Adrenergic Receptor Polymorphisms Research Articles

Role of beta-2 adrenergic receptor polymorphism (rs1042714) on body weight and glucose metabolism response to a meal-replacement hypocaloric diet

ObjectivesThe beta-2 adrenergic receptor (ADRB2) is involved in energy balance regulation. The objective of our study was to evaluate the role of the rs1042714 genetic variant of ADRB2 gene on weight loss, body composition, and metabolic changes secondary to partial meal replacement (pMR) hypocaloric diet in women with obesity. MethodsWe conducted an interventional study in 95 premenopausal women with body mass index ≥ 35 kg/m2. The subjects received two intakes per day of a normocaloric hyperproteic formula during 12 wk of a pMR diet. Body weight, body mass index, fat mass, waist circumference, lipid profile, fasting insulin levels, and homeostasis model assessment for insulin resistance were determined. All patients were genotyped rs1042714 and evaluated in a dominant model (CC versus CG + GG). ResultsGenotype frequencies were 31 (37.3%), 38 (45.8%), and 14 (16.9%) for the CC, CG, and GG genotypes, respectively. We found significant interaction effects between ADRB2 variant and pMR-induced changes (CC versus CG + GG) on body weight (–7.1 ± 0.3 versus –13.5 ± 0.5 kg; P = 0.03), body mass index (–0.9 ± 0.1 versus –1.2 ± 0.2 kg/m2; P = 0.03), fat mass (–4.9 ± 0.5 versus –10.2 ±1.2 kg; P = 0.01), waist circumference (–5.1 ± 0.2 versus –10.1 ± 1.9 cm; P = 0.03), glucose (–5.1 ± 1.3 versus –12.5 ± 2.5 mg/dL; P = 0.03), total cholesterol (–18.1 ± 9.3 versus –33.5 ± 4.5 mg/dL; P = 0.03), low-density lipoprotein cholesterol (–9.1 ± 5.3 versus –24.5 ± 4.1 mg/dL; P = 0.04), triacylglycerol levels (–6.1 ± 5.3 versus –31.5 ± 9.5 mg/dL; P = 0.04), fasting insulin levels (–1.8 ± 0.3 versus –6.3 ± 0.5 IU/L; P = 0.03), and homeostasis model assessment for insulin resistance (–0.6 ± 0.3 versus –1.9 ± 0.5 U; P = 0.03). The odds ratio to improve alteration in glucose metabolism adjusted by age and weight loss throughout the study was 0.26 (95% CI, 0.07–0.95; P = 0.02) in G allele carriers. ConclusionsThe G allele of rs1042714 predicts the magnitude of weight loss resulting from a pMR diet. These adiposity improvements produce a better improvement of insulin resistance and percentage of impaired glucose metabolism in G allele carriers.

Association between the Ile164 β2 Adrenergic Receptor Polymorphism and Fatigue in Patients with Rheumatoid Arthritis

Introduction: In the present work, the frequency of inherited polymorphisms of the beta 2 adrenergic receptor (β2AR) gene and their association with fatigue in patients with rheumatoid arthritis (RA) was examined. Methods: An allele-specific polymerase chain reaction was used to determine the common variants of the β2AR at position 16, 27, and 164 in 92 German RA outpatients. Health Assessment Questionnaire (HAQ-DI), Beck Depression Inventory (BDI), Perceived Stress Questionnaire (PSQ-30), Multidimensional Fatigue Inventory (MFI-20) were utilized. Results: 34.7% of German RA patients were diagnosed with associated fatigue. Fatigued patients were more likely to carry the Ile allele at position 164 (OR 7.33, 95% CI 1.09–59.8, p = 0.049). Comparing these risk factors’ contribution to different fatigue dimensions revealed that Ile164 carriers only had significantly higher MFI-20 mean values for general fatigue (p = 0.014) while the clinical difference among other MFI subscales was the largest for mental fatigue (carrier: 8.23, SD: 4.22, noncarrier: 5.67, SD: 1.56, p = 0.089, Cohen’s d = 0.629). Disease activity, perceived stress, and depression were also associated with fatigue with higher mean values for DAS28CRP (p = 0.038), PSQ (p < 0.001), and BDI-II (p < 0.001) in fatigued patients. Physical fatigue was correlated with disease activity (p = 0.009) and depression (p = 0.001) while mental fatigue showed associations with depression (p = 0.001) and perceived stress (p = 0.028). Conclusion: The discovery study indicates that the Ile164 polymorphism might in contrast to other β2AR polymorphisms affect fatigue levels in RA patients. This association was observed especially with mental fatigue. Further replication studies are warranted to determine further role of β2AR polymorphisms in RA patients.

The beta2 -adrenergic receptor - a re-emerging target to combat obesity and induce leanness?

Treatment of obesity with repurposed or novel drugs is an expanding research field. One approach is to target beta2 -adrenergic receptors because they regulate the metabolism and phenotype of adipose and skeletal muscle tissue. Several observations support a role for the beta2 -adrenergic receptor in obesity. Specific human beta2 -adrenergic receptor polymorphisms are associated with body composition and obesity, for which the Gln27Glu polymorphism is associated with obesity, while the Arg16Gly polymorphism is associated with lean mass in men and the development of obesity in specific populations. Individuals with obesity also have lower abundance of beta2 -adrenergic receptors in adipose tissue and are less sensitive to catecholamines. In addition, studies in livestock and rodents demonstrate that selective beta2 -agonists induce a so-called 'repartitioning effect' characterized by muscle accretion and reduced fat deposition. In humans, beta2 -agonists dose-dependently increase resting metabolic rate by 10-50%. And like that observed in other mammals, only a few weeks of treatment with beta2 -agonists increases muscle mass and reduces fat mass in young healthy individuals. Beta2 -agonists also exert beneficial effects on body composition when used concomitantly with training and act additively to increase muscle strength and mass during periods with resistance training. Thus, the beta2 -adrenergic receptor seems like an attractive target in the development of anti-obesity drugs. However, future studies need to verify the long-term efficacy and safety of beta2 -agonists in individuals with obesity, particularly in those with comorbidities.

The effect of alpha-2A adrenergic receptor (ADRA2A) genetic polymorphisms on the depth of sedation of dexmedetomidine: a genetic observational pilot study

BackgroundThe genetic polymorphisms of the alpha-2A adrenergic receptor (ADRA2A), which plays a significant role in sedation, anxiety relief, and antinociception, particularly in dexmedetomidine, may differ in the degree of sedation. This study aimed to investigate the effect of the genetic polymorphisms of ADRA2A (rs11195418, rs1800544, rs2484516, rs1800545, rs553668, rs3750625) on the sedative effects of dexmedetomidine. MethodsA total of 131 patients aged 50 years or more from May 2018 to August 2019 were included in this study. The ADRA2A gene variants were evaluated using the TaqMan Assay. Dexmedetomidine diluted in normal saline to a concentration of 4μg.mL-1 was infused at a dose of 2μg.kg-1 to achieve procedural sedation (modified Ramsay sedation scale 4 [mRSS 4]). ResultsA total of 131 patients were evaluated. The genetic polymorphisms (rs11195418) of the ADRA2A receptor gene demonstrated no variation in our participants. The ADRA2A receptor gene polymorphisms (rs1800544, rs2484516, rs1800545, rs553668, and rs3750625) exhibited no differences in total dexmedetomidine doses (p>0.217), bispectral index at mRSS 4 (p>0.620), and time to obtain mRSS 4 (p>0.349). ConclusionThis study suggested that the genetic polymorphisms of ADRA2A did not affect the sedative efficacy of dexmedetomidine.

Association between Arginine 16 Polymorphism of B2 Adrenergic Receptor and Bronchial Asthma in Children

Background: Asthma is one of the most prevalent health problems. The relationship between β2AR genotypes and response to β2AR agonist therapy is controversial. Some studies have found that the Arg-16 genotype is associated with reduced response to β2AR agonists, whereas others have found that the Gly-16 genotype is associated with reduced response. Objective: to detect gene polymorphism and to determine the association between gene polymorphism and bronchial asthma susceptibility as a risk factor, and to evaluate of the degree of severity of bronchial asthma among cases having a defect in studied gene and those without defect, and also to assess of drug response to β2 agonists concerning gene polymorphism. Methods: This study was carried out at Zagazig university hospitals. 100 Egyptian children with ages ranging from 5 to 12 years were enrolled. They were divided into 2 groups, the asthmatic group included 50 asthmatic children who were diagnosed according to GINA guidelines (2016), and a control group of 50 age and sex-matched healthy children. Results: Arg16Gly heterozygous represents 48%, Arg16 homozygous represents 38% and Gly16 homozygous represents 16% of asthmatic patients, while among the control group Arg16heterozygous represents 38%, homozygous represents 14% and 48% for Gly16 homozygous. There was no significant difference between Arg16Gly genotypes and asthma severity. Also, Arg 16 homozygous showed the best response to treatment with inhaled shortacting beta 2 agonists. Conclusion: there is an association between beta 2 adrenergic receptor polymorphism and the occurrence of bronchial asthma and also between this polymorphism and response to treatment. Also that the polymorphism at codon 16 of the β2 adrenergic receptor gene not a determinant of asthma severity in the Egyptian children.

P339Ser49Gly of beta1-adrenergic receptor is associated with hereditary sick sinus syndrome

Abstract PURPOSE The human beta(1)-adrenergic receptor (ADRB1), an important therapeutic target in cardiovascular diseases, has functional polymorphism on Ser49Gly. Our study aimed to confirm that beta(1)-adrenergic receptor polymorphisms affect hereditary sick sinus syndrome. METHODS Polymerase chain reaction-restriction fragment length polymorphism was used to screen for Ser49Gly. We genotyped polymorphism Ser49Gly of the beta1-AR in 108 patients with hereditary sick sinus syndrome, 59 their healthy relatives and 198 control subjects. Structure of primers was as follows: common 5’-TTGCT-GCCTC-CCGCC-AGCGA-TG-3’, wild 5’-TTGCT-GCCTC-CCGCC-AGCGA-CA-3’, mutant 5’-TCACG-CACAG-CACGT-CCACT-GA-3’. RESULTS Patients with the Ser49Gly genotype shaved associat with hereditary sick sinus syndrome more frequently than in controls and those with Ser49Ser and Gly49Gly (P &amp;lt; 0.01).The patients carrying 49 Gly in the ADRB1 gene was significantly higher odds in SSS than in patients without this allele (p &amp;lt; 0.05). Presence of a Gly49 allele was associated with an increased odds of having hereditary sick sinus syndrome. CONCLUSIONS Our data suggest that patients with the Ser49Gly genotype and Gly49 allele of the beta(1)-adrenergic receptor gene are at increased risk to develop hereditary sick sinus syndrome.

Polymorphism of the Beta-1 Gly389Arg receptor in patients with dual atrioventricular nodal physiology

IntroductionGly389Arg β1 adrenergic receptor polymorphisms seem to exert an influence on the modulation of the adrenergic effect in several types of patients. This study aimed to determine the prevalence of Gly389Arg polymorphisms among patients with evidence of double nodal pathway and to correlate the electrophysiological properties with the different genotypes of the respective polymorphisms. MethodsA cross-sectional, descriptive and analytical study was designed to assess 49 patients, with evidence of double nodal pathway, submitted to electrophysiological study. Genomic DNA was extracted from peripheral blood leukocytes and the genotypes of the Arg389Gly polymorphisms were identified in all individuals by PCR/RFLP (polymerase chain reaction/restriction fragment length polymorphism). ResultsThe majority of patients were female and had supraventricular tachycardia (75.5%). The prevalence of Arg389Arg genotype was found in 32 patients (65.3%), Arg389Gly genotype in 16 patients (32.7%) and Gly389Gly genotype in 1 patient (2%). With respect to the induction of nodal reentrant tachycardia, it was possible to induce non-isoproterenol tachycardia in 32 patients (65.3%), of whom 24 had the Arg389Arg genotype and 8 the Arg389Gly and Gly389Gly genotype (p = 0.05). The resting heart rate of patients of the Arg389Arg genotype was 81 ± 18 bpm and the Arg389Gly and Gly389Gly genotype of 71 ± 9 bpm (p = 0.044). Body mass index (BMI) among patients with genotype Arg389Gly and Gly389Gly was 29.8 ± 7.1 and patients with the Arg389Arg genotype was 26.2 ± 4.6 (p = 0.034). ConclusionThe Arg389Arg genotype was more easily related to triggering arrhythmia, higher resting heart rate and lower BMI.

Estimation of the influence of genetic polymorphisms of opioid, purinergic and adrenergic receptors on opioid therapies

The main aim of this work was to collect and present the polymorphisms that have been identified and tested and that may potentially have an influence on the effect of analgesic therapies. Opioid drugs are one of the most commonly used painkillers in the treatment of postoperative, neoplastic and post-traumatic pain. Opioid receptors and their types: μ, δ, κ, purinergic and adrenergic receptors contribute to nociceptive stimulation and their modulation. The analgesic effect induced by opioids is dependent on many factors, such as age, sex, body mass and the occurrence of different polymorphic variants of genes encoding opioid, purinergic and adrenergic receptors. Many polymorphisms have been identified within the following genes: OPRM, OPRK, OPRD, ADRB1 and P2RX7, encoding the following receptors: μ, κ, δ, purinergic P2X and β1-adrenergic. The most common polymorphism is the single nucleotide polymorphism (SNP-single nucleotide polymorphism). The occurrence of some polymorphic forms may generate differences in expression and have an impact on the physicochemical properties of receptors, which results in different levels of analgesia in the population and the generation of side effects. The relation between the occurrence of polymorphic variants of the genes of receptors participating in nociceptive stimulation and the increased or reduced demand for opioids necessary to achieve analgesia has been confirmed. Mechanisms in which polymorphisms affect the modification of the anesthetic response to opioids in most cases remain unknown. Further research on opioid, purinergic and adrenergic receptors polymorphisms may improve the effectiveness of opioid therapies by regulating the dose to the patient’s individual pain phenotype, and may reduce the risk of side effects resulting from using too high doses of the drug.

Interaction between beta-3 adrenergic receptor genotype and environmental factors on periodontal progression.

The purpose of this longitudinal study was to evaluate the relationship between beta-3 adrenergic receptor polymorphism and environmental factors such as smoking on periodontal disease by considering effect modification. A total of 294 subjects who participated in all follow-up surveys over the 6-year study period were analysed. After dividing subjects into tertiles according to the number of years exposed to smoking, we conducted Poisson regression analysis to compare the incidence rate ratio (IRR) for periodontal disease events during the 6-year study period with beta-3 adrenergic receptor genotype (1: Arg allele carriers, 2: Arg allele non-carriers) for each tertile adjusted for other four variables. The number of years exposed to smoking (mean±standard deviation) for the 1st, 2nd and 3rd tertiles was 0±0, 20.1±9.1 and 45.3±7.7years, respectively. The IRRs±SE were 0.89±0.08 (p=0.218) for the 1st tertile, 1.93±0.36 (p<0.001) for the 2nd tertile and 2.56±0.23 (p<0.001) for the 3rd tertile. There was a clear dose-response relationship between beta-3 adrenergic receptor genotype and periodontal disease progression based on the number of years exposed to smoking.

Role of β-3 adrenergic receptor polymorphism in overactive bladder.

Women with overactive bladder (OAB) have a higher frequency of a single-nucleotide polymorphism (SNP) at codon 64 of the β-3 adrenergic receptor gene (ADRB3). Since the SNP results in an amino acid substitution that could theoretically alter receptor protein function, we hypothesized that those with the SNP would display greater OAB symptom severity. Therefore we aimed to compare OAB severity between women with this SNP and women with the wild type genotype. A retrospective cohort study was performed in women with bothersome OAB from two academic institutions. Banked blood samples were tested for the codon 64 SNP. Women were divided into two groups based on genotype: wild-type (WT) and heterozygous (HZ). We compared mean OAB Symptom Severity questionnaire (OAB-q) scores between groups using t tests. Linear regression was performed to control for potential confounders. Of the 303 women with OAB, 254 (83.8%) had the WT genotype, and 49 (16.2%) the HZ genotype. There were no homozygous women for the rare allele. The majority were Caucasian (86%) and non-Hispanic (97%). There were no significant differences in mean OAB-q symptom severity scores (WT 21.2 ± 7 vs HZ 22.0 ± 6.6; P = 0.49) and quality of life scores (WT 39.6 ± 15.5 vs HZ 39.1 ± 16.6; P = 0.83) between groups. These remained nonsignificant in a linear regression model. In a predominantly non-Hispanic, Caucasian population of women with bothersome OAB, symptom severity was not related to ADRB3 codon 64 SNP genotype.

Dose Response of β-Blockers in Adrenergic Receptor Polymorphism Genotypes.

Background In heart failure (HF) with reduced ejection fraction, 2 clinical trials, the BEST (β-Blocker Evaluation of Survival Trial) and HF-ACTION (Heart Failure: A Controlled Trial Investigating Outcomes of Exercise Training), have reported an effectiveness interaction between the ADRB1 (β-1 adrenergic receptor) Arg389Gly polymorphism and β-blockers (BBs). HF-ACTION additionally reported a dose-related interaction of unclear origin. If confirmed and pharmacogenetically resolved, these findings may have important implications for HF with reduced ejection fraction precision therapy. We used uniform methodology to investigate BB dose-ADRB1 Arg389Gly polymorphism interaction with major clinical end points in BEST/bucindolol and HF-ACTION/other BB databases. Methods This was a retrospective analysis of prospectively designed DNA substudies from BEST (N=1040) and HF-ACTION (N=957). Subjects were genotyped for ADRB1 Arg389Gly and ADRA2C (α2C adrenergic receptor) Ins322-325Del. BB dose was defined as either no/low dose or high dose, according to total daily dose of either bucindolol (BEST subjects) or other BB (HF-ACTION subjects) standardized to carvedilol equivalents. The main outcome of interest was all-cause mortality, and CV mortality/HF hospitalization was a secondary outcome. Results Subjects in each trial had less all-cause mortality with high- versus no/low-dose BB if they had ADRB1 Arg389Arg (BEST: hazard ratio [HR]=0.40, P=0.002; HF-ACTION: HR=0.45, P=0.005) but not Arg389Gly genotype (both P>0.2). Among gene-dose groups, there was a differential favorable treatment effect of 46% for high-dose bucindolol with ADRB1 Arg389Arg versus Gly carrier genotype (HR, 0.54; P=0.018), but not for no/low-dose bucindolol. In contrast, HF-ACTION Arg389Arg genotype subjects taking no/low-dose BB had greater all-cause mortality compared with 389Gly carriers (HR, 1.83; P=0.015), whereas all-cause mortality did not vary by genotype among subjects taking high-dose BB (HR, 0.84; P=0.55). Conclusions The enhanced HF with reduced ejection fraction efficacy of bucindolol in the ADRB1 Arg389Arg versus 389Gly carrier genotypes occurs at high dose. Other BBs taken at low dose have reduced efficacy for Arg389Arg genotype subjects compared with 389Gly carriers, suggesting a greater relative treatment effect at high dose. These data support guideline recommendations to use high, clinical trial target doses of all BBs to treat HF with reduced ejection fraction.

IMPACT OF GLN/GLU27 POLYMORPHISM OF B2 ADRENERGIC RECEPTOR ON BRONCHIAL ASTHMA SUSCEPTIBILITY AND DRUG RESPONSE IN CHILDREN

Background : Bronchial asthma is one of the most prevailed non-communicable diseases among Egyptian children and all over the world. Genetic-environmental interaction can influence the nature of many diseases including asthma and considering β2 agonists as one of the most commonly prescribed bronchodilators for relieving asthma symptoms, so this study was conducted to investigate the possible relationship between Gln27/Glu polymorphism of ADRβ2 from one side and bronchial asthma susceptibility, severity and responsiveness to Albuterol (short-acting ADRβ2 agonist) from the other side. Subjects and methods : A case control study of one hundred Egyptian children was designed. All participants were genotyped using allele-specific Polymerase chain reaction (PCR) to assess single nucleotide polymorphism (SNPs) of ADRβ2. Fifty asthmatics, their mean age was (8.10+2.52), who were selected and classified according to GINA guidelines, 2017 and spirometerically assessed to evaluate pulmonary functions. Another fifty matched healthy participants were selected as a control group with a mean age of (8.44+2.40). Results: Gln allele frequency = 0.59 and Glu allele frequency = 0.41 for cases with Chi- squared X 2 = 0.12 and Gln allele frequency = 0.56 and Glu allele frequency = 0.44 for control participants with X 2 = 0.93 . There were no statistically significant differences between patients and control regarding Gln27/Glu polymorphism. Gln27 was the only genotype having positive association with both asthma severity and drug response, as it represents only 17.2% of all mild cases, 56.3% of all moderate cases and about 80.0% of all sever studied cases; P value (0.003). Conclusion : B2 adrenergic receptor polymorphism at codon 27 is not associated with asthma susceptibility; however it can be a determinant factor for asthma severity and bronchodilating response to B2 agonists in Egyptian asthmatic children, to be confirmed by further Pharmacogenomic studies. Key words: B2 adrenergic receptor, susceptibility, asthma, polymorphism, Phenotype.

Carboxylesterase1, alpha 2a adrenergic receptor and noradrenalin transporter gene polymorphisms and their clinical effects in attention deficit hyperactivity disorder in Turkish children

The objective of this study was to examine the association between ADHD and G1287A polymorphism in the NET1 gene, C1291G polymorphism in the ADRA2A gene on the adrenergic pathway and Gly143Glu polymorphism in the CES1 gene on the metabolic pathway, and their clinical effects.The study population included 114 children with ADHD and 83 healthy controls. 103 patients are followed for 6 months, their scale points are recorded and side effects are questioned in each interview.Every patient in both control and ADHD group are found to have GG genotype when Gly143Glu polymorphism in the CES1 gene is examined, thus we came to a conclusion that Turkish population is homozygote in the mentioned polymorphism. No significant association between NET1 gene G1287A polymorphism genotypes and ADHD was found. It was found that ADRA2A C1291G polymorphism C allele and CC genotype is a risk factor for ADHD (p = 0.003, OR: 2.17, CI: 12.8–37.0) and the risk is higher in males (p = 0.013, OR: 2.43, CI: 12.0–49.5). There was no significant relation between ADRA2A C1291G polymorphism and clinical parameters but it was found that individuals with NET1 G1287A polymorphism AA genotype have less concurrent Oppositional Defiant Disorder diagnosis (18.8% vs. 81.2%, p = 0.039), their initial CTRS-attention deficit points are higher (17.47 ± 3.73 vs.16.15 ± 4.58, p = 0.045).In conclusion, our study showed that the ADRA2A C1291G polymorphism C allele and CC genotype is associated with ADHD. NET1 G1287A polymorphism AA genotype is mainly associated with attention deficit cluster.

Pharmacogenomics of Bucindolol in Atrial Fibrillation and Heart Failure.

We explore the pharmacogenomics of the beta-blocker bucindolol by discussing relevant beta-1 adrenergic receptor (ADRB1) polymorphisms and recent beta-blocker studies. Through this, we will understand how bucindolol may help patients with atrial fibrillation and heart failure with reduced ejection fraction (AF-HFrEF), which carries poor prognosis. Retrospective study of the Heart Failure: A Controlled Trial Investigating Outcomes of Exercise Training trial revealed the interaction between the optimal beta-blocker dose and the ADRB1 Arg389 genotype for HFrEF clinical outcomes. Further, a combinatorial genotype analysis in the Beta-Blocker Evaluation of Survival Trial showed that the Arg389Arg genotype, but not the Gly carrier, was associated with 40% lower mortality risk with bucindolol. Finally, the AF-HFrEF subgroup with the ADRB1 Arg389Arg genotype had greater heart rate reduction and suggestion for mortality benefit. Therapeutic response to beta-blockers varies by beta-blocker mechanism, ADRB1 Arg389 genotype, and clinical setting (AF, HFrEF, AF-HFrEF). The ongoing trial A Genotype-Directed Comparative Effectiveness Trial of Bucindolol and Toprol-XL for Prevention of Symptomatic Atrial Fibrillation/Atrial Flutter in Patients with Heart Failure prospectively identifies AF-HFrEF patients with favorable genotype for bucindolol to prevent AF recurrence.

Polymorphisms in Beta-2 Adrenergic Receptor Gene and Association with Tuberculosis.

Genetic susceptibility for tuberculosis in human has been previously demonstrated. Polymorphisms in genes involved in immune responses may alter the susceptibility of individuals to tuberculosis. Polymorphisms of beta-2 adrenergic receptor (ADRB2) gene can be possibly an important risk factor in tuberculosis. In this study, the association between rs1042713 (Arg16Gly +46A>G) and rs1042714 (Gln27Glu +79C>G) polymorphisms in ADRB2 gene and tuberculosis was evaluated. Genotype distributions of the rs1042713 (Arg16Gly +46A>G) and rs1042714 (Gln27Glu +79C>G) polymorphisms in ADRB2 gene in 106 patients with pulmonary tuberculosis and 88 healthy subjects were studied by PCR-RFLP method in an Iranian population. The frequency of rs1042713*G and rs1042714*G alleles in ADRB2 gene in tuberculosis patients was significantly different from healthy controls [odds ratio (OR)0.176, 95% confidence interval (CI) 0.065-0.48, P value<0.001 and OR0.45, 95% CI 0.247-0.825, P value=0.009, respectively]. There were no significant differences in haplotype analysis between the patients and control subjects. The association was reported between rs1042713 and rs1042714 polymorphisms in ADRB2 gene and tuberculosis for the first time. rs1042713*G and rs1042714*G polymorphisms in ADRB2 gene makes people more susceptible to develop the disease.

Adrenergic Receptor Polymorphism and Maximal Exercise Capacity after Orthotopic Heart Transplantation.

BackgroundMaximal exercise capacity after heart transplantion (HTx) is reduced to the 50–70% level of healthy controls when assessed by cardiopulmonary exercise testing (CPET) despite of normal left ventricular function of the donor heart. This study investigates the role of donor heart β1 and β2- adrenergic receptor (AR) polymorphisms for maximal exercise capacity after orthotopic HTx.MethodsCPET measured peak VO2 as outcome parameter for maximal exercise in HTx recipients ≥9 months and ≤4 years post-transplant (n = 41; mean peak VO2: 57±15% of predicted value). Donor hearts were genotyped for polymorphisms of the β1-AR (Ser49Gly, Arg389Gly) and the β2-AR (Arg16Gly, Gln27Glu). Circumferential shortening of the left ventricle was measured using magnetic resonance based CSPAMM tagging.ResultsPeak VO2 was higher in donor hearts expressing the β1-Ser49Ser alleles when compared with β1-Gly49 carriers (60±15% vs. 47±10% of the predicted value; p = 0.015), and by trend in cardiac allografts with the β1-AR Gly389Gly vs. β1-Arg389 (61±15% vs. 54±14%, p = 0.093). Peak VO2 was highest for the haplotype Ser49Ser-Gly389, and decreased progressively for Ser49Ser-Arg389Arg > 49Gly-389Gly > 49Gly-Arg389Arg (adjusted R2 = 0.56, p = 0.003). Peak VO2 was not different for the tested β2-AR polymorphisms. Independent predictors of peak VO2 (adjusted R2 = 0.55) were β1-AR Ser49Gly SNP (p = 0.005), heart rate increase (p = 0.016), and peak systolic blood pressure (p = 0.031). Left ventricular (LV) motion kinetics as measured by cardiac MRI CSPAMM tagging at rest was not different between carriers and non-carriers of the β1-AR Gly49allele.ConclusionSimilar LV cardiac motion kinetics at rest in donor hearts carrying either β1-AR Gly49 or β1-Ser49Ser variant suggests exercise-induced desensitization and down-regulation of the β1-AR Gly49 variant as relevant pathomechanism for reduced peak VO2 in β1-AR Gly49 carriers.

Association of Beta 2 adrenergic receptor (Thr164Ile) polymorphism with Salbutamol refractoriness in severe asthmatics from Indian population

BackgroundThr164Ile polymorphism in the ADRB2 gene encoding β2 adrenergic receptor (β2AR) has its functional consequence in declining ligand-receptor interactions and depressed coupling of β2AR to adenylcyclase. In the present study, we sought to evaluate the possible association of Thr164Ile polymorphism with asthma susceptibility, pharmacogenetic response to Salbutamol and varying degrees of severity. MethodsThree hundred and ninety eight clinically diagnosed patients and four hundred and fifty six healthy controls were enrolled in the study. Patients were classified into severity classes according to the Global Initiative for Asthma (GINA) guidelines. To assess bronchodilator response, spirometry was performed before and 15min after Salbutamol (200μg) delivery. Responders to Salbutamol were categorized if percentage reversibility was greater than or equal to 12% in them, while those showing reversibility <12% were classified as non-responders. Further, responding phenotypes were stratified into severity groups. Genotyping was carried out by ARMS-PCR technique. Statistical methods were applied to test the significance of the results. ResultsIn the present study, polymorphism was not associated with disease susceptibility however; there was significant association with non-responding asthmatics. In case of severity subsets, the polymorphism was not associated with milder subtypes; although, notable association was observed with moderate and severe asthma subtypes. In addition, the polymorphism was significantly associated with non-responding patients with severe asthma. ConclusionsIn south Indian population, the ADRB2 Thr164Ile polymorphism may not form susceptible variant to develop asthma, however, it can form a predictive maker for bronchodilator (Salbutamol) response in severe asthmatics.

Association between Genetic Polymorphisms of the Beta Adrenergic Receptor and Diurnal Intraocular Pressure in Chinese Volunteers and Glaucoma Patients

ABSTRACTPurpose: To evaluate the relationship between genetic polymorphisms of the beta adrenergic receptor (ADR) and diurnal intraocular pressure (IOP) in Chinese healthy volunteers, normal tension glaucoma (NTG) patients, and primary open-angle glaucoma (POAG) patients.Methods: Fifty healthy volunteers (control group), 55 untreated NTG patients, and 55 untreated POAG patients were recruited. IOP of both eyes was measured at 3-hour intervals from 0600 to 2400 hours. For control group, IOP data from the eye with better mean deviation (MD) of visual field was used for statistical analysis. For glaucoma patients, IOP data from the eye with a greater visual field defect was used for statistical analysis. Genetic polymorphisms of ADR were determined by direct DNA sequencing. The relationship between IOP and genetic polymorphisms was statistically analyzed.Results: R16G (A/G), L84L (G/A), and R175R (C/A) in β2-ADR showed significantly different allele in the three groups (p = 0.005, p = 0.045, and p = 0.045, respectively). For the POAG group, C/C of R389G (C/G) in β1-ADR had a significantly lower diurnal mean IOP (p < 0.001), peak IOP (p = 0.010), trough IOP (p < 0.001), and larger IOP range (p = 0.047) than G carriers; C/C of R389G (C/G) in β1-ADR and G carriers had parallel diurnal IOP curves but significantly different diurnal IOP levels (p = 0.001); C/C of Q27E (C/G) in β2-ADR had a significantly higher diurnal mean IOP (p = 0.045) than G carriers; G/G of L84L (G/A) in β2-ADR had a significantly higher diurnal mean IOP (p = 0.044) than A carriers; C/C of R175R (C/A) in β2-ADR had a significantly higher diurnal mean IOP (p = 0.044) than A carriers; T/T of W64R (T/C) in β3-ADR had a significantly smaller IOP range (p = 0.001) than C carriers.Conclusion: Certain polymorphisms of β2-ADR showed significantly different genotype frequencies in healthy volunteers untreated NTG patients, and POAG patients. Polymorphisms of the β-ADR gene may alter the untreated IOP level of POAG patients.

Association between Beta1 -Adrenergic Receptor Polymorphism and Risk of ICD Shock in Heart Failure Patients.

Sympathetic activation in heart failure patients favors the development of ventricular arrhythmias, thus leading to an increased risk of sudden cardiac death. β1 - and β2 -adrenergic receptor polymorphisms have been linked to the risk of sudden death. Implantable cardioverter-defibrillators (ICD) are implanted in a large percentage of heart failure patients, and beyond preventing sudden cardiac death they provide a continuous monitoring of major ventricular arrhythmias and of their own interventions. We investigated whether functionally relevant β1 - and β2 -adrenergic receptor polymorphisms are associated with risk of ICD shocks, as evidenced in ICD memory. 311 patients with systolic heart failure were enrolled, and number and timing of shocks in ICD memory were recorded. Four selected polymorphisms were determined: β1 -adrenergic receptor polymorphisms Ser(49) Gly and Arg(389) Gly and β2 -adrenergic receptor polymorphisms Arg(16) Gly and Gln(27) Glu. Only Ser(49) Gly was significantly correlated with time free from ICD shocks, both considering time to the first event in a Cox model (hazard ratio 2.117), and modeling repeated events with the Andersen-Gill method (hazard ratio 2.088). Gly allele carriers had a higher probability of ICD shock. The relationship remained significant even after adjusting for ejection fraction and beta-blocker dosage (hazard ratio 1.910). Data from our study suggest that the β adrenoreceptor Gly 49 allele of the β1 -adrenergic receptor Ser(49) Gly polymorphisms may increase the risk of ICD shock in patients with heart failure, independent of beta-blocker dosage.

Impact of the β-1 adrenergic receptor polymorphism on tolerability and efficacy of bisoprolol therapy in Korean heart failure patients: association between β adrenergic receptor polymorphism and bisoprolol therapy in heart failure (ABBA) study.

Background/Aims:We evaluated the association between coding region variants of adrenergic receptor genes and therapeutic effect in patients with congestive heart failure (CHF).Methods:One hundred patients with stable CHF (left ventricular ejection fraction [LVEF] < 45%) were enrolled. Enrolled patients started 1.25 mg bisoprolol treatment once daily, then up-titrated to the maximally tolerable dose, at which they were treated for 1 year.Results:Genotypic analysis was carried out, but the results were blinded to the investigators throughout the study period. At position 389 of the β-1 adrenergic receptor gene (ADRB1), the observed minor Gly allele frequency (Gly389Arg + Gly389Gly) was 0.21, and no deviation from Hardy-Weinberg equilibrium was observed in the genotypic distribution of Arg389Gly (p = 0.75). Heart rate was reduced from 80.8 ± 14.3 to 70.0 ± 15.0 beats per minute (p < 0.0001). There was no significant difference in final heart rate across genotypes. However, the Arg389Arg genotype group required significantly more bisoprolol compared to the Gly389X (Gly389Arg + Gly389Gly) group (5.26 ± 2.62 mg vs. 3.96 ± 2.05 mg, p = 0.022). There were no significant differences in LVEF changes or remodeling between two groups. Also, changes in exercise capacity and brain natriuretic peptide level were not significant. However, interestingly, there was a two-fold higher rate of readmission (21.2% vs. 10.0%, p = 0.162) and one CHF-related death in the Arg389Arg group.Conclusions:The ADRB1 Gly389X genotype showed greater response to bisoprolol than the Arg389Arg genotype, suggesting the potential of individually tailoring β-blocker therapy according to genotype.