β2-AR Gene Research Articles

Regulation of Adrenoceptor and Muscarinic Receptor Gene Expression after Single and Repeated Stress

Although stress is tightly connected with elevated levels of catecholamines, stress effects on target structures of catecholamine action--adrenoceptors (ARs)--has not been deeply studied yet. Similarly, very little is known about changes of muscarinic receptors (MRs) during stress. We determined changes in these receptors in the individual parts of the heart (right atria and ventricles) of animals (rats and mice) exposed to a single and repeated immobilization stress. Changes of tissue catecholamines, beta(2)-AR gene expression, protein levels, and binding sites were determined in rat right ventricles, and changes in beta(1)-, beta(2)-, and beta(3)-AR gene expression were followed in murine right atria. Tissue catecholamines were elevated, while beta(2)-AR mRNA levels and beta(2)-AR proteins and binding were decreased, in rat right ventricles. In murine right atria, beta(1)- and beta(2)-AR gene expression was elevated, while beta(3)-AR mRNA levels and M(2)-MR were reduced. Taken together, our data show that interaction of AR and MR is important for the organism coping with stress and that different heart regions reveal distinct reactions to stress.

Abstract 5570: β-2 Adrenergic Receptors Overexpression Promotes Angiogenesis in the Failing Myocardium through Activation of Vascular Endothelial Growth Factor/Akt Transduction Pathway

β-2 adrenergic receptor (β-2AR) plays a pivotal role in endothelial cell proliferation and promotes angiogenesis in response to hindlimb ischemia. Desensitization/uncoupling of cardiac β-2AR represents a well established phenomenon in heart failure (HF). In this study we aimed to investigate the role of β-2AR in the impairment of angiogenic processes occurring in the failing myocardium. To this purpose, we explored the angiogenic effects of β-2AR in a rat model of post-myocardial infarction (MI) HF. Cardiac adenoviral-mediated β-2AR overexpres-sion has been obtained via direct intramyocardial injection (4 x 10 11 PFU) 4 weeks after MI. We also extended our observation to β-2AR knockout (β2KO) mice developing HF after large anterior MI (infarct size 45 ± 6%). Cardiac β-2AR overexpression in HF rats markedly increased capillary and arteriolar length density, and induced larger left ventricular (LV) hypertrophic responses than that observed in untreated HF animals. Such LV adaptive remodelling was associated to reduced LV diameters and improved cardiac LV fractional shortening (FS) and +dP/dt. At molecular level, cardiac β-2AR gene transfer induced sustained activation of p-Akt and S6 kinase (S6K) phosphorylation and increased p-eNOS and VEGF levels that were instead reduced in untreated HF rats. In β2KO mice, we found a ~25% reduction of cardiac capillary and arteriolar density compared to WT mice. In β2KO mice, MI was associated with a dramatically higher 21-day mortality compared to WT (70% vs 30%, respectively). Survivors β2KO mice showed increased LV end diastolic and systolic diameters, and worse global cardiac contractility compared to controls. Cardiac Akt activation, S6K phosphorylation, p-eNOS, and VEGF-A production were significantly blunted in HF β2KO mice. Conclusions. β-2ARs play an important role in regulating angiogenic responses in post-MI HF hearts. The activation of Akt signal transduction pathway seems to be strongly involved in these mechanisms.

Identification of higenamine in Radix AconitiLateralis Preparataas a beta2-adrenergic receptor agonist1

To screen beta2-adrenergic receptor (beta2-AR) agonists from Radix Aconiti Lateralis Preparata (RALP) as potential drug leads for asthma using a sensitive cell-based agonist assay. The beta2-AR gene was stably expressed by Chinese hamster ovary (CHO) cells also stably expressing a cyclic adenosine monophosphate (AMP) response element-linked enhanced green fluorescent protein reporter gene. The cells were used to screen agonists from high-performance liquid chromatographic fractions of an extract of RALP. The fraction with the highest activity was selected for further compound isolation and the study of the structure-activity relationship. Its active compound was further identified by chromatography and mass spectrometry. Bioactivity-directed fractionation of the crude extract of RALP led to the isolation and characterization of the effective compound, namely hignamine. It could dose-dependently relax the isolated guinea pig trachea strip precontraction with acetylcholine with EC(50) value of (2.60+/-0.36)x10(-5) mol/L. Further in vivo studies also displayed that hignamine could protect experimental asthma model induced by histamine in guinea pigs to prolong the latent periods of asthma. Hignamine, as a beta2-AR agonist existing in the extract of RALP, is the key compound contributing to the successful relief of the bronchoconstriction.

Pharmacogenomics and Sepsis-Induced Renal Failure: Effects of β 2-Adrenoceptor Function on the Course of Sepsis

Endotoxemia caused by Gram-negative bacteria can result in sepsis and organ dysfunction, which includes kidney damage and renal failure. Genetic polymorphisms in cytokine-encoding genes contribute to individual variance in inflammatory responses and have been postulated as being associated with an increased risk for cytokine-mediated disorders, such as sepsis-induced acute renal failure. There is a growing body of evidence that the β2-adrenoceptor (β2-AR) system has an anti-inflammatory influence on the cytokine network during the course of immunological responses. Indeed, activation of β2-ARs can modulate the production of pro- and anti-inflammatory cytokines, such as TNF-β and interleukin( IL)-1, -6, -10, -12, in some tissues and organs. An altered expression or function of β2-ARs has been considered to be a pathogenetic factor in some inflammatory states; for example, allergy, heart failure and renal failure. Previously, we demonstrated that the application of adenoviral mediated β2-AR gene delivery to enhance renal β2-AR activity afforded the kidney protection against endotoxin-induced acute renal failure. These observations would suggest the possibility that the level of β2-AR activity might be associated with β2-AR polymorphisms which may pre-determine the increased risk of organ dysfunction following severe sepsis. At present it seems that β2-AR polymorphisms do not play a role as sepsiscausing genes; however, they might be risk factors, might modify sepsis, and/or might influence the progression of sepsis. Thus, genomic information on β2-AR polymorphisms has a potential use to identify groups of patients with a raised risk of developing severe sepsis and multiple organ dysfunctions.

The effects of beta2 adrenergic receptor gene polymorphism in lipid profiles

BackgroundExplore the interaction between apolipoprotein E (Apo E), phospholipase A2 (PLA2) and β2 adrenergic receptor (β2-AR) gene polymorphisms and lipid profiles in an elderly Chinese population.MethodsFive hundred subjects aged 65 to 74 years were randomly selected from a community in southern Taiwan to assess the relationship between Apo E, PLA2 and β2-AR gene polymorphisms and lipid profiles. Two hundred sixty-seven participants agreed to have venous blood drawn for DNA studies.ResultsTwo statistically significant differences were noted in TC and LDL-C in the Gln27Glu of the β2-AR gene polymorphism (P = 0.007, P = 0.022). The low-income group had a higher HDL-C level (p = 0.076). The Gln27Glu polymorphism Glu/Glu or Gln/Glu subjects had lower TC levels compared to the Gln27Glu polymorphism Gln/Gln subjects (p = 0.092). Lower TC levels (p = 0.082) and lower LDL-C levels (p = 0.045) in subjects with the Cys19Arg16Glu27 haplotype. Lower TC levels (p = 0.06) were also noted in subjects with the Cys19Gly 16Glu27 haplotype. On the other hand, higher VLDL-C levels (p = 0.185) and higher triglyceride (TG) levels (p = 0.190) were noted in subjects with the Cys19Gly 16Gln27 haplotype. The ε2 allele combined with low income had a positive effect on HDL-C (p = 0.0011), after adding the income factor in this study.ConclusionWhen the effects of Apo E and PLA2 on lipid profiles were included in this study, β2-AR gene polymorphisms reduced significant effect on lipid profiles. Similarly, low income increased effect on HDL-C. This study appeared that the results of gene-gene and gene-environment interaction, it should be considered in further studies for lipid profiles.

Polymorphism of Trp64Arg in β3-adrenergic receptor gene and serum LDL-cholesterol concentrations in healthy Japanese

Polymorphism of Trp64Arg in the beta(3)-adrenergic receptor (beta(3)-AR) gene may play a critical role in lipid and lipoprotein metabolism by mediating lipolysis and thermogenesis. Since the frequency of Arg alleles of the beta(3)-AR gene is generally low among many populations, studies on the Arg/Arg genotype in relation to lipid and lipoprotein metabolism are required in countries such as Japan which has a relatively high frequency of the Arg allele. We genotyped 275 clinically healthy Japanese (male/female, 134/141, mean 45.7 years) without medication for beta(3)-AR gene polymorphism by polymerase chain reaction-restriction fragment length polymorphism analysis, and investigated the effects of the gene polymorphism on clinical parameters including body mass index (BMI), blood pressure and serum lipid and lipoprotein concentrations. The genotype frequencies were: Trp/Trp, 68.0%; Try/Arg, 28.0% and Arg/Arg, 4.0%, with an allele frequency of 0.18 for Arg64. When subjects were divided into three groups according to the genotype, a significant increase of serum LDL-cholesterol (LDL-C) concentration in the Arg/Arg group (3.48 +/- 1.59 mmol/L) was observed when compared with those of the Trp/Trp and Arg/Trp groups (3.15 +/- 0.80, 3.25 +/- 0.92 mmol/L, respectively). Genotype differences did not show any significant effect on other parameters. Spearman's rank correlation demonstrated a significant relationship between LDL-C concentrations and the number of Arg alleles, age and BMI. Multiple regression analysis, using LDL-C concentration as a criterion variable and some factors including beta(3)-AR gene polymorphism as explanatory variables, revealed that the number of Arg alleles was a significant and independent factor for LDL-C concentrations, along with age and BMI. These findings suggested a role of the beta(3)-AR gene polymorphism in regulating lipid and lipoprotein metabolism, showing small but significant effects on elevated LDL-C values in subjects with Arg/Arg, but not Trp/Arg and Trp/Trp genotypes.

A functional beta‐2 adrenergic receptor polymorphism and drug response in adult outpatients with depression

OBJECTIVE: To evaluate the hypothesis that Arg16Gly polymorphism in the beta-2 adrenergic receptor (β2AR) is associated with the outcome to the antidepressant treatment. METHODS: A case-control study was performed among patients diagnosed with depression attending several outpatient clinics. They were evaluated and characterized for mood symptoms and response to the antidepressant treatment using the Semi-Structured Interview Guide of the Hamilton Depressive Scale (SIGH-D; 17 items) by a psychiatric specialist. Their genomic DNA was amplified by means of the polymerase chain reaction (PCR), and the polymorphism Arg16Gly of the β2AR gene was determined by restriction fragment length polymorphism (RFLP). Subsequently, the allelic frequencies of the polymorphisms were compared between two groups: 47 with suboptimal response (cases), and 37 with good response (controls). RESULTS: The frequency of the Arg16 allele was significantly higher when comparing cases and controls (52.1% and 33.3%, respectively. Chi(2)= 5.8, odds ratio=2.18, P= 0.016). CONCLUSION: An association was found between the response to antidepressant treatment and the Arg16Gly polymorphism of the β2AR. Further studies could help to establish the role of this polymorphism as a genetic factor predisposing to the drug response in depression.

Role of four polymorphisms of the β-2 adrenergic receptor gen in patients with preterm delivery.

Objective: To determine whether single nucleotide polymorphisms found in the sequence of the β-2 (β2AR) adrenergic receptor are associated with spontaneous preterm delivery. Method: A case-control study in which the allelic, genotype, and haplotype frequencies of four polymorphisms, -47 C/T, -20 C/T, Arg16Gly, and Gln27Glu of the β2AR gene, were determined and compared between 35 women with preterm delivery (cases) and 105 women with term delivery (controls). The study was performed with patients of three hospitals in the city of Medellín, Colombia. The genomic DNA of peripheral blood was isolated, the segment of the gene was amplified by means of the chain reaction of polymerase (PCR), and the polymorphisms were determined by direct sequence method. Results: No significant differences for the allelic frequencies were found for polymorphic loci -47 C/T, -20 C/T, Arg16Gly, and Gln27Glu between the cases group (21.5%, 21.5%, 51.5% and 21.5%, respectively) and controls (21.5%, 21.5%, 57% and 21.5%, respectively; p>0.05). The genotype frequencies were also similar between patients with preterm delivery and those with term delivery (p>0.05 for all the genotypes). Only three of the 16 possible haplotypes (CCGG, TTGC, and TTAC), from the combination between the different alleles, appeared in the participants of this study. The haplotype frequencies were not significantly different between the compared groups either (p>0.05). Conclusion: No association was observed between preterm delivery and any of the polymorphisms or its haplotypes. These results do not support a role of the polymorphisms of the β2AR in spontaneous preterm delivery for these patients.

Polymorphisms at the β2-adrenergic receptor gene influence Alzheimer's disease susceptibility

Increasing evidence indicates that the β2-adrenergic receptor (β2-AR) may play an important role in Alzheimer's disease (AD). We investigated the effect of two polymorphisms in the β2-AR gene: Gly16Arg and Gln27Glu for the risk of sporadic Late Onset Alzheimer's Disease (LOAD) in 109 patients and 109 healthy controls matched for sex and age in a Han Chinese population. Results revealed that both the 16Gly allele and the 27Glu allele of the β2-AR gene were associated with an increased risk of LOAD ( P = 0.009, OR = 1.652 and P = 0.002, OR = 2.846, respectively), and they also showed a highly significant interaction with the Apolipoprotein E gene (APOE) ε4 allele (OR = 4.200 and 9.441, respectively). Examination of the haplotypes identified the Gly16Glu27 haplotype to increase the risk of LOAD ( P = 0.004). Our results suggest that variations in the β2-AR gene play an important role in the pathogenesis of sporadic LOAD, and interact with the ε4 allele to markedly increase the LOAD risk.

Endomyocardial Upregulation of β1 Adrenoreceptor Gene Expression and Myocardial Contractile Reserve Following Cardiac Resynchronization Therapy

Background Congestive heart failure (CHF) is associated with a blunted force-frequency relation (FFR) and myocardial contractile reserve (MCR) partially from a downregulation of β1-adrenoreceptors (β1-AR). We investigated whether acute and chronic cardiac resynchronization therapy (CRT) was capable of reversing the blunted FFR and MCR and if this was associated with upregulation of β1-AR. Methods and Results Left ventricle dP/dtmax was invasively measured in 10 CHF patients (New York Heart Association class ≥3; ejection fraction <25%) during incremental dual chamber (DDD)-CRT pacing at 70, 90, 110, and 130 beats/min, with and without continuous infusion of intravenous dobutamine, immediately after CRT implantation (BL) and 4 months later (FU). In a subgroup of 5 patients, serial left ventricle β1 and β2-AR gene expression was measured using reverse transcriptase-polymerase chain reaction. Four months after the initiation of resynchronization therapy, DDD-CRT pacing results in a significant upward shift of the heart rate versus LV dP/dtmax relationship ( P < .01) with force frequency amplification as evidenced by the steeper slope of the force frequency response ( P = .04). Infusion of dobutamine recruits myocardial contractile reserve and increases the heart rate versus LV dP/dtmax relationship at BL and at FU (both P < .05). However, only at follow-up was an additional force frequency amplification noticed ( P < .05) during dobutamine infusion. This observation was paralleled by a significant upregulation of β1-AR gene expression ( P = .02). Conclusions Chronic CRT is associated with a partial restoration of the FFR and with a recruitment in myocardial contractile reserve, which is paralleled by upregulation of β1-AR.

Association between β2 adrenergic receptor polymorphisms and rheumatoid arthritis in conjunction with human leukocyte antigen (HLA)-DRB1 shared epitope

Objective:In the present work, the frequency of inherited polymorphisms of the β2 adrenergic receptor (β2AR) gene and their association with rheumatoid arthritis (RA) as well as human leukocyte antigen (HLA)-DRB1...

1- and 2-Adrenergic Receptor Gene Variation, -Blocker Use and Risk of Myocardial Infarction and Stroke

The benefits of β-blocker therapy may depend on underlying genetic susceptibility. We investigated the interaction of common variation in β1 and β2 adrenergic receptor (AR) genes with β-blocker use on the risks of myocardial infarction (MI) and ischemic stroke in a case–control study. Participants were treated pharmacologically for hypertension, aged 30–79 years, with incident MI (n = 659) or ischemic stroke (n = 279) between 1995 and 2004, and 2,249 matched controls. We observed an interaction of β-blocker use with β1-AR gene variation on MI risk (P value, 6 degrees of freedom: 0.01) and ischemic stroke risk (P value, 6 degrees of freedom: 0.04). Compared with use of other antihypertensive medications, β-blocker use was associated with higher MI risk in carriers of one or two copies of rs#17875422 (Odds ratio (OR): 2.66, 95% confidence interval (CI); 1.26–5.60) but not in homozygous carriers of the common allele (OR: 0.88, 95% CI: 0.73–1.07). Another variant, rs#2429511, interacted with β-blocker use on both MI and ischemic stroke risks. β-blocker use was associated with higher risk of combined MI and ischemic stroke in carriers of rs#2429511 (OR: 1.24, 95% CI: 1.03–1.50) but not in homozygous carriers of common allele (OR: 0.70, 95% CI: 0.51–0.94). β-blocker use did not interact with β2-AR gene variation on the risks of MI and ischemic stroke. These results, which require replication, suggest genetic variants in the β1-AR gene may determine whether to use β-blockers in hypertension for the primary prevention of cardiovascular disease.

Genetic Variation Within the β1-Adrenergic Receptor Gene Results in Haplotype-Specific Expression Phenotypes

Cardiac beta1-adrenergic receptor (beta1AR) responsiveness in heart failure exhibits interindividual variation that may be attributable to polymorphisms of the intronless beta1AR gene. We sought to ascertain the polymorphisms of the full-length gene and the specific combinations of polymorphisms (haplotypes) in two reference populations. Using whole-gene transfections, we established the impact of beta1AR polymorphisms, within the context of haplotypes, on receptor expression. Fifteen polymorphisms within the 6.1-kb gene with allele frequencies > or =0.05 were found in the 5'-flanking and coding regions, but none in the 3'UTR. These were organized into six common haplotypes. Ethnic-specific and cosmopolitan polymorphisms and haplotypes were noted. Whole-gene transfections of A431 cells revealed an association between haplotype and expression, with as much as twofold differences in expression. Phenotypes clustered into three groups, representing high (two haplotypes), intermediate (three haplotypes), and low (one haplotype) expression. We conclude that the beta1AR gene is highly polymorphic and is commonly found in six haplotypic forms in the population. Receptor expression varies by haplotype, which provides the foundation for cardiovascular association studies with enhanced predictive power using beta1AR haplotypes, or haplotype expression clusters, as compared with individual polymorphisms.

Variable-length poly-C tract polymorphisms of the β2-adrenergic receptor 3′-UTR alter expression and agonist regulation

Beta(2)-adrenergic receptors (beta(2)-AR) expressed on airway epithelial and smooth muscle cells regulate mucociliary clearance and relaxation and are the targets for beta-agonists in the treatment of obstructive lung disease. However, the clinical responses display extensive interindividual variability, which is not adequately explained by genetic variability in the 5'-flanking or coding region of the intronless beta(2)-AR gene. The nonsynonymous coding polymorphism most often associated with a bronchodilator phenotype (Arg16) is found within three haplotypes that differ by the number of Cs (11, 12, or 13) within a 3'-untranslated region (UTR) poly-C tract. To examine potential effects of this variability on receptor expression, BEAS-2B cells were transfected with constructs containing the beta(2)-AR (Arg16) coding sequence followed by its 3'-UTR with the various polymorphic poly-C tracts. beta(2)Arg16-11C had 25% lower mRNA expression and 33% lower beta(2)-AR protein expression compared with the other two haplotypes. Consistent with this lower steady-state expression, beta(2)Arg16-11C mRNA displayed more rapid and extensive degradation after actinomycin D treatment compared with beta(2)Arg16-12C and -13C. However, beta(2)Arg16-12C underwent 50% less downregulation of receptor expression during beta-agonist exposure compared with the other two haplotypes. Thus these haplotypes direct a potential low-response phenotype due to decreased steady-state receptor expression combined with wild-type agonist-promoted downregulation (beta(2)Arg16-11C) and a high-response phenotype due to increased baseline expression combined with decreased agonist-promoted downregulation (beta(2)Arg16-12C). This heterogeneity may contribute to the variability of clinical responses to beta-agonist, and genotyping to identify these 3'-UTR polymorphisms may improve predictive power within the context of beta(2)-AR haplotypes in pharmacogenetic studies.

Exercise training normalizes β-adrenoceptor expression in dogs susceptible to ventricular fibrillation

Previous studies demonstrated an enhanced beta(2)-adrenoceptor (AR) responsiveness in animals susceptible to ventricular fibrillation (VF) that was eliminated by exercise training. The present study investigated the effects of endurance exercise training on beta(1)-AR and beta(2)-AR expression in dogs susceptible to VF. Myocardial ischemia was induced by a 2-min occlusion of the left circumflex artery during the last minute of exercise in dogs with healed infarctions: 20 had VF [susceptible (S)] and 13 did not [resistant (R)]. These dogs were randomly assigned to either 10-wk exercise training [treadmill running; n = 9 (S) or 8 (R)] or an equivalent sedentary period [n = 11 (S) or 5 (R)]. Left ventricular tissue beta-AR protein and mRNA were quantified by Western blot analysis and RT-PCR, respectively. Because beta(2)-ARs are located in caveolae, caveolin-3 was also quantified. beta(1)-AR gene expression decreased ( approximately 5-fold), beta(2)-AR gene expression was not changed, and the ratio of beta(2)-AR to beta(1)-AR gene expression was significantly increased in susceptible compared with resistant dogs. beta(1)-AR protein decreased ( approximately 50%) and beta(2)-AR protein increased (400%) in noncaveolar fractions of the cell membrane in susceptible dogs. Exercise training returned beta(1)-AR gene expression to levels seen in resistant animals but did not alter beta(2)-AR protein levels in susceptible dogs. These data suggest that beta(1)-AR gene expression was decreased in susceptible dogs compared with resistant dogs and, further, that exercise training improves beta(1)-AR gene expression, thereby restoring a more normal beta-AR balance.

β1-ADRENERGIC RECEPTOR GENE MODULATES THE EFFECT OF HEART RATE ON ARTERIAL STIFFNESS: THE BOGALUSA HEART STUDY.

Introduction Heart rate and sympathetic nervous activity are important determinants of arterial stiffness. However, whether the relationship between heart rate and arterial stiffness is modulated by β1-adrenergic receptor (β1-AR) gene variation is not known. This study examines the genetic modulation by β1-AR gene polymorphism (Arg389Gly) on the effect of heart rate on arterial stiffness in young adults. Methods The study cohort included 183 blacks and 502 whites aged 19 to 44 years enrolled in the Bogalusa Heart Study. Aortofemoral pulse wave velocity (af-PWV) was measured by echo-Doppler. Results Heart rate was significantly associated with af-PWV in blacks, whites, and the total sample. However, there was no difference in heart rate between carriers and noncarriers of Gly389 allele in both blacks and whites. Carriers versus noncarriers of the Gly389 allele showed higher values of af-PWV (5.29 m/sec vs 5.19 m/sec, p Conclusions β1-AR gene modulates arterial stiffness and its association with heart rate in young adults.

Impact of rosiglitazone on the expression of β3-AR in the stable cell lines expressed β3-AR gene

The aim of the present study was to investigate the effect of rosiglitazone, a peroxisome proliferator-activated receptor gamma2 (PPAR-gamma2) agonist, on the expression of beta3-adrenergic receptor (beta3-AR) at transcriptional and translational level. We cloned the cDNA sequences of human PPAR-gamma2 (hPPAR-gamma2) gene and human wild type and mutant beta3-adrenergic receptor (hbeta3-AR) genes and established their eukaryotic expression vectors. The pcDNA3.1/hbeta3-AR (mutant and wild type) was transfected into SH-SY5Y cells using electroporation method. The expression level of beta3-AR protein was determined by Western blot analysis. Our results showed that the reverse transcription-PCR products were consistent with theoretical fragment sizes of human PPAR-gamma2 (1544 bp) and human beta3-AR genes (1578 bp). The sequence analysis of PPAR-gamma2 and beta3-AR genes showed that the fragment sizes were the same as that of human PPAR-gamma2 and human beta3-AR genes in Genbank. The pcDNA3.1/hbeta3-AR (mutant and wild type) was successfully cloned to SH-SY5Y cells. We found that the expression of beta3-AR protein was significantly inhibited by rosiglitazone in a concentration-dependent manner in SH-SY5Y cell lines stably expressed beta3-AR genes. The results suggest that rosiglitazone has a concentration-dependent inhibitory effect on the expression of beta3-AR protein, and this inhibitory effect may be due to activation of PPAR-gamma2 receptor.

β 2 -Adrenergic Receptor Polymorphisms and Sudden Cardiac Death

Sudden cardiac death (SCD) is defined as an unexpected death from a cardiac cause generally within 1 hour of the onset of symptoms. The great majority of SCD cases are due to ventricular fibrillation and subsequent hemodynamic collapse. Eighty percent of SCD is attributable to ischemic heart disease, with much of the remainder caused by cardiomyopathies/heart failure and intrinsic conduction system abnormalities.1 These predisposing conditions place patients at risk for SCD, and a trigger for the fatal arrhythmias may come from an imbalance of the parasympathetic and sympathetic nervous systems,2–5 the latter being mediated by cardiac β1- and β2-adrenergic receptors (β1AR, β2AR). Indeed, treatment with β-blockers of patients with heart failure and those who have suffered a myocardial infarction significantly reduces ventricular tachyarrhythmias and SCD. Typically, the pathophysiology of SCD is considered in terms of the underlying disease. However, there is evidence for genetic variability of the β1AR and β2AR genes that has functional consequence in transfected cells, endogenously expressing cells, and transgenic mice.6,7 Familial clustering of certain pathological arrhythmias and the unexplained variability in susceptibility among unrelated individuals to fatal arrhythmias raise the possibility of common polymorphisms such as those of the β1AR or β2AR being genetic risk factors for SCD. Article p 1842 In this issue of Circulation , Sotoodehnia et al8 examined polymorphisms of the β2AR and potential associations with SCD. The study used individuals in the Cardiovascular Health Study (CHS), amounting to 4441 European Americans and 808 African Americans, with SCD occurring in 156 and 39 cases, respectively. In this population, homozygosity for Gln27 was associated with a hazard ratio (HR) of 1.56 (95% confidence interval [CI], 1.17 to 2.09) for SCD compared with …

The Trp64Arg polymorphism in the β 3 ‐adrenergic receptor gene is not associated with pulmonary function in cystic fibrosis

OBJECTIVE As cystic fibrosis (CF) phenotypes are highly variable even in patients carrying the same CFTR mutations, it has been suggested that the course of CF lung disease is influenced by modifying genes other than CFTR. There is recent evidence that CFTR activity isalso regulated through β3-adrenergic receptor (β3-AR) stimulation. We therefore investigated whether polymorphisms in the β3-AR gene contribute to the course of pulmonary function in CF. METHODS The Trp64Arg β3-AR polymorphism was studied by RFLP analysis in 99 CF patients. β3-AR genotypes were related to the annual decline of FEV1, FVC and MEF50 and to age at first infection with P. aeruginosa. RESULTS Genotype distribution was Trp64Trp n=84, Trp64Arg n=14, and Arg64Arg n=1. Frequencies of the β3-AR alleles in CF patients were similar compared to healthy controls. Mean (±SD) follow-up was 14.3±7.8 years. Mean (±SEM) annual decline of pulmonary function was 1.8±0.2 for FEV1, 1.3±0.2 for FVC, and 3.4±0.3 for MEF50. The course of pulmonary function was not different between β3-AR genotypes. There was also no difference in age at first P. aeruginosa infection. Median age at first infection was 7.5 years (quartiles 3.8-15.2 years) in Trp64Trp and 5.7 years (quartiles 3.5-9.4 years) in Trp64Arg patients (p=0.2, Wilcoxon sign rank test). CONCLUSIONS The Trp64Arg β3-AR gene polymorphism was not associated with the course of pulmonary function or with P. aeruginosa airway infection in CF. Therefore, these data do not suggest that the β3-AR gene acts as a modifier of CF lung disease.

Effect of β3-adrenergic receptor gene polymorphism on body weight change in middle-aged, overweight women

To examine the effects of β(3)-adrenergic receptor gene polymorphism on body weight change during a weight reduction program for middle-aged, overweight women with careful consideration of their energy intake and expenditure. Intervention study of weight reduction for 12 weeks in a community setting. Eighty overweight middle-aged women who completed the individualized lifestyle modification program. β(3)-adrenergic receptor gene polymorphism was identified by polymerase chain reaction and consecutive restriction fragment-length polymorphism analysis. Anthropometrical parameters, lifestyle factors, blood lipid and glucose levels, physical activity level and energy intake were measured before and at the end of the program. The numbers of subjects with the Trp64Trp, Trp64Arg, and Arg64Arg genotypes were 45, 30 and 5, respectively. Baseline characteristics among subjects with the 64Arg allele had significantly smaller decrease in body weight and energy intake than those without the 64Arg allele. The change of other clinical characteristics did not differ between the two groups. After adjusting for the %change of energy intake, the %change of body weight did not differ between the two groups. The 64Arg allele of the β(3)-AR gene is not likely to be the factor determining the difficulty in losing body weight in Japanese middle-aged, overweight women. Lifestyle factors, such as the decrease in energy intake, might mask the effect of the 64Arg allele on body weight loss. Specific considerations for the management of energy intake would be needed to promote body weight loss for those with the 64Arg allele.