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

ABSTRACT: AIMS:Women with overactive bladder (OAB) have a higher frequency of a single-nucleotide polymorphism (SNP) at codon 64 of the ?-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. METHODS: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. RESULTS: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. CONCLUSIONS:In a predominantly non-Hispanic, Caucasian population of women with bothersome OAB, symptom severity was not related to ADRB3 codon 64 SNP genotype.

SUBMITTER: Meekins AR

PROVIDER: S-EPMC7216197 | biostudies-literature | 2019 Jun

REPOSITORIES: biostudies-literature

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Association Between Trp64Arg Polymorphism of Beta-3 Adrenergic Receptor Gene and Susceptibility to Overactive Bladder: A Meta-Analysis

Project description:Objective: Some studies have been carried out to investigate the association between Trp64Arg polymorphism in beta-3 adrenergic receptor gene (ADRB3) and susceptibility to overactive bladder (OAB), but the results remain inconsistent. We carried out a meta-analysis to acquire a more accurate estimation. Methods: All eligible studies were searched in PubMed, Web of Science, Embase, and Cochrane Library. Pooled odds ratios, with 95% confidence intervals, were assessed for the association using fixed and random effects models. Results: The overall results of this meta-analysis demonstrated that there might be an association between Trp64Arg polymorphism and susceptibility to OAB in allele model, dominant model, and heterozygote comparison with a relative risk of 2.00 (95% CI 1.36–2.93), 2.13 (95% CI 1.20–3.76), and 2.07 (95% CI: 1.13–3.79), respectively. However, in the recessive model and homozygote comparison, no significant association between ESR1 Trp64Arg polymorphism and susceptibility to OAB was observed, with a relative risk of 2.47 (95% CI 0.63–9.73) and 3.12 (95% CI: 0.79–12.35), respectively. Based on trail sequential analysis, the results turned out to be true positive in the allele model, false positive in the dominant model and heterozygote comparison, and negative in the recessive model and homozygote comparison, respectively. Conclusion: Our analysis indicated that Trp64Arg polymorphisms in ADRB3 might increase the risk of OAB twice in the allele model, but further well-designed studies with large sample sizes are required to confirm the present findings in other modes and comparisons.

| S-EPMC9315387 | biostudies-literature

beta-2-adrenergic receptor gene polymorphism confers susceptibility to Graves disease.

Project description:Graves disease (GD) is an autoimmune disorder with genetic predisposition. The polymorphisms 47A-->G (Arg16Gly) and 79C-->G (Gln27Glu) of the adrenergic beta-2 receptor (ADRB2) gene in the 5q32 region affect the functional reaction to adrenergic stimulation, which contributes to the regulation of immunological response. The -367T-->C polymorphism within the 5'-leading regulatory sequence affects ADRB2 transcriptional activity. The aim of the present study was to investigate whether ADRB2 gene variants are associated with susceptibility to GD. All polymorphisms were studied in Polish GD patients (n=300) and healthy control subjects without a family history of autoimmune disorders (n=301). Genotypes were determined by the MassARRAY system (Sequenom, San Diego, CA). Gly16 and Gln27 allele frequencies were 61.4% and 55.2% among healthy controls, almost the same as previously reported in 4441 white participants of a cardiovascular health study. We found a higher risk of GD in Gln27 carriers (CC or CG genotypes) than in Glu27 homozygous (GG genotype) participants (OR=1.99, 95% CI: 1.27-3.12, p=0.003, pcorr=0.03). The frequency of the 79GG protective genotype was significantly smaller in the GD patients without symptoms of Graves ophthalmopathy compared to controls (10% vs 22%, OR=0.41, 95% CI: 0.234-0.706, p=0.0017, pcorr=0.015). We didn't find any association of -367T--> or 47A-->G genotypes/alleles with Graves disease, however, haplotype analysis has shown a significant difference in haplotype distribution between patients and controls (the global p=0.001) with increased -367T/47A/79C haplotype frequency in GD patients compared to controls (34% vs 25%, p=0.00073, pcorr=0.0044). In conclusion, Gln27 carriers (79CC or 79GC genotypes) have increased risk of Graves disease. Our results suggest that ADRB2 plays a role in susceptibility to Graves disease in humans.

| S-EPMC2526556 | biostudies-literature

Association between Beta Adrenergic Receptor Polymorphism and Ischemic Stroke: A Meta-Analysis.

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β-1 and β-2 adrenergic receptor polymorphism and association with cardiovascular response to orthostatic screening.

Project description:Variation in the beta-1 and beta-2 adrenergic receptor genes (ADRB1 and ADRB2, respectively) may influence cardiovascular reactivity including orthostatic stress. We tested this hypothesis in a head-up tilt (HUT) screening protocol in healthy young adults without history of syncope. Following brachial arterial catheter insertion, 120 subjects (age 18-40, 72 females, Caucasian) underwent 5min 60° HUT. Polymorphisms tested were: Ser49/Gly and Arg389/Gly in ADRB1; and Arg16/Gly, Gln27/Glu, and Thr164/Ile in ADRB2. Three statistical models (recessive, dominant, additive) were evaluated using general linear models with analysis for each physiologic variable. A recessive model demonstrated a significant association between Arg16/Gly and: absolute supine and upright HR; HUT-induced change in cardiac index (CI), stroke index (SI) and systemic vascular resistance (SVR); and supine and upright norepinephrine values. Blood pressure was not influenced by genotype. Fewer associations were present for other polymorphisms: Ser49/Gly and the change in SI (dominant model), and Arg389/Gly and supine and HUT norepinephrine (additive model). We conclude that in this population, there is a robust association between Arg16/Gly and HUT responses, such that 2 copies of Arg16 increase supine and upright HR, and greater HUT-induced decreases in CI and SI, with greater increases in SVR and norepinephrine. ADRB1 gene variation appears to impact SI and plasma NE levels but not HR. Whether ADRB2 gene variation is ultimately disease-causing or disease-modifying, this study suggests an association between Arg16/Gly and postural hemodynamics, with sympathetic noradrenergic activity affected in a similar direction. This may have implications in the development of orthostatic disorders.

| S-EPMC3167015 | biostudies-literature

A GRK5 polymorphism that inhibits beta-adrenergic receptor signaling is protective in heart failure.

Project description:Beta-adrenergic receptor (betaAR) blockade is a standard therapy for cardiac failure and ischemia. G protein-coupled receptor kinases (GRKs) desensitize betaARs, suggesting that genetic GRK variants might modify outcomes in these syndromes. Re-sequencing of GRK2 and GRK5 revealed a nonsynonymous polymorphism of GRK5, common in African Americans, in which leucine is substituted for glutamine at position 41. GRK5-Leu41 uncoupled isoproterenol-stimulated responses more effectively than did GRK5-Gln41 in transfected cells and transgenic mice, and, like pharmacological betaAR blockade, GRK5-Leu41 protected against experimental catecholamine-induced cardiomyopathy. Human association studies showed a pharmacogenomic interaction between GRK5-Leu41 and beta-blocker treatment, in which the presence of the GRK5-Leu41 polymorphism was associated with decreased mortality in African Americans with heart failure or cardiac ischemia. In 375 prospectively followed African-American subjects with heart failure, GRK5-Leu41 protected against death or cardiac transplantation. Enhanced betaAR desensitization of excessive catecholamine signaling by GRK5-Leu41 provides a 'genetic beta-blockade' that improves survival in African Americans with heart failure, suggesting a reason for conflicting results of beta-blocker clinical trials in this population.

| S-EPMC2596476 | biostudies-literature

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.

Project description:Background/aimsWe evaluated the association between coding region variants of adrenergic receptor genes and therapeutic effect in patients with congestive heart failure (CHF).MethodsOne 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.ResultsGenotypic 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.ConclusionsThe ADRB1 Gly389X genotype showed greater response to bisoprolol than the Arg389Arg genotype, suggesting the potential of individually tailoring β-blocker therapy according to genotype.

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The Association of Trp64Arg Polymorphism in the Beta-Adrenergic Receptor With Insulin Resistance: Meta-Analysis.

Project description:BackgroundInsulin resistance is a metabolic disorder that occurs in type 2 diabetes mellitus and obesity. Genetic factors such as β3-adrenoceptor polymorphism (Trp64Arg) may be involved in IR and insulin secretion. However, their association is controversial. Therefore, the current meta-analysis was conducted to clarify the relationship between the Trp64Arg and IR.MethodsThe literature search was performed in PubMed, Embase, and Web of Science using the keywords "Receptors, Adrenergic, beta-3, Receptors, Adrenergic, Insulin Resistance, Protein-Coupled Receptor Kinase 3" from 2005 to February 7, 2021. We used a random-effects model to calculate the pooled effect size. We conducted subgroup analysis and regression analysis to identify sources of heterogeneity; and Egger's test and funnel plot were used to test publication bias. Finally, we conducted a sensitivity analysis.ResultsWe included eight papers with 1,586 subjects. There was a positive correlation between Trp64Arg mutation and insulin level (standardized mean difference = 0.20, 95% confidence intervals: 0.00 to 0.39, I 2 = 57.6%, p = 0.016). However, there was no association between Trp64Arg and the homeostasis model (HOMA-IR) assessment. Egger's tests showed no publication bias; the sensitivity analysis showed that our results were stable. Regression analysis revealed no source of heterogeneity.ConclusionTrp64Arg may be associated with IR. European ancestry, obesity, plasma insulin level, and test status may be potential factors affecting the relationship between Trp64Arg and IR.

| S-EPMC8426512 | biostudies-literature

Association analysis of the beta-3 adrenergic receptor Trp64Arg (rs4994) polymorphism with urate and gout.

Project description:The Arg64 allele of variant rs4994 (Trp64Arg) in the β3-adrenergic receptor gene has been associated with increased serum urate and risk of gout. Our objective was to investigate the relationship of rs4994 with serum urate and gout in New Zealand European, Māori and Pacific subjects. A total of 1730 clinically ascertained gout cases and 2145 controls were genotyped for rs4994 by Taqman(®). Māori and Pacific subjects were subdivided into Eastern Polynesian (EP) and Western Polynesian (WP) sample sets. Publicly available genotype data from the Atherosclerosis Risk in Communities Study and the Framingham Heart Study were utilized for serum urate association analysis. Multivariate logistic and linear regression adjusted for potential confounders was carried out using R version 2.15.2. No significant association of the minor Arg64 (G) allele of rs4994 with gout was found in the combined Polynesian cohorts (OR = 0.98, P = 0.88), although there was evidence, after adjustment for renal disease, for association in both the WP (OR = 0.53, P = 0.03) and the lower Polynesian ancestry EP sample sets (OR = 1.86, P = 0.05). There was no evidence for association with gout in the European sample set (OR = 1.11, P = 0.57). However, the Arg64 allele was positively associated with urate in the WP data set (β = 0.036, P = 0.004, P Corrected = 0.032). Association of the Arg64 variant with increased urate in the WP sample set was consistent with the previous literature, although the protective effect of this variant with gout in WP was inconsistent. This association provides an etiological link between metabolic syndrome components and urate homeostasis.

| S-EPMC5653370 | biostudies-literature

Urodynamic and Bladder Diary Factors Predict Overactive Bladder-wet in Women: A Comparison With Overactive Bladder-dry.

Project description:PURPOSE:To identify factors predicting the presence of overactive bladder syndrome (OAB)-wet, compared with OAB-dry. METHODS:Between September 2007 and September 2013, the medical records of 623 women with OAB who completed a 3-day bladder diary and underwent urodynamic studies in a medical center were retrospectively reviewed. OAB-wet was diagnosed in patients who complained of at least one episode of urgency incontinence in the previous month; otherwise, OAB-dry was diagnosed. Multivariable logistic regression analysis was used to predict the presence of OAB-wet. RESULTS:Age (odds ratio [OR], 1.05; P<0.001), maximal flow rate (Qmax) (OR,1.06; P<0.001), voided volume (OR, 0.996; P=0.001), detrusor pressure at maximal flow rate (PdetQmax) (OR, 1.02; P=0.003), urgency episodes (OR, 1.04; P<0.001) and urodynamic stress incontinence (OR,1.78; P=0.01) were independent predictors for the presence of OAB-wet vs. OAB-dry. If we use bladder contractility index as a variable for multivariable logistic regression analysis, bladder contractility index (OR, 1.012; P<0.001) become an independent predictor for OAB-wet. CONCLUSION:A smaller bladder capacity and more frequent urgency episodes were predictors of OAB-wet, and the above findings indicate that OAB-wet and OAB-dry might be a continuum of OAB. Old age, high Qmax, high PdetQmax and urodynamic stress incontinence were also predictors for OAB-wet, and the above results reveal that OAB-wet and OAB-dry have partially different clinical and urodynamic features. Further studies might be performed to elucidate whether different treatment strategies between OAB-dry and OAB-wet can improve treatment efficacy.

| S-EPMC6449656 | biostudies-literature

Protocol for a multicenter randomized, double blind, controlled pilot trial of higher neural function in overactive bladder patients after anticholinergic, beta-3 adrenergic agonist, or placebo.

Project description:IntroductionOveractive bladder (OAB) syndrome has a negative impact on quality of life and prevalence increases with advanced age. Anticholinergics (AC) and beta-3 adrenergic agonists (β3a) are commonly prescribed medications for treatment of OAB. AC medication has been associated with dementia in population studies and with cortical atrophy in imaging studies. Higher neural effects of both classes of OAB medications have not been evaluated with functional neuroimaging. Longitudinal clinical assessments of cognition after OAB therapy with AC has produced conflicting results. β3a medication is has not been associated with dementia in clinical studies; however, higher neural effects are unknown.Our multicenter, double blind, randomized, placebo-controlled trial uses functional magnetic resonance imaging (fMRI) and cognitive testing to evaluate the effects of AC and β3a on brain functional connectivity in females with non-neurogenic OAB.Methods and analysisand analysis: Female patients with OAB symptoms ages 50-90 years old without baseline cognitive impairment, moderate to severe depression or anxiety, neurologic disorders, or significant incomplete bladder emptying are invited to participate. Subjects are randomized to one of three interventions for 29 ± 1 day: AC (Solifenacin succinate, Teva), β3a (Mirabegron, Myrbetriq, Astellas), or placebo. Functional neuroimaging data at baseline and post-intervention will be analyzed accordingly. Clinical cognitive assessments will be compared from baseline to post-intervention.EthicsAll qualifying patients are properly consented before enrolling in this study that has been approved by the Institutional Review Board of participating institutions.

| S-EPMC7381509 | biostudies-literature

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