Β2-adrenoceptor Polymorphisms Research Articles

Can apical ballooning cardiomyopathy and anterior STEMI be differentiated based on β1 and β2-adrenergic receptors polymorphisms?

AimCatecholamine excess along with an exaggerated sympathetic stimulation appears to play a major role in the pathophysiological mechanism of tako-tsubo cardiomyopathy (TTC), which mimics acute ST-elevation myocardial infarction (STEMI). The aim of the present study was to investigate differences in the distribution of allelic variants of β1- and β2-adrenoceptors between TTC and anterior STEMI patients compared to normal subjects. Methods and resultsβ1- and/or β2-adrenoceptor polymorphisms in 97 patients with TTC (92 females, 96%; mean age 66.8±11.6years; range 35 to 87years) were compared with 81 patients with anterior STEMI (77 females, 95%; mean age 72.5±12.8years; range 32 to 96years) and 101 controls (95 females, 94%; mean age 62.3±10.4years; range 44 to 92years). Differences in genotype frequencies were assessed using the Pearson χ2 test. β1-Adrenoceptor (Gly389Arg) and β2-adrenoceptor (Arg16Gly and Gln27Glu) genotype frequencies were significantly different among groups (p<0.001, p=0.024, p=0.008, respectively). However, differences did not achieve statistical significance when TTC and anterior STEMI patients were compared by post-hoc analysis. The cardiovascular risk factor profile was worse in anterior STEMI patients, who more often had a history of systemic arterial hypertension, diabetes and coronary artery disease. ConclusionsIn a large TTC cohort compared with anterior STEMI patients, β-adrenoceptor polymorphisms were similar. However, the cardiovascular risk factor profile was different between the two groups. β-Adrenoceptor polymorphisms in TTC patients differed from normal subjects.

Exercise Training Restores Sympathetic Response during Exercise in Patients with Acute Coronary Syndrome and Gln27Glu β 2 ‐adrenoceptor Polymorphism

We tested the hypothesis that patients with acute coronary syndrome (ACS) homozygous for the C allele of the β2-adrenoceptor polymorphism (Gln27Gln-CC) would have increased muscle sympathetic nerve activity (MSNA) response during exercise compared to patients carrying the G allele (Gln27Glu-CG and Glu27Glu-GG). In addition, exercise training would restore this response in CC patients.Thirty-days after ischemic event, 61 patients without ventricular dysfunction were divided into two groups: 1) CC and 2) CG+GG. From these patients, twenty-five underwent to exercise training for 8 weeks (CC, n=17; CG+GG, n=8). MSNA (microneurography) and blood pressure (BP, oscillometric device) were measured at rest and during 3-min of handgrip exercise (30% maximal voluntary contraction). At baseline, MSNA (P=0.03) and BP (P=0.04) responses during exercise were higher in CC group when compared to CG+GG. Exercise training significantly decreased MSNA response during exercise in CC group (Δ=12±2 vs. 5±2bursts/100HB, P=0.02), but not in CG+GG group (Δ=7±3 vs. 7±3bursts/100HB, P=0.96). The BP did not change after training in both groups. We conclude that patients with ACS homozygous for the C allele of the β2-adrenoceptor polymorphism have increased MSNA response during exercise. Importantly, exercise training reverts the exaggerated MSNA response in CC patients. These findings strength the idea that exercise training should be recommended to patients with ACS, especially those homozygous for the C allele of the β2-adrenoceptor polymorphism (Gln27Gln-CC). Funding: FAPESP and CNPq

P192 A pilot study to assess the influence of β2-adrenoceptor polymorphism on small airway function and asthma control

Introduction and ObjectivesIt is increasingly recognised that small airway dysfunction is associated with suboptimal asthma control. We have previously reported that β2-adrenoreceptor polymorphism at position 16 (i.e. Arg/Gly) is not...

Abstract 369: The Mechanisms of the Onset and Development of Dyslipidemia May Be Different Between Nonobese and Obese, Normotensive Individuals

Background: We have previously reported the strong linkage of β2-adrenoceptor (ADRB2) polymorphisms to the onset and development of obesity, hypertension and insulin resistance (IR), which are a part of a criteria of metabolic syndrome (MetS). Objective: To clarify the effects of ADRB2 polymorphisms on the onset of dyslipidemia, another criteria of MetS, we evaluated the relationships between ADRB2 polymorphisms and deterioration of lipid metabolism in normotensives with a longitudinal study of 5 years. In addition, we compared the mechanisms of the onset of dyslipidemia between nonobese and obese subjects. Methods: In 329 normotensive men including 206 nonobese and 123 overweight/obese men, we measured BMI, BP, fasting glucose, insulin, total cholesterol (Tch), HDLch, LDL+VLDLch, triglycerides (TG) and plasma norepinephrine (NE) annually over 5 years. Subjects who had a significant change (≥10%) over 5 yrs in BP or BMI were excluded. The ADRB2 polymorphisms (Arg16Gly) were determined. Results: Significant increases in HOMA (≥10%) was noted in 24 (11.7%) nonobese and 22 (17.9%) obese subjects (nonobese vs obese, P&lt;0.05). Significant increases in Tch, TG, LDL+VLDL or decreases in HDL were observed in 34, 38, 39, and 28 subjects, respectively. All subjects with deterioration in lipids showed increases in HOMA, and all subjects with significant increases in HOMA had deterioration in lipids. In nonobese subjects, subjects with deterioration in lipids and IR had greater plasma NE at entry and NE elevations over 5 yrs, whereas in obese subjects only greater NE elevations were observed in those with deterioration in lipids, but entry NE were similar. The frequencies of Gly16 allele were significantly higher in subjects with deteriorations in lipids. Lipids and HOMA at entry were similar between subjects with and without Gly16 allele, but increases in lipids and HOMA were greater in those with Gly16 allele. Conclusions: The Gly16 allele of ADRB2 polymorphism is associated with deterioration of lipid metabolism accompanied by increased HOMA and plasma NE. There may be different contributions of IR and sympathetic activity to the onset and development of dyslipidemia between nonobese and obese individuals.

391 BETA2-ADRENOCEPTOR POLYMORPHISMS (ARG16GLY) IS RELATED TO RESISTANCE TO WEIGHT LOSS INDUCED IMPROVEMENTS OF CARDIAC- AND RENAL COMPLICATIONS

Background: Obesity is an independent risk factor for cardiovascular and renal complications. We previously reported that the Arg16Gly, β2-adrenoceptor (ADRB2) polymorphism, accompanying high plasma norepinephrine (NE) could predict future weight gain, BP elevation and renal injury. The 1st line of treatment for obesity is weight loss (WL). In this study, we evaluated the relationships between ADRB2 polymorphisms (Arg16Gly), prevalence of LVH and renal function (creatinine clearance) over 2 years with WL program. Methods: Obese Japanese men (n = 154) were measured BMI, BP, plasma NE, leptin, creatinine, creatinine clearance (CCr), LVH determined by ECG and ADRB2 polymorphisms (Arg16Gly, Gln27Glu) before and after WL program (low caloric diet + exercise) over 2 years. Significant WL was defined >10% WL of entry BMI. Results: Significant WL was noted in 97 (63%) subjects and the frequencies of Gly16 were 39% for WL group vs. 54% for non-WL group (P < 0.05). At entry, subjects with Gly16 allele had higher levels of plasma NE, leptin, creatinine, higher prevalence of LVH, and lower CCr compared to those without Gly16 allele. WL group had lower fat-mass, NE, leptin and creatinine and LVH prevalence and higher CCr at entry compare dto non-WL group. WL group had greater changes in BMI, fat-mass, creatinine and CCr, and greater % reductions in NE and leptin over a 2-year period. Changes in fat-mass correlated with changes in creatinine, CCr, NE and BP over 2 years. Changes in plasma NE correlated with changes in CCr. In multiple regression analysis, plasma NE, fat-mass and BP levels were determinants for prevalence of LVH at entry and 2-year period. Conclusions: ADRB2 polymorphisms (Arg16Gly) accompanying high plasma NE is related to the prevalence of LVH and improving CCr with WL. Arg16Gly associated with high plasma NE may play an important role in cardio- and renal-complications in obesity.

BETA1 (ARG389GLY, SER49GLY)- AND BETA2 (ARG16GLY)-ADRENOCEPTOR POLYMORPHISMS ARE RELATED TO LEFT VENTRICULAR HYPERTROPHY USING ECG IN MIDDLE-AGED, NORMOTENSIVE SUBJECTS: PP.22.358

Objective: Left ventricular hypertrophy (LVH) accompanying elevated sympathetic nervous activity (SNA) is more common in hypertensive and obese people. Elevated SNA is an important mechanism in cardiovascular complications and cardiac morbidity and mortality. β2-adrenoceptor (ADRB2) polymorphisms are closely linked to hypertension and obesity, and β1-adrenoceptor (ADRB1) play roles directly with the heart. We evaluated the relationships between ADRB1 polymorphisms, ADRB2 polymorphisms and LVH. Methods: In 215 nonobese, normotensive Japanese men, ADRB1 polymorphisms (Arg389Gly, Ser49Gly), ADRB2 polymorphisms (Arg16Gly, Gln27Glu), BMI, BP, heart rates (HR), total body fat-mass, waist-to-hip ratio (W/H), plasma norepinephrine (NE), insulin, leptin and ECG were measured. LVH was determined by the Sokolow-Lyon voltage criteria. Results: Twenty-four subjects (11.2%) showed LVH on ECG. Subjects with LVH had higher NE, BP levels and HR compared to those without LVH (all P < 0.05), but BMI, fat-mass, W/H, insulin and leptin were similar. Subjects with LVH had higher frequencies of Gly389 or Gly49 alleles of ADRB1 polymorphisms (χ2 = 49.94, P = 0.002; χ2 = 11.43, P = 0.001, respectively), and Gly16 or Glu27 alleles of ADRB2 polymorphisms (χ2 = 9.59, P = 0.002; χ2 = 3.12, P = 0.059, respectively). Distributions of Gly389 and Gly49 alleles of ADRB1 polymorphisms and Gly16 and Glu27 alleles of ADRB2 were 39.5%, 27.9%, 74.4% and 11.2%, respectively. Subjects with Gly389 or Gly49 had higher frequencies of LVH, higher NE and HR (all P < 0.05), whereas BMI, fat-mass, W/H, BP, insulin and leptin were similar. Subjects with Gly16 had higher frequencies of LVH and greater BMI, fat-mass, systolic BP, NE and insulin compared to those without Gly16 allele (all P < .05). In multiple regression analysis, plasma NE was a significant determinant for systolic BP and LVH in all subjects. Conclusions: Subjects carrying Gly389 and Gly49 alleles of ADRB1 polymorphisms and Gly16 allele of ADRB2 polymorphisms had higher frequency of LVH accompanying high plasma NE. ADRB1 polymorphisms might relate to LVH directly through elevated SNA, but ADRB2 polymorphisms might relate to LVH through obesity and hypertension associated with elevated SNA and insulin resistance.

Relationships of Beta2- and Beta3--Adrenoceptor Polymorphisms with Obesity, Hypertension and Metabolic Syndrome

Obesity, hypertension, diabetes mellitus (especially type 2 diabetes mellitus) and metabolic syndrome are rapidly growing public health problems. Heightened sympathetic nerve activity is a well-established observation in obesity, hypertension and diabetes mellitus. Human obesity, hypertension and diabetes have strong genetic as well as environmental determinants. Reduced energy expenditure and resting metabolic rate are predictive of weight gain, and the sympathetic nervous system participates in regulating energy balance through thermogenesis. The thermogenic effects of catecholamines in obesity have been mainly mediated via the β2 and β3-adrenergic receptors in humans. Further, β2-adrenoceptors importantly influence vascular reactivity and may regulate blood pressure. Genetic polymorphisms of the β-adrenoceptor gene have been shown to alter the function of several adrenoceptor subtype and thus to modify the response to catecholamine. Among β2-adrenoceptor polymorphisms, Arg16Gly, Gln27Glu, and Thr164Ile are considered the most functionally important. β2-adrenoceptor genes have been studied in relation to obesity. Genetic variations in the β3-adrenoceptor, such as the Try64Arg variant, are also associated with both obesity and hypertension. However, the precise relationships of the polymorphisms of β2- and β3-adrenoceptor genes with sympathetic nervous system activity, obesity, hypertension and metabolic syndrome have not been fully clarified. A few studies regarding the relationships between sympathetic nervous activity and adrenoceptor polymorphisms in the same studies have been reported. Masuo et al. have observed in a series of studies in a Japanese male cohort that: 1) β2-adrenoceptor polymorphisms are associated with heightened sympathetic nerve activity, and predict the future onset of obesity and hypertension in nonobese individuals, 2) β2-adrenoceptor polymorphisms accompanied by heightened sympathetic nerve activity and abdominal obesity, predict weight loss resistance during a weight loss program, and also predict rebound weight gain, 3) β2-adrenoceptor polymorphisms are linked to blunted leptin-mediated sympathetic nerve activation, leptin-resistance and resultant obesity, 4) β2-adrenoceptor polymorphisms are related to insulin-resistance, in both nonobese and obese normotensive individuals, and 5) β3-adrenoceptor polymorphism is directly linked to obesity and hypertension, but only in obese individuals. These suggest that β2- and β3-adrenoceptor polymorphisms accompanying heightened sympathetic nerve activity play a major role in the onset and the maintenance of obesity, hypertension and insulin resistance. This article provides the current topics involving the influence of the sympathetic nervous system and β2- and β3-adrenoceptor polymorphisms in obesity, hypertension and metabolic syndrome (type 2 diabetes). Keywords: Beta2-adrenoceptor polymorphisms, beta3-adrenoceptor polymorphisms, sympathetic nervous system activity, obesity, hypertension, type 2 diabetes mellitus, metabolic syndrome

β2 Adrenoceptor Polymorphisms Predict Response to β2-Agonists in Children With Acute Asthma

Martin AC, Zhang G, Rueter K, et al. J Asthma. 2008;45(5):383–388 PURPOSE OF THE STUDY. To evaluate the influence of single-nucleotide polymorphisms in the β2-adrenoceptor gene on the response to inhaled β2 agonists in children with acute asthma exacerbations. STUDY POPULATION. There were 148 children aged 2 to 16 years presenting to the emergency department (ED) with an acute asthma exacerbation recruited between July 2002 and September 2004. METHODS. The ED physician's diagnosis was based on the presence of wheezing with increased difficulty of breathing. Children were excluded if they had wheeze attributable to other factors (ie, cystic fibrosis, bronchopulmonary dysplasia, foreign body). The standard management of children presenting with an asthma exacerbation included oxygen if saturations were ≤94%, β2 agonist (salbutamol) and an anticholinergic (ipratropium bromide) via metered-dose inhaler with large-volume spacer at 20-minute intervals for the first hour, and prednisolone 1 mg/kg (maximum 40 mg). The initial severity of the asthma episode was determined by using a previously validated scoring system with a possible score of 5 to 15 (5–7 indicated mild; 8–11, moderate; 12–15, severe). An age-specific score of 1 to 3 was assigned to 5 variables (oxygen saturation, respiratory rate, work of breathing, auscultation, and ability to talk). Response to inhaled β2 agonist was measured by determining the time taken to reduce the frequency of β2 agonists from 20-minute intervals to administration at 1, 2, and 4 hourly intervals, with longer times indicating poorer response to treatment. Polymerase chain reaction was used on peripheral blood samples to amplify the 2 polymorphisms of interest (Arg16Gly and Gln27Glu). RESULTS. There were 58 (39.2%) patients who were homozygous Gln27Gln, 69 (46.6%) patients who were heterozygous Gln27Glu, and 21 (14.2%) patients who were homozygous Glu27Glu. Subjects homozygous for Gln were slowest to respond to inhaled β2 agonists and took the longest to reach 1, 2, and 4 hourly β2-agonist treatments (time to 1 hourly: 2.6 ± 2.9 hours; time to 2 hourly: 10.6 ± 9.3 hours; time to 4 hourly: 29.8 ± 23.5 hours). Heterozygotes for Gln had an intermediate response (time to 1 hourly: 2.0 ± 2.8 hours; time to 2 hourly: 10.7 ± 18.1 hours; time to 4 hourly: 28.5 ± 26.2 hours). Homozygotes for Glu had the most rapid response (time to 1 hourly: 1.4 ± 1.2 hours; time to 2 hourly: 6.8 ± 8.9 hours; time to 4 hourly: 24.3 ± 22.2 hours). No significant associations were found between Arg16Gly and response to treatment. After controlling for asthma severity score, previous use of asthma medications, age, gender, and concurrent upper respiratory infection symptoms, homozygotes for Gln were still more likely to have the slowest response to treatment. No associations were found between β2-adrenoreceptor genotype and asthma severity scores or asthma patterns. CONCLUSIONS. This study demonstrates an association between single-nucleotide polymorphisms and response to β2-agonist treatment for children during an acute asthma exacerbation as compared with stable nonacute disease. Children who are homozygous for β2-adrenoceptor Gln27Gln respond less effectively to inhaled β2-agonist therapy. REVIEWER COMMENTS. As the authors pointed out in the report, most children are treated effectively during an acute asthma exacerbation. The length of treatment with inhaled β2 agonists, however, can be variable and unpredictable. The results of this study explain, at least in part, this variability. In the future, knowledge of a patient's β2-adrenoceptor genotype can possibly guide decisions about duration and need for additional therapies during an acute asthma exacerbation.

Abstract 5161:β 1 (Arg389Gly, Ser49Gly)- and β2 (Arg16Gly) -adrenoceptor Polymorphisms are Related to Left Ventricular Hypertrophy in Middle-aged, Nonobese, Normotensive Men, but Through Different Mechanisms

Objective: β2-adrenoceptor (ADRB2) polymorphisms are closely linked to hypertension and obesity, and both of them are major cardiac risk. Left ventricular hypertrophy (LVH) is more common in people who have hypertension or obesity. We examined the relationships between ADRB1 and ADRB2 polymorphisms and LVH in nonobese, normotensive subjects. Methods: In 447 middle-aged, normotensive, nonobese men, ADRB1 (Arg389Gly, Ser49Gly) and ADRB2 (Arg16Gly, Gln27Glu) polymorphisms, BMI, BP, heart rates (HR), total body fat-mass, waist-to-hip ratio (W/H), plasma norepinephrine (NE) and ECG were measured after overnight fasting in the supine position. LVH was determined by ECG. Results: Thirty-nine subjects (8.7%) showed LVH on ECG. Subjects with LVH had higher plasma NE and HR compared to those without LVH (both P&lt;.05). Distributions of Gly389 and Gly49 alleles of ADRB1 polymorphisms were 23.5% (Arg/Arg:Arg/Gly:Gly/Gly=270:144:33) and 14.1% (Ser/Ser:Ser/ Gly:Gly/Gly=327:114:6). Thirty-seven subjects with LVH (94.9%) carried Gly389 and Gly49 alleles, especially homozygous for Gly389 or Gly49. Subjects with Gly389 or Gly49 alleles had higher frequencies of LVH (20.9% vs. 0.7%, 30.8% vs. 0.6%). Subjects carrying Gly389 or Gly49 alleles had higher plasma NE and HR (both P&lt;.05), whereas BMI, fat mass, W/H and BP were similar. The Gly16 and Glu27 alleles of ADRB2 polymorphisms were noted in 42.8% (Arg/Arg :Arg/Gly:Gly/Gly=69:245:133) and 36.6% of the subjects (Gln/Gln:Gln/Glu:Glu/ Glu=176:215:56). Twenty-nine subjects with LVH (74.4%) carried Gly16 allele, especially Gly16 homozygous. Subjects with Gly16 allele had higher frequencies of LVH (P&lt;.05), and they had greater BMI, fat mass, W/H, BP, HR and NE compared to those without Gly16 allele (all P&lt;.05). Conclusions: Subjects carrying Gly389 and Gly49 alleles of ADRB1 polymorphisms and Gly16 allele of ADRB2 polymorphism had higher frequency of LVH accompanying high plasma NE. ADRB1 and ADRB2 polymorphisms play important roles in LVH even in nonobese, normotensive subjects. ADRB1 polymorphisms might relate to LVH through heightened sympathetic nerve activity, but ADRB2 polymorphisms might relate to LVH through obesity, hypertension and heightened sympathetic nerve activity.

Neurovascular Role of Sympathetic Nervous System and Beta-Adrenoceptor Polymorphisms in Obesity and Hypertension

Obesity, hypertension, and obesity-related hypertension are rapidly growing public health problems. Heightened sympathetic nerve activity is well-established observations in obesity and hypertension. Reduced energy expenditure and resting metabolic rate are predictive of weight gain, and the sympathetic nervous system participates in regulating energy balance through thermogenesis. The thermogenic effects of catecholamines in obesity have been mainly mediated via the β2 and β3-adrenergic receptors in humans. Further, β-adrenoceptors importantly influence vascular reactivity and insulin resistance. Obesity and hypertension have a strong genetic determinant. Genetic polymorphisms of the β- adrenoceptor gene have been shown to alter the function of β2- and β3-adrenoceptor subtype and thus to modify the response to sympathetic nerve activity (catecholamines). Among β2-adrenoceptor polymorphisms, Arg16Gly and Gln27Glu are considered the most functionally important in relation to obesity and hypertension. Genetic variations in the β3- adrenoceptor, such as the Try64Arg variant, are also associated with both obesity and hypertension. However, the precise relationships of the polymorphisms of β2- and β3-adrenoceptor genes with obesity and hypertension have been conflicting. Focusing on the relationships between the sympathetic nervous system and β2- and β3-adrenoceptor polymorphisms in obesity and hypertension might help to understanding these conflicting findings. The purpose of this article is to provide the current findings on the relationships between β-adrenoceptor polymorphisms, obesity, and hypertension including our own findings.

Influence of β2‐adrenoceptor polymorphisms on the response to chronic use of albuterol in asthmatic children

Several studies have suggested that after regular use of short acting beta2-agonists the bronchodilator effect of the drug may decline and this condition would be related to polymorphisms of the beta2-adrenergic receptor (beta2-AR). To assess the frequency of beta2-AR polymorphisms in asthmatic children from Argentina, and to evaluate their influence on bronchodilator desensitization to albuterol over a 4-week treatment. beta2-AR genotypes were determined in 117 children with asthma and 101 of them were under 4 weeks treatment with albuterol. Spirometric changes in FEV(1) were recorded at the beginning (day 1) and at the end of the study (day 30) and compared to genotypes at position 16 and 27 of the receptor. The frequency of the polymorphisms was calculated in all population. The presence of glutamine at position 27 (Gln27) was significantly more frequent in this Argentinean study population than in other Caucasian populations. The homozygosity for Gln27 polymorphism was associated to a desensitization of the receptor with a decline in the bronchodilator response to albuterol after chronic use. Gln27 polymorphism might be a marker for adverse clinical outcomes with chronic beta2-agonist exposure in children with asthma from Argentina.

β2-Adrenoceptor Polymorphisms Predict Response to β2-Agonists in Children with Acute Asthma

The aim of this study was to determine the influence of single nucleotide polymorphisms in the β2-adrenoceptor gene, on the response to inhaled β2-agonists in children with acute asthma. We hypothesised that children with polymorphisms that generate enhanced receptor downregulation in vitro, Gly16 and Gln27, would have a slower response to β2-agonist therapy during acute asthma. One hundred and forty-eight children with acute asthma were recruited and genotyped for β2Arg16Gly and β2Gln27Glu. For Gln27Glu, individuals Gln27Gln took longest to stretch out to 1, 2 and 4 hourly β2-agonists, followed by heterozygotes who were intermediate and Glu27Glu who responded most rapidly (1hourly: 2.6hr vs. 2.0 vs. 1.4, p = 0.02; 2 hourly: 10.6hr vs. 10.7 vs. 6.8, p = 0.07; 4 hourly: 29.8hr vs. 28.5 vs. 24.3, p = 0.30). The ability to prospectively identify children who respond less effectively to β 2-agonists during an acute asthma attack has the potential to allow the generation of genotype-specific treatment pathways.

Exploration of the β2-adrenergic receptor regulatory regions: the next step in the holy grail of asthma pharmacogenetics research

exploration of the β2-adrenergic receptor (ADRB2) has been the holy grail of asthma pharmacogenetics research since the gene was cloned two decades ago. The evolution in our understanding of genetic variants in the ADRB2 reflects both the progress and the limitations in exploring the contributions

β2-Adrenoceptor Polymorphisms and Asthma From Childhood to Middle Age in the British 1958 Birth Cohort: A Genetic Association Study

Hall IP, Blakey JD, Al Balushi KA, et al. Lancet. 2006;368:771–779 PURPOSE OF THE STUDY. To determine if functionally relevant polymorphisms in the β2-adrenoceptor gene (ADRB2) could predict prognosis in childhood asthma and determine long-term asthma prevalence. STUDY POPULATION. Participants of a previously studied United Kingdom birth cohort (N = 8018) that had been followed to 35 years were followed for an additional 10 years. The participants were identified before the age of 16. METHODS. Parental interviews were conducted at ages 7, 11, and 16 years followed by patient interviews at ages 23, 33, and 42 years regarding history of wheezing and asthma. Those with a childhood history of wheezing had spirometry performed at age 34 to 35, and repeated at age 44 to 45. DNA blood samples were also obtained at ages 44 to 45. The variants in the coding region selected for genotyping were Arg16Gly, Gln27Glu, and Thr164Ile. A separate population of severely asthmatic subjects was recruited to search for potential novel polymorphisms within the ADRB2 gene. The effect of ADRB2 variants on the prevalence and severity of asthma and/or wheezing in childhood (7 years old) and adulthood (at 42 years old) and the persistence of wheezing illness from childhood (age 0–16 years) into adulthood (42 years old) were studied. RESULTS. No single-nucleotide polymorphism was associated with lifetime onset of asthma or onset of asthma during any specific age range during childhood or adulthood. In comparing the frequency and prevalence of the 3 genotypic variants to the prognosis of children with wheeze or asthma, asthma persistence was associated with both the Arg16 and Gln27 alleles. The association with asthma prognosis could not be related to allergy. No significant associations were found with spirometry results and the polymorphisms. No new coding variants were discovered. Meta-analyses of previously published studies, together with the data from this study, showed that the previously described associations of the Gln27Glu and Arg16Gly variants with either asthma or severity, in both children and adults, were lost by inclusion of the results of this study. CONCLUSIONS. The Arg16 and Gln27 polymorphisms may have a small effect on prognosis of wheezing in childhood with persistent asthma and/or wheezing. However, asthma prevalence in the British population was not related to any β2-adrenoceptor polymorphisms. REVIEWER COMMENTS. Although previous studies have focused on correlating genotypic determinations in position 16 and 27 of ADRB2 with asthma severity, this unique birth-cohort study examined these genotypic associations with asthma prevalence and prognosis. The small prognostic effect of the Arg16 and Gln27 polymorphisms (being more common in those with persistent wheezing or asthma) seen in this study needs to be confirmed by additional studies. If confirmed, one could genotypically identify children with asthma who are more likely to have persistence of symptoms. In addition, one could determine if long-term asthma outcomes after early and persistent therapeutic interventions in children were genotype related.

Abstract 3559: β2-adrenoceptor Protein Expression Is Different Between Buffy Coat And Adipose Tissue

Background: Obesity and hypertension are associated with β2-adrenoceptor polymorphisms accompanying with heightened sympathetic nerve activity. In the present study we compared β2-adrenoceptor protein expression between buffy coats (white blood cells as a representive for whole-body) and abdominal subcutaneous fat to further evaluate the contributions of sympathetic nerve activity and β2-adrenoceptor to obesity and hypertension. Methods: In 17 obese normotensive Caucasian men (BMI≥30.0 kg/m2) and 8 age-matched lean Caucasian men (BMI&lt;25 kg/m2), we measured BMI, blood pressure (BP), whole-body plasma norepinephrine (NE) spillover, NE clearance, plasma leptin, and β2-adrenoceptor protein concentration and leptin receptor protein concentration in buffy coats and in abdominal subcutaneous adipose tissue. The β2-adrenoceptor protein expression and leptin receptor protein expression were analysed by Western blotting. Results: Obese subjects had significantly higher whole-body NE spillover (673±245 ng/mL vs. 431±156, P&lt;0.05), plasma leptin (15.2±4.3 ng/mL vs. 4.8±2.4, P&lt;0.01), and BP levels (P&lt;0.05) compared to lean subjects, but the whole-body NE clearance rate was similar. Obese subjects had significantly greater expression of β2-adrenoceptor protein in buffy coats (P&lt;0.05) compared to lean subjects, while they had significantly less β2-adrenoceptor protein expression in abdominal fat (P&lt;0.05). Leptin receptor protein expression in both buffy coats and abdominal fat were greater in obese subjects compared to lean subjects. Conclusions: Obese subjects had greater β2-adrenoceptor protein expression in buffy coats, but less β2-adrenoceptor protein expression in fat. This may suggest that blunted sympathetic nerve activity in adipose tissue (observed by less β2-adrenoceptor protein expression in fat) might relate to obesity and heightened sympathetic nerve activity in whole-body (observed by greater β2-adrenoceptor protein expression in buffy coats and higher NE spillover) may be linked to hypertension. The findings support the concept of selective leptin resistance. Sympathetic nerve activity and β2-adrenoceptor, not leptin, plays an important role is mechanisms of obesity and obesity-related hypertension.

Analysis of the association between bronchial hyperresponsiveness and genetic polymorphism of β2-adrenoceptor in adolescents with long-term asthma remission

Purpose : We hypothesized that the persisting bronchial hyperresponsiveness (BHR) of adolescents with asthma remission may be controlled mainly by genetic factors, and the BHR of symptomatic asthma by airway inflammation. β2-adrenoceptor gene is considered to be a candidate gene in the development of BHR. Thus, β2-adrenoceptor gene polymorphism may be associated with the BHR of adolescents with asthma remission, but not with the BHR of symptomatic asthma. To evaluate this hypothesis, β2-adrenoceptor gene polymorphism at 2 sites (Arg16-Gly, Gln27-Glu) were examined. Methods : Two hundred two adolescents with BHR (PC202-adrenoceptor polymorphism were evaluated by PCR-based methods. Results : Gly/Gly allele and Gly16-Gln27 haplotype were more prevalent in the remission group than in the control group (P=0.01, P=0.02), although there was no difference between the symptomatic group and the control group. In the remission group, there was significant difference in geometric mean of PC20 among the 3 groups subdivided by the number of Gly16-Gln27 haplotype, showing that the Gly16-Gln27 haplotype was positively associated with BHR. However, no association was found between Gly16-Gln27 haplotype and BHR in the symptomatic group. Conclusion : This study demonstrates that β2-adrenoceptor polymorphism at amino acid 16 and 27 was associated with BHR persisting in adolescents with asthma remission.

The influence of the AA 16 β2-adrenoceptor polymorphism on systemic and airway responses in asthma

Background The impact of the polymorphic amino acids 16 and 27 of the β 2-adrenoceptor ( β 2-AR) on the susceptibility to bronchodilator tolerance remains unclear since clinical studies thus far have shown discordant results. Tolerance towards the effects of inhaled β 2-AR agonists generally is more easily shown for systemic parameters than for airway effects and can be substantial. This study evaluates whether differences exist between position 16 homozygous genotyped asthmatics, in tolerance development towards airway responses and the systemic effect hypokalemia. Methods Twenty patients were genotyped for amino acids 16 and 27 of the β 2-AR gene. Time-effect curves for FEV 1 and serum potassium concentration were constructed after s.c. administration of terbutaline after two-week treatment periods with either terbutaline inhalation or matching placebo in a double-blind, randomised and cross-over design. Statistical analysis was done by a repeated measures multivariate analysis on area under time-effect curve (AUC). Main results Pre-treatment with inhaled terbutaline did not influence the improvement in FEV 1 in response to s.c. terbutaline and there were no significant differences between Arg-16 and Gly-16 individuals in this respect. Pre-treatment with inhaled terbutaline resulted in an overall increase of baseline plasma potassium before administration of s.c. terbutaline (3.78–3.95 mmol/L, p=0.034). However, this effect appeared to be solely confined to the Arg-16 homozygous individuals, leading to a statistically highly significant difference between the Arg-16 and Gly-16 subjects ( p=0.005). However, there was no genotype related difference in the decrease in plasma potassium response to s.c. terbutaline relative to baseline. Conclusion In patients carrying the Arg-16 genotype the development of hypokalemia by s.c. terbutaline is attenuated after pre-treatment with inhaled terbutaline, be it on the basis of higher baseline values.

Abstract 4187: Glu27 β 2 -Adrenoceptor Polymorphism Enhances Body Weight Loss and 24h-Ambulatory Blood Pressure Reduction in Obese Women

Introduction: Obesity has been linked to genetic and environmental determinants. Glu27 β 2 -adrenoceptor polymorphism has been associated with obesity and hypertension. In addition, muscle vasodilatation during physiological maneuvers is increased in individuals with Glu27 β 2 -adrenoceptor polymorphism. Not known is the impact of hypocaloric diet and exercise training on body weight and blood pressure (BP) in obese individuals with Glu27 β 2 -adrenoceptor polymorphism. Methods: From an initial sampling of 216 volunteers, we studied 42 middle-age normotensive obese women selected to represent two genotypes: 19 with Glu27 β 2 -adrenoceptor polymorphism and 23 wild type Gln27 (883± vs 86±2kg, P30.48, respectively). Hypocaloric diet consisted of a 600kcal/day reduction. Exercise training consisted of three 60-min exercise session/week during 4 months. Twenty-four hour ambulatory BP, cardiac output (CO, carbon dioxide rebreathing), and muscle sympathetic nerve activity (MSNA, microneurography) were evaluated pre and post interventions. Results: Hypocaloric diet and exercise training significantly decreased body weight, body mass index (BMI), 24-hour systolic BP, 24-hour pulse pressure, and CO in Glu27 and Gln27 groups. However, the comparisons between groups showed that the reduction in body weight (10.7±1 vs 7.4±1kg, P =0.02), BMI (4.1±0.4 vs 2.8±0.2kg/m 2 , P =0.01), 24-hour systolic BP (5.1±1 vs 2.2±1mmHg, P =0.05), 24-hour pulse pressure (3.6±1 vs 1.5±1mmHg, P =0.01), and CO (0.8±0.2 vs 0.4±0.1L/min, P =0.04) were significantly greater in Glu27 group than in Gln27group. No significant differences in diastolic BP, mean BP, and MSNA levels between groups were found. Conclusions: Obese women with Glu27 of the β 2 -adrenoceptor are more susceptible to body weight loss, and BP and CO reduction after hypocaloric diet and exercise training than wild type Gln27 obese women.

β2-adrenoceptor polymorphisms and asthma from childhood to middle age in the British 1958 birth cohort: a genetic association study

Functionally relevant polymorphisms of the beta2-adrenoceptor gene (ADRB2) are common in white populations, but their contribution to the burden of airways disease in the population is uncertain. We aimed to relate the long-term prevalence of asthma or wheeze to functional coding region polymorphisms in the ADRB2 gene. The British 1958 birth cohort consisted of all people born in Britain during a week in 1958. Asthma, wheezy bronchitis, and wheezing were ascertained by interview at ages 7, 11, 16, 23, 33, and 42 years, and lung function tests at 35 and 45 years. DNA samples from 8018 participants in the 45-year follow-up were genotyped for three coding variants in the ADRB2 gene. We extend the follow-up of this nationwide cohort by a further 10 years and relate asthma prevalence, prognosis, and lung function to functional coding region polymorphisms in the ADRB2 gene in the cohort members who contributed DNA samples. We also compared and combined our findings with those reaching significance in two previous meta-analyses. Half the cohort (4105 of 8018) had some history of wheezing illness by age 42 years. Neither lifetime prevalence nor age at onset were related to ADRB2 coding variants. However, the common polymorphisms Arg16Gly (rs1042713, Arg 16 allele frequency 36.3%) and Gln27Glu (rs1042714, Glu 27 allele frequency 44.6%) were significantly associated with persistence of asthmatic symptoms from childhood to middle age. Among homozygotes for the Arg16-Gln27 haplotype at these loci, 19.3% (41 of 212) childhood wheezers had five or more wheezing episodes in the past year at age 42, compared with 11.9% (71 of 599) with no copy of this haplotype. However, only 3% of all frequent adult wheezing was statistically attributable to this haplotype. The less common Thr164Ile polymorphism (rs1800888, Ile allele frequency 1.5%) was not a major predictor of either frequency or prognosis of asthma. Our data do not support the findings of previous meta-analyses when considered in isolation or when combined with their contributory studies. ADRB2 polymorphisms might predict a small component of the long-term prognosis in childhood asthma, but are not important determinants of asthma incidence or prevalence in the British population.

Association of beta-2-adrenoceptor polymorphisms and pulmonary function in patients with chronic obstructive pulmonary disease

Aims: The Dutch Hypothesis suggests that asthma and chronic obstructive pulmonary disease may share some pathogenic mechanisms. There is considerable evidence that polymorphisms of the β2 adrenoceptor have disease-modifying roles in juvenile onset asthma, determining severity and response to β agonists, but not determining disease susceptibility. There is evidence from family and twin studies to suggest that chronic obstructive pulmonary disease (COPD) also has a significant genetic component. We therefore hypothesized that β2 adrenoceptor polymorphisms would have similar disease modifying roles in patients with COPD. Methods: One hundred and ninety-five COPD subjects and 142 matched controls were recruited. All had detailed clinical phenotyping. Subjects were genotyped for the Agr Gly polymorphism at codon 16, the Gln Glu polymorphism at codon 27, and the SNPC/T-47 promoter polymorphism. Results: In patients with COPD (mean age 67, 57% male), individuals with the homozygous Gly16/homozygous Glu27/homozygous SNP −47*C genotype had significantly worse lung function as measured by forced expiratory volume 1, expressed as a percentage of its predicted value (39.2 compared with 45.8, P = 0.004), and for forced vital capacity (FVC) percent predicted (77.2 compared with 70.4, P = 0.02). The polymorphisms had no effect on disease susceptibility. Conclusion: The Arg16, Gln27, SNPC/T-47 β2 adrenoceptor polymorphisms may have disease modifying roles in patients with COPD.