of genotype on administered phenylephrine was compared by analysis of variance and linear regression. Ninety-six women completed the protocol with full data available for analysis. In the unadjusted analysis, there were no significant differences in phenylephrine dose administered among different genotypes at codons 16 and 27. When adjusted for covariates (maternal body mass index, baseline systolic and diastolic blood pressure, neonatal weight, and ethnicity), there was an increase of 200 μg (95% confidence interval, 4-396; P = 0.04) in phenylephrine administered to Arg16 homozygous genotype subjects compared with Gly16 homozygous genotype subjects. Phenylephrine dose requirements to maintain SBP after spinal anesthesia are affected by ADRB2 genotype but to a lesser extent than ephedrine. This suggests that previous work demonstrating a large effect of ADRB2 genotype on ephedrine dose requirements may be explained, at least in part, by a differential response to ephedrine based on ADRB2 genotype. It also suggests that there may be ADRB2-mediated differences in the physiologic response to spinal anesthesia.

Polymorphism in theADRB2Gene Explains a Small Portion of Intersubject Variability in Pain Relative to Cervical Dilation in the First Stage of Labor

Variability in labor pain has been associated with demographic, clinical, and psychological factors. Polymorphisms of the β2-adrenergic receptor gene (ADRB2) influence sensitivity to experimental pain in humans and are a risk factor for chronic pain. The authors hypothesized that polymorphisms in ADRB2 may influence labor pain. After Institutional Review Board approval and written informed consent, the authors prospectively obtained hourly pain reports from 233 nulliparous parturients during the first stage of labor, of which 199 were included in the current analysis. DNA from blood samples was genotyped at polymorphisms in the genes for the β2-adrenergic receptor, the μ opioid receptor subtype 1, catechol-O-methyltransferase, fatty acid amide hydrolase, and the oxytocin receptor. Labor pain as a function of cervical dilation was modeled with previously described methods. Patient covariates, ADRB2 genotype, and obstetrical and anesthesia treatment were evaluated as covariates in the model. Labor pain more rapidly became severe in parturients heterozygous or homozygous for the G allele at rs1042714 in the ADRB2 gene. Labor pain increased more rapidly after artificial rupture of membranes, augmentation with oxytocin, and in younger women. Inclusion of covariates explained approximately 10% of the variability between subjects. ADRB2 genotype explained less than 1% of the intersubject variability. ADRB2 genotype correlates with labor pain but explained less than 1% of the intersubject variance in the model.