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Beta2-Adrenergic Receptor Gene Polymorphisms in Egyptian Patients with Acute Myocardial Infarction  [PDF]
Eman Toraih,Mohammad H. Hussein,Dahlia I. Badran
Advances in Molecular Biology , 2014, DOI: 10.1155/2014/471635
Abstract: Background. Beta2-adrenergic receptor (ADRB2) gene polymorphisms, Arg16Gly and Gln27Glu, have been implicated in the pathogenesis of cardiovascular diseases. The aim of this study was to determine the association of these two polymorphisms with the risk of myocardial infarction (MI) in the Egyptian population. Methods. Blood samples were collected from 68 MI patients and 75 healthy controls. They were assessed for the presence of cardiovascular risk factors and genotyped for the Arg16Gly (rs1042713) and Gln27Glu (rs1042714) polymorphisms using allelic-discrimination polymerase chain reaction. Results. There is no significant difference in genotype and allele frequencies at codon 16 between MI patients and controls (). However, at codon 27, MI risk was higher in Gln27 homozygous participants than in Glu27 carriers (). The haplotype frequency distribution showed significant difference among cases and controls (); homozygotes for Gly16/Gln27 haplotype were more susceptible to MI than Gly16/Glu27 carriers. Patients with Arg16/Gln27 haplotype had higher serum total cholesterol levels () and lower frequency of diabetes in MI patients (). However, both Glu27 genotypes and haplotype showed lower frequency of hypertension (). Conclusions. Our findings suggested that the ADRB2 gene polymorphisms may play an important role in susceptibility of MI among Egyptian population. 1. Introduction Myocardial infarction (MI) is a major cause of morbidity and mortality worldwide, accounting for up to 40% of all deaths [1, 2]. It is caused by myocardial cell death due to prolonged ischemia [3]. MI is a multifactorial, polygenic disorder driven by interactions of an individual’s genetic background and several environmental factors [4–7]. Greater understanding of MI etiology is mandatory to identify individuals at high risk and to improve prevention and therapy of this common and important condition. Cardiovascular risk factors, as smoking, obesity, hypertension, dyslipidemia, and diabetes, have long been known [8]. However these risk factors do not explain why some individuals are more susceptible to these environmental determinants in comparison to others with the same given risk factors. Several genomic association studies, family-based and twin studies, and linkage analysis provide insights into multiple susceptible genes underlying MI disease [9, 10]. The beta 2-adrenergic receptors (-AR), a member of the G-protein-coupled receptor superfamily, have attracted great attention due to their multiple physiological and health effects, particularly those involving cardiovascular
Association of beta 2 -adrenergic receptor gene polymorphisms and nocturnal asthma in Saudi patients  [cached]
Al-Rubaish Abdullah
Annals of Thoracic Medicine , 2011,
Abstract: Background and Objectives : Two polymorphisms of beta 2 -adrenergic receptor (β2 -AR) gene, namely the substitution from arginine (Arg) to glycine (Gly) at codon 16 and from glutamine (Gln) to glutamic (Glu) at codon 27, are linked with functional changes in the β2 -AR in the respiratory system even though they are not deemed to be susceptibility genes for asthma per se. The objective of this study was to investigate this association in a subset of asthmatic patients, namely those with nocturnal asthma. Methods : The β2 -AR gene polymorphisms at codon 16 and 27 were assessed in 40 patients clinically diagnosed with nocturnal asthma and 96 normal controls. Genomic DNA was obtained from whole blood and genotyping was carried out by a PCR based restriction fragment length polymorphism technique. Results : There was a statistically significant difference in genotype frequencies at codon 16 (Arg/Gly) between nocturnal asthmatic patients and normal control subjects (P < 0.05). However, there was no statistically significant difference in allele frequencies between the two groups. In addition, there was a significant association between Arg16-Gly genotype with nocturnal asthma compared to homozygous Gly16 (codominant model P = 0.0033, OR = 3.69: 95% CI: 1.49-9.12). However, there were no statistically significant differences in genotype and allele frequencies at codon 27 (Gln/Glu) between the normal control and nocturnal asthmatic groups (χ2 = 1.81, P = 0.41). The results also indicate that linkage disequilibrium existed between the β2 -AR codon 16 and β2 -AR codon 27 polymorphism (/ D / = 0.577). The data for all haplotypes did not show a statistically significant association. Conclusion : We present the genotype and allele frequencies of β2 -AR gene polymorphisms in normal Saudi subjects and nocturnal asthmatic patients. There was a significant difference in genotype frequencies at codon 16 (Arg/Gly). However, our study indicates a poor association of individual single nucleotide polymorphisms with nocturnal asthma.
Beta-2 adrenergic receptor gene polymorphisms Gln27Glu, Arg16Gly in patients with heart failure
Alfredo Mansur, Rosana Fontes, Regina Canzi, Raphael Nishimura, Airlane Alencar, Antonio de Lima, José Krieger, Alexandre Pereira
BMC Cardiovascular Disorders , 2009, DOI: 10.1186/1471-2261-9-50
Abstract: We studied 501 patients with heart failure of different etiologies. Mean age was 58 years (standard deviation 14.4 years), 298 (60%) were men. Polymorphisms were identified by polymerase chain reaction-restriction fragment length polymorphism.During the mean follow-up of 12.6 months (standard deviation 10.3 months), 188 (38%) patients died. Distribution of genotypes of polymorphism Arg16Gly was different relative to body mass index (χ2 = 9.797;p = 0.04). Overall the probability of survival was not significantly predicted by genotypes of Gln27Glu, Arg16Gly, or Thr164Ile. Allele and haplotype analysis also did not disclose any significant difference regarding mortality. Exploratory analysis through classification trees pointed towards a potential association between the Gln27Glu polymorphism and mortality in older individuals.In this study sample, we were not able to demonstrate an overall influence of polymorphisms Gln27Glu and Arg16Gly of beta-2 receptor gene on prognosis. Nevertheless, Gln27Glu polymorphism may have a potential predictive value in older individuals.Genetic polymorphisms have been studied with the hypotheses of influencing presentation, course and prognosis of patients with heart failure [1]. Beta-2 adrenergic receptor gene polymorphisms Gln27Glu, Arg16Gly, and Thr164Ile were suggested to have a significant effect in patients with heart failure. In a study of 259 patients with ischemic or idiopathic dilated cardiomyopathy, prognosis was less favorable in patients harboring the allele Ile164 relative to patients harboring the allele Thr164. In patients harboring alleles Gly16 and Glu27, previoulsy associated with increased down regulation of beta-2 adrenergic receptors, a statistically significant difference relative to prognosis has not been demonstrated. However, a trend to a prognostic influence of allele Gly16 was suggested by an apparent and non-significant lower survival rate in patients harboring allele Gly16 [2]. The polymorphisms Thr164Ile,
Association of Gln27Glu and Arg16Gly Polymorphisms in Beta2-Adrenergic Receptor Gene with Obesity Susceptibility: A Meta-Analysis  [PDF]
Hongxiu Zhang, Jie Wu, Lipeng Yu
PLOS ONE , 2014, DOI: 10.1371/journal.pone.0100489
Abstract: Background The beta2-adrenergic receptor (ADRB2) gene polymorphism has been implicated in susceptibility to obesity, but study results are still controversial. Objective The present meta-analysis is performed to determine whether there are any associations between the Gln27Glu (rs1042714) or the Arg16Gly (rs1042713) polymorphisms in ADRB2 and obesity susceptibility. Methods The PubMed (1950–2014), Embase (1974–2014), and China National Knowledge Infrastructure (CNKI, 1994–2014) databases were searched using the search terms (“Beta2-adrenergic receptor”, “β2-adrenergic receptor” or “ADRB2”), “polymorphism,” and “obesity”. Fixed- or random-effects pooled measures were determined on the bias of heterogeneity tests across studies. Publication bias was examined by Egger's test and the modified Begg's test. Results Eighteen published articles were selected for meta-analysis. Overall analyses showed that rs1042714 (Gln27Glu) was associated with significantly increased obesity risk in the heterozygote model (Gln/Glu vs. Gln/Gln: OR: 1.16, 95% CI: 1.04–1.30, I2 = 49%, P = 0.009) and the dominant model (Gln/Glu + Glu/Glu vs. Gln/Gln: OR: 1.2, 95% CI: 1.00–1.44, I2 = 55%, P = 0.04), whereas no significant association was found in the other models for rs1042714. Also, no significant association was found between the rs1042713 (Arg16Gly) gene polymorphism and the risk of obesity in all genetic models. In addition, neither rs1042713 (Arg16Gly) nor rs1042714 (Gln27Glu) showed any significant association with obesity susceptibility when the population were stratified based on gender. Conclusion Our meta-analysis revealed that the rs1042714 (Gln27Glu) polymorphism is associated with obesity susceptibility. However, our results do not support an association between rs1042713 (Arg16Gly) polymorphisms and obesity in the populations investigated. This conclusion warrants confirmation by more case-control and cohort studies.
Neurohumoral activation in heart failure: the role of adrenergic receptors
Brum, Patricia C.;Rolim, Natale P.L.;Bacurau, Aline V.N.;Medeiros, Alessandra;
Anais da Academia Brasileira de Ciências , 2006, DOI: 10.1590/S0001-37652006000300009
Abstract: heart failure (hf) is a common endpoint for many forms of cardiovascular disease and a significant cause of morbidity and mortality. the development of end-stage hf often involves an initial insult to the myocardium that reduces cardiac output and leads to a compensatory increase in sympathetic nervous system activity. acutely, the sympathetic hyperactivity through the activation of beta-adrenergic receptors increases heart rate and cardiac contractility, which compensate for decreased cardiac output. however, chronic exposure of the heart to elevated levels of catecholamines released from sympathetic nerve terminals and the adrenal gland may lead to further pathologic changes in the heart, resulting in continued elevation of sympathetic tone and a progressive deterioration in cardiac function. on a molecular level, altered beta-adrenergic receptor signaling plays a pivotal role in the genesis and progression of hf. beta-adrenergic receptor number and function are decreased, and downstream mechanisms are altered. in this review we will present an overview of the normal beta-adrenergic receptor pathway in the heart and the consequences of sustained adrenergic activation in hf. the myopathic potential of individual components of the adrenergic signaling will be discussed through the results of research performed in genetic modified animals. finally, we will discuss the potential clinical impact of beta-adrenergic receptor gene polymorphisms for better understanding the progression of hf.
Neurohumoral activation in heart failure: the role of adrenergic receptors  [cached]
Brum Patricia C.,Rolim Natale P.L.,Bacurau Aline V.N.,Medeiros Alessandra
Anais da Academia Brasileira de Ciências , 2006,
Abstract: Heart failure (HF) is a common endpoint for many forms of cardiovascular disease and a significant cause of morbidity and mortality. The development of end-stage HF often involves an initial insult to the myocardium that reduces cardiac output and leads to a compensatory increase in sympathetic nervous system activity. Acutely, the sympathetic hyperactivity through the activation of beta-adrenergic receptors increases heart rate and cardiac contractility, which compensate for decreased cardiac output. However, chronic exposure of the heart to elevated levels of catecholamines released from sympathetic nerve terminals and the adrenal gland may lead to further pathologic changes in the heart, resulting in continued elevation of sympathetic tone and a progressive deterioration in cardiac function. On a molecular level, altered beta-adrenergic receptor signaling plays a pivotal role in the genesis and progression of HF. beta-adrenergic receptor number and function are decreased, and downstream mechanisms are altered. In this review we will present an overview of the normal beta-adrenergic receptor pathway in the heart and the consequences of sustained adrenergic activation in HF. The myopathic potential of individual components of the adrenergic signaling will be discussed through the results of research performed in genetic modified animals. Finally, we will discuss the potential clinical impact of beta-adrenergic receptor gene polymorphisms for better understanding the progression of HF.
Combinatorial Pharmacogenetic Interactions of Bucindolol and β1, α2C Adrenergic Receptor Polymorphisms  [PDF]
Christopher M. O'Connor, Mona Fiuzat, Peter E. Carson, Inder S. Anand, Jonathan F. Plehn, Stephen S. Gottlieb, Marc A. Silver, JoAnn Lindenfeld, Alan B. Miller, Michel White, Ryan Walsh, Penny Nelson, Allen Medway, Gordon Davis, Alastair D. Robertson, J. David Port, James Carr, Guinevere A. Murphy, Laura C. Lazzeroni, William T. Abraham, Stephen B. Liggett, Michael R. Bristow
PLOS ONE , 2012, DOI: 10.1371/journal.pone.0044324
Abstract: Background Pharmacogenetics involves complex interactions of gene products affecting pharmacodynamics and pharmacokinetics, but there is little information on the interaction of multiple genetic modifiers of drug response. Bucindolol is a β-blocker/sympatholytic agent whose efficacy is modulated by polymorphisms in the primary target (β1 adrenergic receptor [AR] Arg389 Gly on cardiac myocytes) and a secondary target modifier (α2C AR Ins [wild-type (Wt)] 322–325 deletion [Del] on cardiac adrenergic neurons). The major allele homozygotes and minor allele carriers of each polymorphism are respectively associated with efficacy enhancement and loss, creating the possibility for genotype combination interactions that can be measured by clinical trial methodology. Methodology In a 1,040 patient substudy of a bucindolol vs. placebo heart failure clinical trial, we tested the hypothesis that combinations of β1389 and α2C322–325 polymorphisms are additive for both efficacy enhancement and loss. Additionally, norepinephrine (NE) affinity for β1389 AR variants was measured in human explanted left ventricles. Principal Findings The combination of β1389 Arg+α2C322–325 Wt major allele homozygotes (47% of the trial population) was non-additive for efficacy enhancement across six clinical endpoints, with an average efficacy increase of 1.70-fold vs. 2.32-fold in β1389 Arg homozygotes+α2C322–325 Del minor allele carriers. In contrast, the minor allele carrier combination (13% subset) exhibited additive efficacy loss. These disparate effects are likely due to the higher proportion (42% vs. 8.7%, P = 0.009) of high-affinity NE binding sites in β1389 Arg vs. Gly ARs, which converts α2CDel minor allele-associated NE lowering from a therapeutic liability to a benefit. Conclusions On combination, the two sets of AR polymorphisms 1) influenced bucindolol efficacy seemingly unpredictably but consistent with their pharmacologic interactions, and 2) identified subpopulations with enhanced (β1389 Arg homozygotes), intermediate (β1389 Gly carriers+α2C322–325 Wt homozygotes), and no (β1389 Gly carriers+α2C322–325 Del carriers) efficacy.
The role of adrenergic receptor polymorphisms in heart failure
Biolo, A.;Rosa, A.S.;Mazzotti, N.G.;Martins, S.;Belló-Klein, A.;Rohde, L.E.;Clausell, N.;
Brazilian Journal of Medical and Biological Research , 2006, DOI: 10.1590/S0100-879X2006001000003
Abstract: the main function of the cardiac adrenergic system is to regulate cardiac work both in physiologic and pathologic states. a better understanding of this system has permitted the elucidation of its role in the development and progression of heart failure. regardless of the initial insult, depressed cardiac output results in sympathetic activation. adrenergic receptors provide a limiting step to this activation and their sustained recruitment in chronic heart failure has proven to be deleterious to the failing heart. this concept has been confirmed by examining the effect of ?-blockers on the progression of heart failure. studies of adrenergic receptor polymorphisms have recently focused on their impact on the adrenergic system regarding its adaptive mechanisms, susceptibilities and pharmacological responses. in this article, we review the function of the adrenergic system and its maladaptive responses in heart failure. next, we discuss major adrenergic receptor polymorphisms and their consequences for heart failure risk, progression and prognosis. finally, we discuss possible therapeutic implications resulting from the understanding of polymorphisms and the identification of individual genetic characteristics.
Single nucleotide polymorphisms in the apolipoprotein B and low density lipoprotein receptor genes affect response to antihypertensive treatment
Ulrika Liljedahl, Lars Lind, Lisa Kurland, Lars Berglund, Thomas Kahan, Ann-Christine Syv?nen
BMC Cardiovascular Disorders , 2004, DOI: 10.1186/1471-2261-4-16
Abstract: Ten single nucleotide polymorphisms (SNP) in genes related to lipid metabolism were analysed by a microarray based minisequencing system in DNA samples from ninety-seven hypertensive subjects randomised to treatment with either 150 mg of the angiotensin II type 1 receptor blocker irbesartan or 50 mg of the β1-adrenergic receptor blocker atenolol for twelve weeks.The reduction in blood pressure was similar in both treatment groups. The SNP C711T in the apolipoprotein B gene was associated with the blood pressure response to irbesartan with an average reduction of 19 mmHg in the individuals carrying the C-allele, but not to atenolol. The C16730T polymorphism in the low density lipoprotein receptor gene predicted the change in systolic blood pressure in the atenolol group with an average reduction of 14 mmHg in the individuals carrying the C-allele.Polymorphisms in genes encoding proteins in the lipid metabolism are associated with the response to antihypertensive treatment in a drug specific pattern. These results highlight the potential use of pharmacogenetics as a guide for individualised antihypertensive treatment, and also the role of lipids in blood pressure control.Hypertension is a complex trait caused by multiple environmental and genetic factors interacting through the cardiac, vascular and endothelial systems. Several drug classes with different mechanisms of action, including inhibitors of the renin-angiotensin-aldosterone system (RAAS), calcium channel blockers, adrenergic receptor blockers and diuretics, are available for treatment of hypertension. However, the response to antihypertensive treatment is highly variable between individuals, which makes it difficult to predict the efficacy of a specific drug in the individual patient [1-3]. Currently, there are no clinically useful biochemical or metabolic markers for predicting the individual responses to antihypertensive treatment [4-6].Twin studies have estimated that as much as half of the variability in
The basis of beta-adrenergic bronchodilation.  [cached]
Kumar M
Journal of Postgraduate Medicine , 1981,
Abstract:
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