β2-AR Gene Research Articles

Association of T190C polymorphism of β3 adrenergic receptor gene with response to carvedilol in patients with chronic heart failure

To assess the association of T190C polymorphism of β3 adrenergic receptor gene (β3-AR) with chronic heart failure (CHF), and to evaluate the effect of this polymorphism on clinical response to β-AR blockade among patients with CHF. Three hundred and thirty patients with stable CHF receiving basic therapy for heart failure were included. Before initiation and 5 months after the maximal tolerated dose of carvedilol was reached, all indices including heart rate (HR), blood pressure (BP), left atrial diameter (LAD), left ventricular end-diastolic diameter (LVEDD), left ventricular end-systolic diameter (LVESD), left ventricular ejection fraction (LVEF), brain natriuretic peptide (BNP) level, 6 min walk distance were measured and compared with the indices of those with a T190C genotype. Distribution of the T190C polymorphisms in the control group and CHF group was compared. The frequencies of T190C genotypes of the β3-AR gene have fit with the Hardy-Weinberg equilibrium. No significant difference was found between the frequencies of T190C alleles and genotypes between the two groups (P > 0.05). Compared with CC-homozygotes, TT-homozygous patients showed substantially greater improvement in LVEF and BNP (all P < 0.01). No difference has been detected in the prevalence of the three genotypes between healthy and CHF subjects. The T190C variation of the β3-AR gene was not associated with increased risk for CHF. CHF patients with a T allele have greater response to carvedilol than those carrying a C allele in ethnic Han Chinese.

Association between polymorphism of β3-adrenoceptor gene and overactive bladder: a meta-analysis.

Genetic variations in the human β3-adrenoceptor (β3-AR) gene are known to be involved in insufficient relaxation of the bladder muscle during urine storage. The Trp64Arg polymorphism in the β3-AR gene has been found to be an important regulator of the development of overactive bladder (OAB). However, the association between this polymorphism and OAB remains controversial. Therefore, we conducted a meta-analysis to explore the association between the Trp64Arg polymorphism and OAB risk. We examined 2 case-control studies, including a total of 149 OAB cases and 270 healthy controls. The meta-analysis results showed that the Arg allele of the β3-AR gene is positively associated with OAB susceptibility, while Arg allele carriers (Trp64Arg + Arg64Arg) showed positive associations with OAB. These results also demonstrated that the Trp64Arg polymorphism in the β3-AR gene is involved in the pathogenesis of OAB.

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

Background and PurposeThe purpose of this meta-analysis was to determine the precise association between beta-2 adrenergic receptor (β2AR) polymorphism and Ischemic stroke.MethodsPublished case control studies on association between β2AR and ischemic stroke were searched from electronic databases. Pooled Odds ratio and 95% Confidence interval were calculated by using software RevMan version 5.2.ResultsA total of three studies involving 1,642 cases and 1,673 controls, which were published from 2007 to 2014, were subjected to meta-analysis for allelic association and 518 cases and 510 controls for genotypic association. Pooled analysis of two studies for genotypic association suggested that subjects carrying Gln27Glu polymorphism of β2AR had an increased risk for Ischemic stroke under recessive model (OR 2.09; 95% CI; 1.20 to 3.64) and under dominant model (OR 1.47; 95% CI 1.14 to 1.90). Pooled analysis of three studies for allelic association showed a significantly higher Glu27 allele of β2AR in the patients with ischemic stroke (OR 1.58; 95% CI; 1.38 to 1.81).ConclusionsThe present meta-analysis suggests that Gln27Glu polymorphism of β2AR gene is associated with increased risk for ischemic stroke.

The Impact of β 2 Adrenergic Receptor Polymorphisms on the Outcomes in Cardiovascular Diseases

Cardiovascular diseases (CVD) include a heterogeneous group of multifactorial conditions and represent the major health problem in the western society. Many studies have evidenced that inter-individual variability affects the prognosis and the response to pharmacological treatment in patients with CVD. The identification of genetic markers to select patients more susceptible to develop cardiovascular complications has a therapeutic interest for undertaking individualized therapeutic approach. The sympathetic nervous system acts through adrenergic receptor subtypes and plays a key role in the development and prognosis of CVD. In particular, β-2 adrenergic receptors (β2AR), expressed in a wide variety of tissues, are critical regulators of cardiac output, peripheral vascular resistance and metabolism. Several variations with multiple single-nucleotide polymorphisms have been identified in β2AR gene. There are 3 common β2AR polymorphisms characterized in more detail for their influence on functional receptor activity. In particular, the changing an arginine for a glycine at position 16 of the receptor protein (Arg16Gly) is associated with increased agonist-induced down-regulation; the substitution of glutamine with glutamic acid at position 27 (Gln27Glu) leads to resistance to down-regulation; the substitution of threonine with isoleucine (Thr164Ile) at position 164 causes receptor uncoupling from the G protein. Many studies have indicated the association of β2AR polymorphisms with various cardiovascular and metabolic diseases and have contributed to indicate the β2AR gene variants an appropriate target for investigating possible links between receptor polymorphisms, drug responses and susceptibility to CVD. However, the reports on the association of β2AR polymorphisms with clinical outcomes of CVD have been contradictory. In this review, we will illustrate the effects of β2ARs genetic variability on the management of CVD.

Abstract 13230: Attenuation of Clock-bmal1 Transcriptionally Decreases the Expression of β1-ar to Anticipate the Occurrence of Ventricular Arrhythmia After Chronic Heart Failure

Circadian rhythms influence the incidence of sudden cardiac death after chronic heart failure (CHF) but the underlying mechanisms are not well defined. We sought to investigate the role of the β-adrenergic receptor (β-AR) in cardiac circadian disorders and ventricular arrhythmia(VA) after CHF. CHF guinea pigs was created by transverse aorta constriction. Circadian variations of the myocardial expressions ofβ1-AR, β2-AR and circadian genes CLOCK and BMAL1 were examined by real time reverse transcription polymerase chain reaction, Western blot and immunohistochemistry. Sham operated animals showed circadian oscillations in the expression ofβ1-AR and CLOCK-BMAL1(P&lt;0.05). However, the expression ofβ1-AR and CLOCK-BMAL1 were attenuated in guinea pigs with CHF(P&lt;0.05). Then, electrocardiograms of Langendorff-perfused hearts with isoprenaline(β-AR nonselective agonist ,ISO), ISO + CGP-20712A(β1-AR selective antagonist, CGP) and ISO + ICI118551(β2-AR selective antagonist, ICI) at CT3 and CT15 were recorded and ventricular arrhythmias were induced by programmed electrical stimulation (PES). During ISO and ISO + ICI infusion, the diurnal variation in response of β-AR activation translated to a greater incidence of VA in CT15(P&lt;0.05). Next, infections of Ad-CLOCK and/or Ad-BMAL1 were applied to overexpress CLOCK, BMAL1 and CLOCK-BMAL1 in the guinea pig ventricular cardiomyocytes. Ad-CLOCK and Ad-BMAL1 co-infection resulted in overexpression of β1-AR and a greater incidence of arrhythmic activity in myocytes. At last, chromatin immunoprecipitation assay(ChIP) and luciferase(LUC) were applied to determine whether CLOCK-BMAL1 transcriptionally regulateβ1-AR expression. ChIP-qPCR analysis and luciferase revealed that BMAL1 could bind to enhancer of β1-AR to regulate arrhythmia severity after CHF(P&lt;0.05). We conclude that circadian rhythms of myocardial β1-AR and CLOCK-BMAL1 activities are disturbed after CHF. Attenuation of CLOCK-BMAL1 transcriptionally decreases the expression of β1-AR to anticipate the occurrence of ventricular arrhythmias after CHF.

GW25-e0796 Attenuation of CLOCK-BMAL1 transcriptionally decreases the expression of β1-AR to anticipate the occurrence of ventricular arrhythmia after chronic heart failure

Circadian rhythms influence the incidence of sudden cardiac death after chronic heart failure (CHF) but the underlying mechanisms are not well defined. We sought to investigate the role of the β-adrenergic receptor (β-AR) in cardiac circadian disorders and ventricular arrhythmia(VA) after CHF. CHF guinea pigs was created by transverse aorta constriction. Circadian variations of the myocardial expressions ofβ1-AR, β2-AR and circadian genes CLOCK and BMAL1 were examined by real time reverse transcription polymerase chain reaction, Western blot and immunohistochemistry. Sham operated animals showed circadian oscillations in the expression ofβ1-AR and CLOCK-BMAL1(P<0.05). However, the expression ofβ1-AR and CLOCK-BMAL1 were attenuated in guinea pigs with CHF(P<0.05). Then, electrocardiograms of Langendorff-perfused hearts with isoprenaline(β-AR nonselective agonist ,ISO), ISO + CGP-20712A(β1-AR selective antagonist, CGP) and ISO + ICI118551(β2-AR selective antagonist, ICI) at CT3 and CT15 were recorded and ventricular arrhythmias were induced by programmed electrical stimulation (PES). During ISO and ISO + ICI infusion, the diurnal variation in response of β-AR activation translated to a greater incidence of VA in CT15(P<0.05). Next, infections of Ad-CLOCK and/or Ad-BMAL1 were applied to overexpress CLOCK, BMAL1 and CLOCK-BMAL1 in the guinea pig ventricular cardiomyocytes. Ad-CLOCK and Ad-BMAL1 co-infection resulted in overexpression of β1-AR and a greater incidence of arrhythmic activity in myocytes. At last, chromatin immunoprecipitation assay(ChIP) and luciferase(LUC) were applied to determine whether CLOCK-BMAL1 transcriptionally regulateβ1-AR expression. ChIP-qPCR analysis and luciferase revealed that BMAL1 could bind to enhancer of β1-AR to regulate arrhythmia severity after CHF(P<0.05). We conclude that circadian rhythms of myocardial β1-AR and CLOCK-BMAL1 activities are disturbed after CHF. Attenuation of CLOCK-BMAL1 transcriptionally decreases the expression of β1-AR to anticipate the occurrence of ventricular arrhythmias after CHF.

P343Effect of T3 on human induced pluripotent stem cell-derived cardiomyocyte maturation

Purpose: Human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CM) hold great potential for regenerative medicine and in vitro screening. However, the phenotype is immature and more closely resembles foetal/neonatal cardiomyocytes. The aim of this study is to drive hiPSC-CM to a more mature state using thyroid hormone, triiodothyronine (T3), which has a role in cardiomyocyte maturation during development. Methods: hiPSC-CM (Cellular Dynamics) were treated with 30nM T3 for up to 4 weeks. Expression of β1 adrenergic receptor (β1AR) was assessed by qPCR (Taqman). Beating rates were determined using a Nikon Eclipse TE2000E microscope with Digital sight camera and NIS Elements3.2 software video tracking. Ca2+ dynamics were studied using Fluo-4AM loaded cells imaged with a Nikon Eclipse T6200 and Redshirt NeuroCMOS camera at 0.5KHz with 1Hz, 15V, 5ms field stimulation. Comparative proteomic analysis (4 week T3) was performed by mass spectrometry using isobaric tags. Data expressed as mean ±SEM; statistical significance determined by student's t-test (n=3). Results: 4 week T3 treatment resulted in a 1.5-fold increase in basal beating rate. T3 increased β1AR gene expression and remained stable for up to 2 weeks (p<0.05). CGP 20712A (10μM), a β1AR inverse agonist, decreased the beating rate of T3-treated cells (39.3±9.7bpm) to basal levels in untreated cells (25.7±9bpm). Ca2+ transient analysis revealed alterations in Ca2+ handling. 4 week T3 treatment resulted in decreased time to transient peak from 244±4.0 ms to 90.7±15 (p<0.0006). Time to 50% decay also decreased from 309.2±6.6ms to 287.3±2.3ms (p<0.05) and transient duration (start to 75% decay) decreased from 695.4±6.4ms to 537.9±21.3ms (p<0.002). Proteomic analysis revealed increases in proteins involved in regulating sarcoplasmic reticulum (SR) function including; phospholamban (17.2%), SERCA (27.6%) and calsequestrin2 (303.8%). In addition increases in mitochondrial enzymes, including ATP5B (32.7%), and α/βMHC ratio were detected along with decreases in slow skeletal troponin I (-43.7%) and C (-36.2%) isoforms. Conclusions: T3 treatment induced alterations in expression of proteins involved in SR function, mitochondrial metabolism and cytoskeletal composition. In addition, T3 treatment improved Ca2+ handling and increased β1AR function, with increases in beating rate possibly driven by constitutive β1AR activity. Collectively these data provide evidence for a shift towards a more mature phenotype and indicate that this may be an effective strategy to drive maturation of hiPSC-CM.

Genetic suppression of β2-adrenergic receptors ameliorates tau pathology in a mouse model of tauopathies

Accumulation of the microtubule-binding protein tau is a key event in several neurodegenerative disorders referred to as tauopathies, which include Alzheimer's disease, frontotemporal lobar degeneration, Pick's disease, progressive supranuclear palsy and corticobasal degeneration. Thus, understanding the molecular pathways leading to tau accumulation will have a major impact across multiple neurodegenerative disorders. To elucidate the pathways involved in tau pathology, we removed the gene encoding the beta-2 adrenergic receptors (β2ARs) from a mouse model overexpressing mutant human tau. Notably, the number of β2ARs is increased in brains of AD patients and epidemiological studies show that the use of beta-blockers decreases the incidence of AD. The mechanisms underlying these observations, however, are not clear. We show that the tau transgenic mice lacking the β2AR gene had a reduced mortality rate compared with the parental tau transgenic mice. Removing the gene encoding the β2ARs from the tau transgenic mice also significantly improved motor deficits. Neuropathologically, the improvement in lifespan and motor function was associated with a reduction in brain tau immunoreactivity and phosphorylation. Mechanistically, we provide compelling evidence that the β2AR-mediated changes in tau were linked to a reduction in the activity of GSK3β and CDK5, two of the major tau kinases. These studies provide a mechanistic link between β2ARs and tau and suggest the molecular basis linking the use of beta-blockers to a reduced incidence of AD. Furthermore, these data suggest that a detailed pharmacological modulation of β2ARs could be exploited to develop better therapeutic strategies for AD and other tauopathies.

Heart ventricles specific stress-induced changes in β-adrenoceptors and muscarinic receptors.

The left and right ventricles fulfill different role in heart function. Here we compare chamber specific changes in local catecholamine concentrations; gene expression and the receptor protein amount of all three β-adrenoceptors (β-AR) in rat right heart ventricles exposed to acute (1 session) and repeated (7 sessions) immobilization stress (IMMO) vs. previously observed changes in left ventricles. Density of muscarinic receptors as main cardio-inhibitive receptors was also measured. In the right ventricles, noradrenaline and adrenaline were increased. No β1-AR changes were observed, in spite of the increased sympathetic activity. On the other hand, we have found a decrease of β2-AR gene expression (reduction to 30%) after 7 IMMO and protein (to 59%) after 1 IMMO. β3-AR gene expression was increased after 7 IMMO. Muscarinic receptor density was not changed. When comparing correlation in left and right ventricles, there was strong correlation between adrenaline and β2-AR gene expression, protein and β3-AR gene expression in the left ventricles while only correlation between adrenaline and β2-AR mRNA and protein in the right ventricles was found. Our results show that maintenance of cardiac homeostasis under stress conditions are to a great extent achieved by a balance between different receptors and also by a balanced receptor changes in left vs. right ventricles. Taken together, decrease of cardio-stimulating β2-AR represents a new important mechanism by which β2-AR contributes to the heart physiology.

The β2-adrenoreceptor gene promoter polymorphisms may modulate β2-agonist- and glucocorticoid-induced IgE synthesis

Backgroundβ2-adrenoreceptor (β2-AR) agonists and glucocorticoids (GCS) were shown to induce IgE synthesis in human PBMCs. Serum total IgE levels are associated with single nucleotide polymorphisms (SNPs) of the β2-AR gene. We aimed to assess the association of the effect of fenoterol (β2-AR agonist) on IL-4-driven and budesonide-induced IgE synthesis with genetic variants of β2-AR. MethodsThe study included 25 individuals: 13 with allergic asthma and/or allergic rhinitis and 12 healthy volunteers. PBMCs were cultured with IL-4, fenoterol and/or budesonide, and IgE concentrations in supernatants were assessed. Five SNPs in positions: −47, −20, 46, 79 and 252 of β2-AR were determined by direct DNA sequencing. ResultsIn −47 T/T and −20 T/T patients, incubation with fenoterol resulted in decreased IgE production, whereas in −47 C/T and −47 C/C as well as in −20 C/T and −20 C/C individuals, it was enhanced. In contrast to fenoterol, budesonide-induced IgE synthesis was significantly increased in −47 T/T and −20 T/T patients as compared to −47 C/T, −47 C/C, −20 C/T and −47 C/C individuals. Polymorphisms in positions 46, 79 and 252 were not associated with fenoterol- or budesonide-modulated IgE synthesis. No differences in the distribution of IgE synthesis was seen between atopic and non-atopic individuals carrying the same alleles. ConclusionsThe differential effect of β2-agonists and GCS on IgE synthesis may be associated with genetic variants of promoter region of the β2-AR gene.

No association of G‐protein‐coupled receptor kinase 5 or β‐adrenergic receptor polymorphisms with Takotsubo cardiomyopathy in a large Australian cohort

Takotsubo cardiomyopathy (TC) is an increasingly recognized syndrome in which patients present with chest pain and ST changes, and are observed to have reversible LV apical ballooning in the absence of angiographically significant coronary artery stenosis. Although the pathophysiology remains unclear, the syndrome occurs almost exclusively in women, and is often triggered by stress. Recent small studies have reported association of TC with functional variants in the G-protein-coupled receptor kinase 5 (GRK5) gene, as well as in the β1-adrenergic receptor (β1AR) and β2AR. We tested these associations in a larger cohort of 92 TC patients. In addition we examined for the association of polymorphisms in the oestrogen receptor α (ERα) and catechol-O-methyl transferase (COMT) with the occurrence of TC, by comparing the allele frequency of these variants in the TC cohort with that in previously genotyped large Caucasian cohorts. Ninety-two patients with TC were recruited from four Australian centres; they had an age range of 41-90 years (mean ± SD = 66.3 ± 9) and 89/92 were female. There were no significant differences in allelic frequency in the TC group vs. the historic control database for any of the loci. In the largest genotyped TC cohort in the literature, we have found no association of genetic variants in the ERα, β1AR, β2AR, or COMT genes, or with the previously implicated GRK5, with occurrence of the syndrome.

Association of polymorphism of β3-adrenergic receptor gene and the leptin gene with Kazak obese children in Xinjiang

Objective To investigate the association between C2549A polymorphism of leptin gene and the Trp64Arg polymorphism of the β3-adrenergic receptor gene(β3-AR gene) and obesity in Kazak school-age children. Methods Totally 92 obese children and 71 healthy controls were selected from 6 to 12 years old in Kazak school-age children from the area around Urumqi.Genotype of the C2549A polymorphism of leptin gene and the Trp64Arg polymorphism of β3-AR gene were determined by polymerase chain reaction and restriction fragment length polymorphism met-hods. Results 1.The difference in distribution of the β3-AR gene Trp64Arg genotype of obesity and healthy controls of Kazak children was statistically significant(χ2=10.472, P 0.05).2.The differences in distribution of the leptin C2549A genotype and alleles of the 2 groups were all statistically significant, and the odds ratio of the alleles(0.608) and 95%CI 0.380-0.972 suggested that the mutation occurrence of obesity might have certain protective effect.3.The difference in distribution of the genotype of β3-AR gene Trp64Arg polymorphism and leptin gene promoter area C2549A polymorphism in the same individual joint action of 2 groups was statistically significant(χ2=15.978, P 0.05). Conclusions 1.There were distributions of the Trp64Arg polymorphism of β3-AR gene and the C2549A polymorphism of leptin gene in Kazak school-aged children in Xinjiang.2.These results suggested that C2549A mutation of leptin gene might have certain protective effect in Kazak children obesity, and the Trp64Arg polymorphism of β3-AR gene might be associated with Kazak children obesity.3.These results suggested that the Trp64Arg polymorphism of β3-AR gene and the C2549A polymorphism of leptin gene in the same individual joint action might be associated with Kazak children obesity in Xinjiang. Key words: Leptin gene; β3-adrenergic receptor gene; Gene polymorphism; Obesity; Kazak children

Anti-hypertrophic and anti-oxidant effect of beta3-adrenergic stimulation in myocytes requires differential neuronal NOS phosphorylation

RationaleStimulation of β3-adrenoreceptors (β3-AR) blunts contractility and improves chronic left ventricular function in hypertrophied and failing hearts in a neuronal nitric oxide synthase (nNOS) dependent manner. nNOS can be regulated by post-translational modification of stimulatory phosphorylation residue Ser1412 and inhibitory residue Ser847. However, the role of phosphorylation of these residues in cardiomyocytes and β3-AR protective signaling has yet to be explored. ObjectiveWe tested the hypothesis that β3-AR regulation of myocyte stress requires changes in nNOS activation mediated by differential nNOS phosphorylation. Methods and resultsEndothelin (ET-1) or norepinephrine induced hypertrophy in rat neonatal ventricular cardiomyocytes (NRVMs) was accompanied by increased β3-AR gene expression. Co-administration of the β3-AR agonist BRL-37433 (BRL) reduced cell size and reactive oxygen species (ROS) generation, while augmenting NOS activity. BRL-dependent augmentation of NOS activity and ROS suppression due to NE were blocked by inhibiting nNOS (L-VNIO). BRL augmented nNOS phosphorylation at Ser1412 and dephosphorylation at Ser847. Cells expressing constitutively dephosphorylated Ser1412A or phosphorylated Ser847D nNOS mutants displayed reduced nNOS activity and a lack of BRL modulation. BRL also failed to depress ROS from NE in cells with nNOS-Ser847D. Inhibiting Akt decreased BRL-induced nNOS-Ser1412 phosphorylation and NOS activation, whereas Gi/o blockade blocked BRL-regulation of both post-translational modifications, preventing enhancement of NOS activity and ROS reduction. BRL resulted in near complete dephosphorylation of Ser847 and a moderate rise in Ser1412 phosphorylation in mouse myocardium exposed to chronic pressure-overload. Conclusionβ3-AR regulates myocardial NOS activity and ROS via activation of nNOS involving reciprocal changes in phosphorylation at two regulatory sites. These data identify a novel and potent anti-oxidant and anti-hypertrophic pathway due to nNOS post-translational modification that is coupled to β3-AR receptor stimulation.

β2 Adrenergic Receptor, Protein Kinase A (PKA) and c-Jun N-terminal Kinase (JNK) Signaling Pathways Mediate Tau Pathology in Alzheimer Disease Models

Alzheimer disease (AD) is characterized by neurodegeneration marked by loss of synapses and spines associated with hyperphosphorylation of tau protein. Accumulating amyloid β peptide (Aβ) in brain is linked to neurofibrillary tangles composed of hyperphosphorylated tau in AD. Here, we identify β2-adrenergic receptor (β2AR) that mediates Aβ-induced tau pathology. In the prefrontal cortex (PFC) of 1-year-old transgenic mice with human familial mutant genes of presenilin 1 and amyloid precursor protein (PS1/APP), the phosphorylation of tau at Ser-214 Ser-262 and Thr-181, and the protein kinases including JNK, GSK3α/β, and Ca(2+)/calmodulin-dependent protein kinase II is increased significantly. Deletion of the β2AR gene in PS1/APP mice greatly decreases the phosphorylation of these proteins. Further analysis reveals that in primary PFC neurons, Aβ signals through a β2AR-PKA-JNK pathway, which is responsible for most of the phosphorylation of tau at Ser-214 and Ser-262 and a significant portion of phosphorylation at Thr-181. Aβ also induces a β2AR-dependent arrestin-ERK1/2 activity that does not participate in phosphorylation of tau. However, inhibition of the activity of MEK, an upstream enzyme of ERK1/2, partially blocks Aβ-induced tau phosphorylation at Thr-181. The density of dendritic spines and synapses is decreased in the deep layer of the PFC of 1-year-old PS1/APP mice, and the mice exhibit impairment of learning and memory in a novel object recognition paradigm. Deletion of the β2AR gene ameliorates pathological effects in these senile PS1/APP mice. The study indicates that β2AR may represent a potential therapeutic target for preventing the development of AD.

The study of single nucleotide polymorphisms of β2-adrenergic receptor in pancreatic carcinoma

Objective To investigate the single nucleotide polymorphisms (SNPs) at codons 16 and 27 of β2-AR gene in pancreatic carcinoma and non-neoplastic pancreatic tissues,and the correlations between these SNPs and the expression of β2-AR protein in pancreatic carcinoma.Methods A total of 64 cases of pancreatic carcinoma (PC) and 20 non-neoplastic pancreatic tissues (NPC) were genotyped at codons 16 and 27 by PCR-restriction fragment length polymorphism (PCR-RFLP) and DNA sequencing.The correlations between the distribution of genotypes and clinicopathological characteristics of pancreatic carcinoma were analyzed.The expression of β2-AR protein was detected by immunohistochemistry in pancreatic carcinoma.Results The distributions of genotype frequency at codons 16 and 27 in PC and NPC were in accordance with the Hardy-Weinbery equeilibrium.The frequencies of their genotypes (AA,AG and GG) and frequencies of alleles A and G at codon 16 between PC and NPC showed no difference.The genotype frequencies were associated with TNM grade,lymph node metastasis,one-year survival rate (P=0.03,0.05,0.04),but they were not associated with patients' gender,age,histological differentiation and size of tumor.The allele G at codon 16 was frequently appeared in tumors with high TNM grade,lymph node metastasis,low one-year survival rate (P＝ 0.01,0.03,0.02),and high expressions of β2-AR protein (P =0.02).The frequencies of two genotypes (CC and CG) and frequencies of alleles C and G at codon 27 showed no difference between PC and NPC.The genotype frequencies and allele frequencies of codon 27 were not associated with patients' clinicopathological features,and expressions of β2-AR protein.Conclusions SNPs of β2-AR gene were associated with biological behaviors of pancreatic carcinoma.Allele G at codon 16 was associated with high risks of lymph node metastasis,high TNM grade,low one-year survival rate,and high expressions of β2-AR protein.Allele G at codon 16 might facilitate the progression and metastasis of pancreatic carcinoma through elevating the expression of β2-AR.SNPs at codon 16 of β2-AR are new useful biomarkers for predicting biological behaviors and survival of pancreatic carcinoma and might be used as a new gene therapeutic target. Key words: Pancreatic neoplasms; Receptors,adrenergic,beta-2 ; Polymorphism,single nucleotide

Trp64Arg (rs4994) polymorphism of β3-adrenergic receptor gene is associated with hyperuricemia in a Chinese male population

β3-Adrenergic receptor (β3-AR) gene is associated with insulin resistance and may affect serum uric acid levels. Our aim was to determine the possible association between β3-AR gene Trp64Arg polymorphism (rs4994) and hyperuricemia in a Chinese male population. A total of 410 hyperuricemic and 420 normouricemic male subjects were genotyped in this study. The genotypic and allelic frequencies were compared between the two groups. Body mass index (BMI), waist to hip ratio (WHR), systolic blood pressure (SBP), diastolic blood pressure (DBP), serum uric acid, urea nitrogen, creatinine, triglyceride, total cholesterol, low-density lipoprotein-cholesterol (LDL-C), high-density lipoprotein-cholesterol (HDL-C) and fasting plasma glucose (FPG) were determined. The frequencies of CC genotype and C allele for Trp64Arg polymorphism were higher in hyperuricemic group than in normouricemic group (p<0.01 and p<0.05, respectively). In both hyperuricemic and normouricemic groups, subjects with mutated C allele of Trp64Arg polymorphism showed significantly higher average uric acid levels than TT genotype carriers (p<0.01 and p<0.01, respectively). Univariate and multivariate logistic regression showed that carrier of mutated C allele of Trp64Arg polymorphism was significantly associated with hyperuricemia occurrence (p=0.003, OR=1.587, 95% CI 1.175-2.145 and p=0.003, OR=1.676, 95% CI 1.051-3.617). Trp64Arg polymorphism was associated with hyperuricemia in a Chinese male population and should be an independent risk factor for hyperuricemia.

The Arg16Gly Polymorphism in the B2-Adrenergic Receptor Gene is Associated with Bronchial Hyperresponsiveness and Allergic Rhinitis in the Bulgarian Population

ABSTRACTBronchial Hyperresponsiveness (BHR) is a risk factor for asthma but it can be observed in allergic rhinitis (AR) and healthy subjects, too. The mechanisms of genetic susceptibility to BHR are unknown. In general, it is thought to result from both genetic and environmental factors. Some studies have demonstrated that nonspecific airway hyperresponsiveness is associated with a specific β2-adrenergic receptor (β2-AR) genotype in asymptomatic healthy subjects. The present study was performed to determine the impact of single nucleotide polymorphism (SNP) on allergic rhinitis patients with evidence for bronchial hyperresponsiveness. One hundred allergic rhinitis patients analyzed for BHR and forty healthy controls were genotyped for polymorphism of the β2-AR gene. Nonspecific airway hyperesponsiveness was measured using the methacholine bronchoprovocation (BPT) test. Polymerase chain reaction (PCR) was used to identify (Arg16/Gly) polymorphism at codon 16 in the β2-AR gene. It was observed that allergic rhinitis patients who are homozygous for the Gly16 allele are more responsive to methacholine than patients who carry the Arg16 allele.

Pharmacogenetics of β1-Adrenergic Receptor Blockers in Heart Failure Therapy: A Systematic Review

Background: β1-adrenergic receptor blockers are an important drugs recommended as first-line treatment of Heart Failure (HF) as they improve survival in left ventricular systolic dysfunction due to chronic β1-Adrenergic Receptor (β1-AR) activation. However, responses to these drugs are variable among patients due to genetic polymorphism in β1-AR gene. We conducted a systematic review to summarize all published case-control and prospective studies on pharmacogenetics of β1-adrenergic receptor blockers (β1-ARBs) used for the management of HF. Methods and findings: We performed a systematic search of the literature using Medline (source PubMed, January 1, 1980 to November 30, 2011) with restrictions for English language and polymerase chain reaction assay method of genotyping the receptor polymorphism. Both experimental and observational studies investigating the pharmacogenetics effect of β1-adrenergic receptor blockers in heart failure were included. The main outcome measure was improvement of HF symptoms which is reflected in a decrease in mortality, hospitalisation and the rate of major clinical events. Of the 30 included studies, 17 articles reporting on effect of genetic polymorphisms of β1-AR on heart failure, 11 articles reporting on pharmacogenetics of β1-ARBs in HF, and 2 articles reporting on both β1-AR gene polymorphisms and pharmacogenetics of β1-ARBs, were included into the results. Conclusions: The findings of the current study have shown that β1-AR polymorphisms have an effect on survival and improvement in left ventricular ejection fraction in HF patients who were Arg389 homozygotes carriers treated with metoprolol and bucindolol. Therefore, the Arg389 of β1-AR variation alters the β1-ARBs therapeutic response, and might be used to individualize treatment of HF.

Impact of UCP1 and β3AR gene polymorphisms on age-related changes in brown adipose tissue and adiposity in humans

Brown adipose tissue (BAT) is involved in the regulation of whole-body energy expenditure and adiposity. The activity and prevalence of BAT decrease with age in humans. To examine the effects of single nucleotide polymorphisms of the genes for uncoupling protein 1 (UCP1) and β3-adrenergic receptor (β3AR), key molecules of BAT thermogenesis, on age-related decline of BAT activity and accumulation of body fat in humans. One hundred ninety-nine healthy volunteers (20-72 years old (y.o.)) underwent fluorodeoxyglucose-positron emission tomography (FDG-PET) and computed tomography (CT) after 2-h cold exposure to assess BAT activity. The visceral and subcutaneous fat areas at the abdominal level were estimated from the CT images. They were genotyped for -3826 A/G polymorphism of the UCP1 gene and 64 Trp/Arg mutation of the β3AR gene. BAT was detected in 88 subjects out of 199 (44%), more in younger (30 y.o., 55%) than older subjects (>40 y.o., 15%). BAT prevalence of older subjects tended to be lower in the UCP1 G/G group than the A allele group (A/A and A/G), and also in the β3AR Arg allele group (Trp/Arg and Arg/Arg) than the Trp/Trp group. When compared subjects who had two or more base substitutions on the two genes (the 2-4 allele group) with those who had less than two base substitutions (the 0-1 allele group), BAT prevalence was comparable in younger subjects (62% vs 50%) but lower in older subjects (0% vs 24%, P<0.05). Visceral fat area of the 2-4 allele group was higher than that of the 0-1 allele group (P<0.05) in older subjects, but not in younger subjects. UCP1 -3826 A/G and β3AR 64 Trp/Arg substitutions accelerate age-related decrease in BAT activity, and thereby may associate with visceral fat accumulation with age.

β2AR Antagonists and β2AR Gene Deletion Both Promote Skin Wound Repair Processes

Skin wound healing is a complex process requiring the coordinated, temporal orchestration of numerous cell types and biological processes to regenerate damaged tissue. Previous work has demonstrated that a functional β-adrenergic receptor autocrine/paracrine network exists in skin, but the role of β2-adrenergic receptor (β2AR) in wound healing is unknown. A range of in vitro (single-cell migration, immunoblotting, ELISA, enzyme immunoassay), ex vivo (rat aortic ring assay), and in vivo (chick chorioallantoic membrane assay, zebrafish, murine wild-type, and β2AR knockout excisional skin wound models) models were used to demonstrate that blockade or loss of β2AR gene deletion promoted wound repair, a finding that is, to our knowledge, previously unreported. Compared with vehicle-only controls, β2AR antagonism increased angiogenesis, dermal fibroblast function, and re-epithelialization, but had no effect on wound inflammation in vivo. Skin wounds in β2AR knockout mice contracted and re-epithelialized faster in the first few days of wound repair in vivo. β2AR antagonism enhanced cell motility through distinct intracellular signalling mechanisms and increased vascular endothelial growth factor secretion from keratinocytes. β2AR antagonism promoted wound repair processes in the early stages of wound repair, revealing a possible new avenue for therapeutic intervention.