The Arg389Gly beta1-adrenoceptor polymorphism and catecholamine effects on plasma-renin activity.

OBJECTIVES: The purpose of this research was to find out whether, in humans, dobutamine-induced hemodynamic effects and increase in plasma-renin activity (PRA) might be beta1-adrenoceptor (beta1AR) genotype-dependent. BACKGROUND: In vitro Arg389Gly-beta1AR polymorphism exhibits decreased receptor signaling. METHODS: We studied 10 male homozygous Arg389-beta1AR subjects and 8 male homozygous Gly389beta1AR subjects; to avoid influences of codon 49 polymorphism, all were homozygous Ser49-beta1AR. Subjects were infused with dobutamine (1 to 6 microg/kg/min) with or without bisoprolol (10 mg orally) pretreatment, and PRA, heart rate, contractility, and blood pressure were assessed. RESULTS: With regard to PRA, dobutamine increased PRA more potently in Arg389-beta1AR versus Gly389-beta1AR subjects. Bisoprolol markedly suppressed the dobutamine-induced PRA increase in Arg389- but only marginally in Gly389-beta1AR subjects. With regard to hemodynamics, dobutamine caused larger heart rate and contractility increases and diastolic blood pressure decreases in Arg389- versus Gly389-beta1AR subjects. Bisoprolol reduced dobutamine-induced heart rate and contractility increases and diastolic blood pressure decreases more potently in Arg389- versus Gly389-beta1AR subjects. CONCLUSIONS: Codon 389 beta1AR polymorphism is a determinant not only of hemodynamic effects but also of PRA. Thus, beta1AR polymorphisms may be useful for predicting therapeutic responses to betaAR-blocker treatment.     

The Arg 389 Gly beta1-adrenergic receptor gene polymorphism and human fat cell lipolysis.

BACKGROUND: The beta1-adrenoceptor is a candidate gene for obesity because of its role in catecholamine-induced energy homeostasis. A common Arg 389 Gly variant polymorphism has been shown in recombinant cells to influence its-coupling properties. OBJECTIVE: To investigate the effect of the Arg 389 Gly beta1-adrenoceptor polymorphism on catecholamine-induced lipolysis in native human fat cells obtained by subcutaneous biopsy. SUBJECTS: Two-hundred and ninety-eight apparently healthy male and female subjects with a wide variation in body mass index (BMI, 18-60 kg/m2). MEASURES: The lipolytic sensitivities and maximum lipolytic action of noradrenaline and the selective adrenoceptor agonists dobutamine (beta1), terbutaline (beta2) and CGP 12177 (beta3) were determined in isolated subcutaneous adipocytes and related to beta-adrenoceptor radioligand binding parameters. RESULTS: No differences in the sensitivity or maximum lipolytic capacity of the agonists were found between the genotypes. This was true both when all subjects were analyzed together and when subgroups (lean, obese, men, women) were analyzed separately. Radioligand binding to beta1- or beta2-adrenoceptors was also similar between genotypes. The polymorphism had no important influence on either BMI or the distribution of obese and non-obese subjects between the genotypes. CONCLUSION: The distribution of the Arg 389 Gly polymorphism is similar in lean and obese subjects and has no apparent effect on the lipolytic response to beta-adrenergic stimulation in native human adipocytes. This suggests, despite the altered coupling properties reported in recombinant cells, that the Arg 386 Gly polymorphism has no important influence on human obesity.     

Association between obesity and a polymorphism in the beta(1)-adrenoceptor gene (Gly389Arg ADRB1) in Caucasian women

INTRODUCTION: Genetic variants affecting adrenoceptors have been suggested to influence body fatness. A putative gain-of-function polymorphism in the beta(1)-adrenoceptor was recently discovered (Gly389Arg ADRB1). We examined the association between Gly389Arg ADRB1 and obesity status in a large cohort of well-characterized individuals. METHODS: First, a large cohort of 931 Caucasian women (55.0+/-12.2 y) were genotyped for Gly389Arg ADRBbeta1 and we examined the association of the Arg allele with body weight and BMI (Gly/Gly, n=54; Gly/Arg, n=360; Arg/Arg, n=517). To further examine phenotypes regulating energy balance and body fatness, we examined the contribution of the Arg allele to body composition (DEXA), fat distribution (CT scan), resting energy expenditure, energy and macronutrient intake, maximal oxygen capacity, and physical activity in a subsample of 214 women from the main cohort that had been carefully characterized (Gly/Gly, n=19; Gly/Arg, n=82; Arg/Arg, n=113). RESULTS: In the entire cohort (n=931), allele frequencies were 0.25 and 0.75 for the Gly and Arg alleles, respectively. In this cohort, we found that each Arg allele was associated with greater body weight of 2.91 kg (P=0.01) and BMI of 0.86 kg/m(2) (P=0.05). Accordingly, in the subsample of women, each Arg allele was associated with greater fat mass (3.71 kg; P=0.008). Other phenotypes were not significantly associated with the presence of the Arg allele. CONCLUSIONS: This is the first study to investigate the relationship between the Gly389Arg ADRB1 variant and obesity. We found that the Arg allele is associated with greater body weight and BMI in Caucasian women due to a greater fat mass.     

The Arg389Gly beta1-adrenergic receptor gene polymorphism and susceptibility to faint during head-up tilt test.

AIMS: To investigate the association of the Gly389 allele with positive head-up tilt test (HUT) in a Mexican Mestizo population. METHODS AND RESULTS: HUT results were compared between carriers (one or two copies of the Gly389 allele) and non-carriers (Arg389Arg genotype) of the Gly389 allele of the beta(1)AR gene in 50 patients with unexplained syncope. Thirty-three patients (66%) had a positive HUT. Patients with a positive HUT had a higher Gly389 allele frequency compared with those with a negative test (30.3 vs. 3%; OR 13; pC = 0.012). Moreover, when comparing positive HUT in passive drug-free phase, positive HUT in pharmacological (nitrate) phase, and negative (both phases), a decreasing gradient in the frequencies of the Gly389 allele was found among the three groups: 45.4, 22.7, and 3%, respectively. CONCLUSION: An association of positive tilt table testing to a single nucleotide polymorphism with a Gly to Arg switch at position 389 of the beta(1)AR was found. This polymorphism may contribute to susceptibility to faint during orthostatic challenge.     

β1肾上腺素能受体Gly 389Arg多态性与原发性高血压的关系

目的:探讨汉族人群β1肾上腺素能受体Gly 389Arg多态性与原发性高血压的关系. 方法:采用聚合酶链反应-限制性长度片段多态性技术分析原发性高血压患者和正常人群β1肾上腺素能受体Gly 389Arg多态性.结果:高血压组Arg/Arg,Arg/Gly,Gly/Gly基因型频率分别为59.06%、35.09%、5.85%,正常对照组分别为43.55%、45.97%、10.48%;两组间三种基因型频率分布有统计学差异(x2=7.420,P＜0.05);高血压组Arg等位基因频率为76.61%,Gly等位基因频率为23.39%,正常对照组分别为66.53%、33.47%,两组间等位基因频率分布存在统计学差异(x2=7.299,P＜0.05);高血压组Arg纯合子基因型频率和Arg等位基因频率均明显高于对照组. 结论:β1肾上腺素能受体Gly 389Arg多态性可能与原发性高血压发病有关.     

β_1肾上腺素能受体Gly389Arg多态性与原发性高血压的关系

目的探讨汉族人群β1肾上腺素能受体Gly389Arg多态性与原发性高血压的关系。方法采用聚合酶链反应-限制性长度片段多态性技术分析原发性高血压患者和正常人群β1肾上腺素能受体Gly389Arg多态性。结果高血压组Arg/Arg,Arg/Gly,Gly/Gly基因型频率分别为59.06%、35.09%、5.85%,正常对照组分别为43.55%、45.97%、10.48%;两组间三种基因型频率分布有统计学差异(χ2=7.420,P<0.05);高血压组Arg等位基因频率为76.61%,Gly等位基因频率为23.39%,正常对照组分别为66.53%、33.47%,两组间等位基因频率分布存在统计学差异(χ2=7.299,P<0.05);高血压组Arg纯合子基因型频率和Arg等位基因频率均明显高于对照组。结论β1肾上腺素能受体Gly389Arg多态性可能与原发性高血压发病有关。     

Arg389Gly polymorphism of the human beta1-adrenergic receptor in patients with nonfatal acute myocardial infarction

Background

We sought to investigate the relation between the Arg389Gly polymorphism in the human β1-adrenergic receptor (ADRB1) gene and acute myocardial infarction (AMI). It was previously reported that augmented sympathetic activity might play an important role as a trigger of AMI by enhanced hemodynamic or mechanical forces through ADRB1 activation. Recently, a common polymorphism has been identified at amino acid position 389 (Arg or Gly) of the human ADRB1, within a region important for receptor-Gs protein coupling and subsequent agonist-stimulated adenylyl cyclase activation.

Methods

To investigate the relation between the Arg389Gly polymorphism in the ADRB1 gene and AMI, we genotyped 354 patients with AMI and 354 age- and sex-matched control subjects by use of polymerase chain reaction amplification and the restriction fragment length polymorphism analysis.

Results

The prevalence of the Arg389 homozygote (CC) genotype was significantly more frequent in patients with AMI than in control subjects (68.1% vs 47.2%, P < .0001). In logistic regression models, the odds ratio (OR) of Arg389 homozygote (CC) versus Arg389Gly heterozygote (CG) + Gly389 homozygote (GG) genotypes between control subjects and patients with AMI was 2.86 (95% CI 1.92-4.26, P = .0001). The association of the Arg389Gly polymorphism of ADRB1 with AMI was statistically significant and independent of other risk factors.

Conclusion

Our findings suggest that the genotype of Arg389Gly polymorphism in the human ADRB1 gene is associated with AMI.     

比索洛尔治疗心力衰竭疗效和β1受体多态性的相关性研究

目的 探讨β1受体(Arg389Gly)基因多态性和靶剂量比索洛尔治疗慢性心力衰竭(心衰)疗效的相关性,预测心衰的预后.方法 110例心衰患者,靶剂量比索洛尔治疗3个月后作β1受体Arg389Gly多态性测定,将患者分成CC组(Arg389Arg)、CG组(Arg389Gly)、GG组(Gly389Gly),观察治疗前后各项心功能指标变化的组间差异.另选取100例正常健康人群,比较正常人群和心衰患者之间基因型频率.结果 本试验测定的上海地区健康人群和心衰患者β1受体Arg389Arg、Arg389Gly、Gly389Gly基因型频率分别为0.53、0.40和0.07,0.51、0.40和0.09,均符合HardyWeinberg定律(x2=0.135,P=0.713;x2=0.002,P=0.966).心衰患者三种基因型之间一般临床特征、心脏结构和心功能情况差异无统计学意义(P＞0.05).比索洛尔治疗后,左室射血分数在CC组和GG组分别升高了(7.37±6.72)%和(1.33±2.87)%,脑利钠肽在CC组和GG组分别下降了(177.67±111.87)ng/L和(75.67±123.63)ng/L,两组间差异有统计学意义(均为P＜0.01).结论 上海地区健康人群和心衰患者β1受体389位点基因型频率分布相似,β1受体Arg389Gly多态性和心衰的严重程度无关.CC组心衰患者对β1受体阻滞剂治疗更为敏感,预后也较GG组好.     

Studies of associations between the Arg389Gly polymorphism of the beta1-adrenergic receptor gene (ADRB1) and hypertension and obesity in 7677 Danish white subjects.

AIMS: Activation of the beta(1)-adrenergic receptor (ADRB1) causes increased lipolysis in adipose tissue and enhances cardiac output. Analysis of the association of the functional ADRB1 Arg389Gly variant with obesity and hypertension has given ambiguous results. To clarify the potential impact of this variant on obesity and hypertension in the general population, we examined the Arg389Gly variant in a relatively large-scale population-based study. METHODS: Case-control studies and quantitative trait analyses were carried out in 7677 Danish Caucasians who were genotyped for the Arg389Gly variant (dbSNP rs1801253) using matrix-assisted laser desorption/ionization time-of-flight mass spectrometry. RESULTS: A weak association between the Gly allele of the Arg389Gly variant and obesity was observed when comparing cases (n = 1540) defined as body mass index (BMI) > 30 kg/m(2) with control subjects (n = 6108) defined as BMI < or = 30 kg/m(2) for both allele frequencies (P = 0.05) and genotype distribution (P = 0.05). Case-control studies (cases n = 2518; control n = 3981) examining the effect on hypertension showed no association with allele frequencies (P = 0.3) or genotype distribution (P = 0.5); however, in the quantitative trait analyses, individuals carrying the Gly allele had slightly but significantly lower diastolic (Arg/Arg = 81.9 mmHg vs. Gly-allele carriers = 81.5 mmHg) and systolic (Arg/Arg = 129.4 mmHg vs. Gly-allele carriers = 128.8 mmHg) blood pressure as well as a lower mean arterial blood pressure. CONCLUSION: Our results suggest that the Arg389Gly polymorphism does not have any clinically important impact on the pathogenesis of obesity in Danish white subjects. Furthermore, despite the observed minor influence on blood pressure, this variant is most likely not to be a major contributor to the development of hypertension.     

Conservation of the cardiostimulant effects of (-)-norepinephrine across Ser49Gly and Gly389Arg beta(1)-adrenergic receptor polymorphisms in human right atrium in vitro

OBJECTIVE: The goal of this study was to determine whether the cardiostimulant effects of the endogenous beta(1)-adrenergic receptor (AR) agonist, (-)-norepinephrine are modified by polymorphic (Serine49Glycine [Ser49Gly], Glycine389Arginine [Gly389Arg]) variants of beta(1)-ARs in the nonfailing adult human heart. BACKGROUND: Human heart beta(1)-ARs perform a crucial role in mediating the cardiostimulant effects of (-)-norepinephrine. An understanding of the significance of Ser49Gly and Gly389Arg polymorphisms in the human heart is beginning to emerge, but not as yet in adult patients who have coronary artery disease (CAD). METHODS: The potency and maximal effects of (-)-norepinephrine at beta(1)-ARs (in the presence of beta(2)-AR blockade with 50 nM ICI 118,551 [erythro-DL-1(7-methylindan-4-yloxy)-3-isopropylamino-butan-2-ol]) for changes in contractile force and shortening of contractile cycle duration were determined in human right atrium in vitro from 87 patients undergoing coronary artery bypass grafting who were taking beta-blockers before surgery. A smaller sample of patients (n = 20) not taking beta-blockers was also investigated. Genotyping for two beta(1)-AR polymorphisms (Ser49Gly and Gly389Arg) was determined from a sample of blood taken at the time of surgery. RESULTS: (-)-Norepinephrine caused concentration-dependent increases in contractile force and reductions in time to reach peak force and time to reach 50% relaxation. There were no differences in the potency or maximal effects of (-)-norepinephrine in the right atrium from patients with different Ser49Gly and Gly389Arg polymorphisms. CONCLUSIONS: The cardiostimulant effects of (-)-norepinephrine at beta(1)-ARs were conserved across Ser49Gly and Gly389Arg polymorphisms in the right atrium of nonfailing hearts from patients with CAD managed with or without beta-blockers.     

An evaluation of the beta-1 adrenergic receptor Arg389Gly polymorphism in individuals with heart failure: a MERIT-HF sub-study

BACKGROUND: The Glycine389 variant of the beta-1 adrenergic receptor (beta1AR) generates markedly less cAMP when stimulated in vitro than the more prevalent Arginine389 variant. AIMS: The aim of this MERIT-HF sub-study was to ascertain whether this Glycine389 variant favourably influences outcome in heart failure similar to that observed with beta-blockers. METHODS: We identified the genotype at amino acid 389 of the beta1AR in 600 patients enrolled in the MERIT-HF study (UK and Dutch participants). A risk-ratio (RR) for each genotype was calculated using the combined endpoint of all cause mortality or hospitalisation (time to first event). A pharmacogenetic effect of this polymorphism was also sought by evaluating the effect of Metoprolol CR/XL on heart rate amongst the three genotypes. RESULTS: The prevalence of the three genotypes was ArgArg 51.3%, ArgGly 40.2%, GlyGly 8.5%. The presence of the Gly allele was not associated with a significant benefit on the combined endpoint, RR=0.94; confidence intervals (CI), 0.69-1.29 (P=0.72). This is in contrast to the highly significant benefit of Metoprolol CR/XL observed in this sub-study population, RR=0.60; CI, 0.44-0.83 (P=0.002). No effect of the polymorphism was observed on the magnitude of heart rate reduction attained by Metoprolol CR/XL. CONCLUSION: In contrast to the benefits of beta-1 selective blockade, we have demonstrated that the Gly389 allele does not confer a significant mortality/morbidity benefit in heart failure patients. We have found no evidence of a pharmacogenetic effect of this biochemically functional polymorphism.     

An evaluation of the beta-1 adrenergic receptor Arg389Gly polymorphism in individuals at risk of coronary events. A WOSCOPS substudy.

AIMS: The Glycine389 variant of the beta-1 adrenergic receptor generates markedly less cAMP when stimulated in vitro than the more prevalent Arginine389 variant and may confer protection against coronary events similar to that observed with beta-blockers. The aim of this study was to ascertain whether this Glycine389 variant protects against coronary events. METHODS AND RESULTS: We identified the genotype at position 389 of the beta1AR in 1554 individuals taken from men enrolled in the West of Scotland Coronary Prevention Study. Men with a coronary event (event group) were each matched for age and smoking status with two control subjects from the same cohort who had not had a coronary event (control group). We compared the distribution of genotypes in the event and control groups. Conditional logistic regression was used to calculate odds ratios for each of the genotypes. The prevalence of the three genotypes in the entire cohort was ArgArg 53.5%, ArgGly 39.6%, GlyGly 6.9%. The Arg389Gly beta-1 adrenergic receptor polymorphism was not associated with coronary events. Using the ArgArg genotype as the reference, the odds ratio for the ArgGly genotype was 1.1 (95% CI, 0.88-1.38) and for the GlyGly genotype it was 1.05 (95% CI, 0.68-1.62). CONCLUSION: Our longitudinal case-control study demonstrates that the Glycine389 variant of the beta-1 adrenergic receptor does not protect against coronary events.     

The Arg16Gly polymorphism of human beta2-adrenoreceptor is associated with type 2 diabetes in Taiwanese people

OBJECTIVE: The significance of the association of amino terminal polymorphisms in beta2-adrenoreceptor (ADRB2) with obesity and type 2 diabetes is controversial and differs among ethnic groups. In this study, the association of ADRB2 with risk and age of onset of type 2 diabetes has been examined in a Taiwanese population. DESIGN: The study design is a case-control study to investigate the impact of the two amino acid polymorphisms in ADRB2. PATIENTS AND MEASUREMENTS: This study includes 130 patients with type 2 diabetes [female : male = 1 : 1, age: 52.4 +/- 10.0 years; body mass index (BMI): 24.2 +/- 2.9 kg/m2; mean +/- SD] and 130 controlled subjects matched for gender, age and BMI with normal glucose tolerance (female : male = 1 : 1, age: 51.7 +/- 10.6 years; BMI: 23.9 +/- 2.7 kg/m2). The Arg16Gly and Gln27Glu polymorphisms of ADRB2 were determined by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) assays. The genotypic and allelic frequencies between two groups were compared and the relationship between the genotypes and clinical phenotypes was examined. RESULTS: A difference in genotypic frequency in the Arg16Gly polymorphism was noted between groups in this gender-, age- and BMI-matched case-control study (P = 0.039). Multivariate regression analysis revealed that the Arg16Gly polymorphism was the only independent factor for development of type 2 diabetes (P = 0.021). In addition, we utilized the log-rank test to compare the differences in age of onset between wild-type and nonwild-type polymorphisms. The Arg16Gly polymorphism was independently associated with age of onset in type 2 diabetes (P = 0.017). There was no difference in the Gln27Glu polymorphism between diabetic and control groups in this study. CONCLUSIONS: In a Taiwanese population, homozygosity of Arg16 in the ADRB2 gene was associated with a higher frequency (odds ratio 1.87, 95% confidence interval 1.34-2.40) for development of type 2 diabetes. Moreover, this polymorphism was also associated with an earlier onset of type 2 diabetes. However, the Glu27Gln polymorphism had no impact on either BMI or type 2 diabetes in a Taiwanese population.     

Association between nonspecific airway hyperresponsiveness and Arg16Gly beta2-adrenergic receptor gene polymorphism in asymptomatic healthy Japanese subjects

BACKGROUND: Nonspecific airway hyperresponsiveness (AHR), a cardinal feature of asthma, is thought to result from several genetic and environmental factors. Asymptomatic AHR in nonasthmatic healthy subjects might be a risk factor for the development of asthma. Genetic variations in codons 16 and 27 of the human beta(2)-adrenergic receptor (beta(2)-AR) alter receptor function in vitro and are associated with various asthma-related phenotypes, including asthma severity and AHR. To date, however, few reports have examined the impact of beta(2)-AR gene polymorphism on AHR in asymptomatic healthy subjects. OBJECTIVE: To determine whether polymorphism of the beta(2)-AR gene (Arg16Gly and Gln27Glu) might influence nonspecific AHR in asymptomatic healthy Japanese subjects. DESIGN AND PARTICIPANTS: A cohort of 120 asymptomatic healthy subjects was analyzed using a stepwise linear regression model. Nonspecific airway responsiveness was measured using a continuous methacholine inhalation method (Astograph; Chest; Tokyo, Japan). We used values of the cumulative dose of inhaled methacholine measured at the inflection point at which respiratory conductance starts to decrease (Dmin) as an index of AHR. Genotyping to identify polymorphisms at codons 16 and 27 was conducted using an assay combining kinetic real-time quantitative polymerase chain reaction with allele-specific amplification. RESULTS: The Gly16Gly genotype was associated with lower Dmin values. The log Dmin value of asymptomatic healthy subjects carrying the Arg16 allele (Arg16/Arg or Arg16/Gly, n = 90) was 1.09 +/- 0.56 (mean +/- SD), while those homozygous for the Gly16 allele (n = 30) yielded a log Dmin value of 0.85 +/- 0.56 (p < 0.05). CONCLUSION: This study indicates that a specific beta(2)-AR polymorphism at codon 16 might be a genetic determinant of AHR, as judged by methacholine-induced bronchoconstriction in asymptomatic healthy subjects.     

The effect of the Gly16Arg polymorphism of the beta(2)-adrenergic receptor gene on plasma free fatty acid levels is modulated by physical activity.

The lipolytic effects of catecholamines are mediated through members of the beta(2)-adrenergic receptor (BAR-2) family. Previous studies have suggested that genetic variants in the BAR-2 gene may be associated with obesity in some populations. To our knowledge, no studies have directly examined the effects of this polymorphism on circulating nonesterified fatty acid (NEFA) levels. To explore this issue further, a cohort of 604 Caucasian individuals (aged 40-65 yr) was genotyped for a common polymorphism in the BAR-2 gene (Gly16Arg), and the relationships between genotype, body mass index (BMI), NEFA, and lipid levels were examined. Women bearing the Arg16 allele had higher BMI values (P < 0.01) than Gly16Gly women. Women carriers of the Arg16Arg genotype had lower fasting plasma NEFAs (P < 0.01) and greater suppression of NEFAs (P < 0.01) after an oral glucose load than women bearing the Gly16 allele. In multivariate analysis after adjustment for age, sex, and smoking status, the interaction between the BAR-2 genotype and BMI in determining fasting NEFA concentrations was statistically significant (P < 0.05). The availability of objective measures of total energy expenditure in this population permitted the further examination of interactions, particularly that between genotype and physical activity. In the population as a whole, after adjustment for confounding by age, smoking, and BMI, the effect of the Arg16Arg genotype on the suppression of NEFA levels was modified by physical activity level (P for interaction <0.05). These data suggest the existence in this population of a gene-physical activity interaction on NEFA levels.     

Influence of lipoprotein lipase gene Ser447Stop and beta1-adrenergic receptor gene Arg389Gly polymorphisms and their interaction on obesity from childhood to adulthood: the Bogalusa Heart Study

OBJECTIVE: To investigate the influence of lipoprotein lipase (LPL) Ser447Stop and beta1-adrenergic receptor (ADRB1) Arg389Gly gene polymorphisms, individually and in combination, on obesity from childhood to adulthood. DESIGN AND SUBJECTS: A community-based cohort of 1331 subjects (30% black and 70% white subjects) was followed over an average period of 23 years from childhood (age range: 4-17 years) to adulthood (age range:18-44 years). MEASUREMENT: Body mass index (BMI, kg/m2) and LPL Ser447Stop and the ADRB1 Arg389Gly genotypes.Results:The frequency of the ADRB1 Gly389 allele was 0.25 in white subjects vs 0.39 in black subjects (P < 0.001); 0.08 vs 0.05 (P = 0.280) for the LPL Stop447 allele. There was no association between the LPL Stop447 allele and BMI among white and black subjects either in childhood and adulthood levels or annual change from childhood to adulthood. The ADRB1 Gly389 allele was associated with lower BMI only in black adults (P = 0.017). Further, the interaction effect of the LPL Stop447 allele and ADRB1 Gly389 allele on adult BMI or its annual change was significant in white subjects and in the total sample (P = 0.03-0.006). Childhood values tended to show a similar trend. Having both ADRB1 Gly389 allele and LPL Stop447 allele was associated with 71% (95% confidence interval: 26-89%) less odds for developing obesity from childhood to adulthood after adjusting for age, race, sex, and childhood BMI. CONCLUSION: While Gly389 allele of the ADRB1 gene lowers obesity in black subjects, this allele in conjunction with Stop447 allele of the LPL gene lowers obesity in adults and attenuates the development of obesity from childhood to adulthood. These findings underscore the importance of gene-gene interaction in the assessment of genetic influences on complex traits such as obesity.     

Association analysis of Arg16Gly polymorphism of the beta2-adrenergic receptor gene in offspring from hypertensive and normotensive families

Objective: Since β2 -adrenergic receptors ( β2 AR) can influence blood pressure not only by vasodilation, but also participate in noradrenaline release from sympathetic nerve endings, we have studied whether Arg16Gly polymorphism of the β2 AR gene is associated with predisposition to essential hypertension and increased plasma noradrenaline concentration in offspring from normotensive (SN) and hypertensive parents (SH). Design and methods: The study population consisted of 105 young SN and 101 SH subjects matched for age and body mass index. Arg16Gly polymorphism of the β2 AR gene was determined by polymerase chain reaction (PCR) technique and subsequent incubation with NcoI restriction enzyme. Resulting fragments were separated using electrophoresis on a 4.2% Metaphor agarose gel. Results: SH already had significantly higher systolic BP, and a tendency to higher diastolic BP than the SN group. The frequency of Arg/Arg homozygotes was significantly increased in SH when compared to SN (25% vs 15%). Results of logistic regression analysis showed the highest relative risk for the Arg/Arg genotype and suggested a recessive action of the Arg16 variant. There was an increased diastolic BP in Arg/Arg homozygotes of the SN group ( p = 0.029). This genotype also had a tendency to increased heart rate in both groups ( p = 0.049). There was no relationship of this polymorphism with plasma noradrenaline concentration. Conclusion: Our findings suggest that genetic variability of the β2 AR gene is implicated in predisposition to essential hypertension. However, the contradictory results between individual studies indicate that the action of the β2 AR gene is indirect, through multiple intermediate phenotypes and gene interactions.     

Metabolic and hormonal effects of preferential beta 1 and beta 2-adrenoceptor stimulation in man

The changes of blood glucose, serum potassium (K+), plasma non-esterified fatty acids (NEFA), plasma insulin and plasma renin activity (PRA) following the preferential stimulation of beta-1 and beta-2 adrenoceptors were studied in 7 healthy subjects during a 60-min infusion of prenalterol, a new, relatively beta-1 selective agonist and salbutamol, a well known, relatively beta-2 selective agonist. Two different high and low doses were used for both agents: 300 micrograms and 600 micrograms and 1 mg and 2 mg for salbutamol and prenalterol, respectively. The levels of PRA seemed equally increased by the two agents in proportion to the dose infused, thus suggesting an equally important role for beta-1 and beta-2 adrenoceptors in renin release. Blood glucose did not change during prenalterol infusions, while increased by 12 +/- 2 mg/100 ml (mean +/- SE; p less than 0.01) and 25 +/- 3 mg/100 ml (p less than 0.01) on salbutamol, at low and high dose, respectively. Similarly the decrement of serum K+ was significantly more pronounced (p less than 0.01) after salbutamol infusion (0.6 +/- 0.07 mEq/L and 1.0 less than 0.09 mEq/L, at low and high dose, respectively) than after prenalterol (0.1 +/- 0.07 mEq/L and 0.3 +/- 0.05 mEq/L). These metabolic effects should suggest a main beta-2 adrenoceptor involvement.(ABSTRACT TRUNCATED AT 250 WORDS)     

The different effects of a Gln27Glu beta 2-adrenoceptor gene polymorphism on obesity in males and in females

OBJECTIVES: To investigate the role of a polymorphism in codon 27 (Gln27Glu) of the beta 2-adrenoceptor gene for obesity in males compared to previously investigated females with an association of this polymorphism to obesity. DESIGN: Population-based study. SETTING: Medical department at a University Hospital. SUBJECTS: A total of 138 non-related Swedish males with body mass indexes (BMI) in the range 19.4-53.4 kg m-2 were recruited as: healthy volunteers, healthy obese subjects and subjects undergoing surgery for uncomplicated gallstone or abdominal hernia. In order to investigate the impact of gender, the results were compared with a subset of an earlier investigated female population of 109 Swedish females. Obesity was defined as a BMI > 27 kg m-2. MAIN OUTCOME MEASURES: Genotype examination of beta 2-adrenoceptor polymorphism in codon 27 with polymerase chain reaction and restriction fragment length polymorphism. RESULTS: The allele frequency of Gln27 and Glu27 did not differ between males and females when obese and non-obese subjects were investigated together. However, in obese males, the frequency of the Glu27 allele was significantly decreased (P = 0.034), whereas the frequency of this allele was increased in obese females (P = 0.013). No impact of the female androgen status on the distribution of the Gln27Glu polymorphism could be demonstrated in the obese females. CONCLUSION: A positive association between obesity and the Glu27 genetic variant in the beta 2-adrenoceptor exists in females, whereas in males there is a negative correlation between Glu27 and obesity. The findings suggest that different genetic factors contribute to obesity in males and females.