The Gly16-->Arg16 and Gln27-->Glu27 polymorphisms of beta2-adrenergic receptor are associated with metabolic syndrome in men

Endogenous catecholamines contribute to regulation of adipose tissue lipolysis, glucose homeostasis, and vascular tone. The goal of the present study was to assess the association between the Gly(16)-->Arg(16) and Gln(27)-->Glu(27) polymorphisms of the beta(2)-adrenergic receptor and metabolic syndrome. Participants were recruited in a population survey and included 1195 men and women. Metabolic syndrome was defined according to National Cholesterol Education Program Adult Treatment Panel III guidelines. There were 276 patients with metabolic syndrome and 872 controls. The Gly(16)-->Arg(16) (P < 0.005) and Gln(27)-->Glu(27) (P < 0.04) polymorphisms were associated with metabolic syndrome in men, but not in women. In multivariate analyses adjusting for age, physical activity, smoking habits, alcohol consumption, and body mass index, the odds ratio of metabolic syndrome was 1.83 (95% confidence interval, 1.10-3.05) and 2.43 (95% confidence interval, 1.19-4.95) in men bearing the Gly(16)/Arg(16) and Arg(16)/Arg(16) genotypes, respectively. Similarly, the odds ratios of metabolic syndrome were 0.99 (95% confidence interval, 0.50-1.93) and 1.67 (95% confidence interval, 0.84-3.33) in men bearing the Gln(27)/Glu(27) and Gln(27)/Gln(27) genotypes, respectively. Because both variants were in linkage disequilibrium, a haplotype analysis was performed. There was no evidence of any statistically significant association between beta(2)-adrenergic receptor haplotypes and metabolic syndrome. In conclusion, these data suggest that the Arg(16) and Gln(27) variants of the beta(2)-adrenergic receptor gene contribute to metabolic syndrome susceptibility in men.     

Gln27Glu variant of the beta2-adrenergic receptor gene is not associated with obesity and diabetes in Japanese-Americans

The beta(3)-adrenergic receptor (AR) gene variant (Trp64Arg) has been reported to be associated with obesity and insulin resistance in humans. However, this association remains controversial. We investigated the relationships between the beta(2)-AR gene variant (Gln27Glu) and obesity, insulin resistance, and serum lipids in Japanese-Americans. The frequency of an abnormal Gln27Glu allele in the beta(2)-AR gene in 652 subjects was 0.092 in males, 0.077 in females, and 0.084 overall, markedly lower than the previously reported value of 0.4 in Caucasian men and women. In both males and females, there were no differences in the indices of obesity, insulin resistance, and serum lipid levels between the subjects with and without the beta(2)-AR gene (Gln27Glu) variant in patients with normal glucose tolerance (NGT), impaired glucose tolerance (IGT), or diabetes (DM). The frequency of the beta(2)-AR gene (Gln27Glu) variant tended to increase with worsening of glucose tolerance, but the differences were not statistically significant. Furthermore, there were no differences in the frequency of the beta(2)-AR gene variant in either males or females with obesity (body mass index [BMI], > or = 25.2). Even in Japanese-Americans, who have a more westernized life style than Japanese, the association of the beta(2)-AR gene (Gln27Glu) variant with the parameters of obesity, insulin resistance, and serum lipid level has yet to be clarified. We conclude that the beta(2)-AR gene (Gln27Glu) variant might not be an important factor for obesity or IGT in Japanese subjects.     

The Gln27Glu polymorphism in the beta2-adrenergic receptor gene is not associated with morbid obesity in Austrian women

OBJECTIVE: Beta-adrenergic receptors (betaARs) play an important role in the regulation of energy expenditure and lipid mobilization. A Gl-27Glu polymorphism in the beta2-adrenergic receptor (beta2AR) gene has recently been associated with several indices of obesity in a female Caucasian population, while the same polymorphism exhibited no association with obesity in another, albeit male, population. METHODS: We have therefore studied possible associations of the Gln27Glu and the Gly16Arg polymorphisms in the beta2AR with BMI, plasma leptin and UCP-1 mRNA expression in the intraperitoneal adipose tissue in a population of Caucasian women. RESULTS: The frequencies of the Gln27 and the Gly16 alleles as well as the beta2AR haplotypes were similar in our morbidly obese and lean subjects. Furthermore, no association was found between the Gln27Glu or the Gly16Arg polymorphisms and plasma leptin or adipose tissue UCP-1 gene expression in either group. CONCLUSIONS: We conclude that the two polymorphisms in the beta2AR gene studied are not a major factor contributing to obesity in our population.     

Haplotype association analysis of the polymorphisms Arg16Gly and Gln27Glu of the adrenergic beta2 receptor in a Swedish hypertensive population

The Arg16Gly and the Gln27Glu polymorphisms in the gene for the beta2-adrenergic receptor (beta2AR) have been linked to an increased risk for cardiovascular disease. The aim of the present study was to evaluate the significance of these haplotypes for development of myocardial infarction (MI) as well as other cardiovascular phenotypes. In a prospective study cohort (CAPPP), 522 hypertensive patients (174 MI and 348 matched controls) were analysed for the Arg16Gly and the Gln27Glu polymorphisms by dynamic allele-specific hybridisation. The haplotype could successfully be determined in 516 patients. Haplotype was not significantly associated with MI. Systolic blood pressure (SBP) was higher in patients with Arg16Gly+Gln27Gln and lower in patients with Arg16Gly+Gln27Glu as compared with the other haplotypes. Haplotype was not associated with body mass index, diastolic blood pressure, cholesterol, LDL, HDL triglycerides or a diagnosis of diabetes mellitus. The present study found no evidence that haplotype for the two most common polymorphisms in the beta2AR are associated with development of MI in a Swedish hypertensive population, but haplotype may be associated with SBP.     

Arg16Gly polymorphism in beta2-adrenergic receptor gene is not associated with thyrotoxic periodic paralysis in Korean male patients with Graves' disease

BACKGROUND: Thyrotoxic periodic paralysis (TPP) occurs most frequently in Asian males and present with an acute episode of proximal muscle weakness in the setting of thyrotoxicosis. Despite the fact that mutations were described in genes encoding ion channels in familial hypokalaemic periodic paralysis, no definite genetic variants were found in TPP. beta2-adrenergic receptors (ADRB2s) are expressed in skeletal muscle and stimulate the sodium pump. Single nucleotide polymorphisms in ADRB2 gene were identified and may act as disease modifiers in various diseases. OBJECTIVE: We were to demonstrate that ADRB2 gene might be a susceptibility gene for TPP in Korean male patients with Graves' disease. DESIGN AND PATIENTS: In a series of 28 male TPP patients and 31 control patients, three polymorphisms in ADRB2 gene have been studied: a T to C substitution at -47 (-47T/C), Arg16Gly and Gln27Glu. Control patients were male Graves' patients without history of paralysis. RESULTS: The distributions of the -47C, Gly16 and Glu27 alleles in all patients were 0.02, 0.34 and 0.02, respectively. The genotype Arg16/Arg16 was not significantly associated with TPP (odds ratio 0.53; 95% confidence interval, 0.19-1.50; corrected P = 0.897). Also, the frequency of genotype Gly16/Gly16 was not significantly different in TPP patients than in controls (0.07 vs. 0.23; odds ratio, 0.26; 95% confidence interval, 0.05-1.40; corrected P = 0.45). Allele frequencies of ADRB2 in patients with TPP did not differ from controls. CONCLUSIONS: The polymorphism of the ADRB2 gene may not confer genetic susceptibility to TPP in Korean male patients with Graves' disease.     

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.     

Gln27Glu polymorphism of the beta2 adrenergic receptor gene in healthy Japanese men is associated with the change of fructosamine level caused by exercise

Adrenaline plays a major role in the maintenance of blood glucose level by promoting glycogenolysis during prolonged exercise predominantly via the beta2 adrenergic receptor (beta2AR). Because beta2ARs are mainly present in the muscle and liver, beta2AR gene polymorphism may affect changes in glucose metabolism caused by exercise. We, therefore, investigated the effect of beta2AR gene polymorphism on glucose metabolism in healthy Japanese men. The study group consisted of 124 unrelated healthy Japanese men who were aged 21-69 years (mean +/- S.D.: 45.3+/-11.7). They participated in an exercise program which was defined as low-moderate intensity at 20-60min per day, 2-3 days per week for 3 months. The genotype of Gln27Gln was detected in 109 subjects (87.9%), of Gln27Glu in 15 subjects (12.1%) and of Glu27Glu in none, and that of Arg16Arg, Arg16Gly and Gly16Gly in 32 (25.8%), 79 (63.7%) and 13 subjects (10.5%), respectively. There was no association between these polymorphisms and the metabolic characteristics at baseline. The change in fructosamine level as a result of exercise showed that the carrier of the Glu allele had a better response to exercise than the non-carrier. In conclusion, Gln27Glu polymorphism was associated with the change in fructosamine level resulting from exercise, but not Arg16Gly polymorphism.     

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.     

Association of Trp64Arg polymorphism of the beta3-adrenergic receptor gene and no association of Gln223Arg polymorphism of the leptin receptor gene in Japanese schoolchildren with obesity

OBJECTIVE: To investigate whether Trp64Arg polymorphism of the beta3-adrenergic receptor (beta3-AR) gene and Gln223Arg polymorphism of the leptin receptor (Ob-R) gene are associated with obesity in Japanese schoolchildren. DESIGN: Population study of participants from a rural town located within 50 km northeast of Tokyo based on school medical examinations. SUBJECTS: 553 Japanese schoolchildren (291 boys and 262 girls) who were 9-15 y old with a mean age of 11.9 +/- 1.8 y. MEASUREMENTS: DNA was extracted from whole blood and genotyped by PCR-RFLP. Height, weight and blood pressure were measured in school medical examinations. Total cholesterol, triglyceride and HDL-cholesterol concentrations were measured by an autoanalyzer. Obesity index, body mass index (BMI) and LDL-cholesterol concentration were calculated by the respective formulae. RESULTS: In Trp64Arg polymorphism of the beta3-AR gene, the number of obese subjects with Trp/Arg or Arg/Arg genotypes was significantly higher than that of the non-obese subjects (chi2=5.79, P=0.02). The obesity index of subjects with the Arg/Arg or Arg/Trp genotype was significantly higher than that of those with the Trp/Trp genotype (8.2 +/- 18.7% vs 4.5 +/- 15.8%, P=0.04). Moreover, after adjustments for age and gender, BMI of subjects with the Trp/Arg or Arg/Arg genotype was significantly higher than that of those with the Trp/Trp genotype (19.4 +/- 3.6 kg/m2 vs 18.9 +/- 3.2 kg/m2, P= 0.02). However, no significant differences were observed in the clinical characteristics among the genotype groups of the Ob-R gene. CONCLUSIONS: Trp64Arg polymorphism of the beta3-AR gene appears to be a genetic risk factor for obesity in Japanese children, but Gln223Arg polymorphism of the Ob-R gene does not appear to be associated with obesity.     

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。     

beta2-adrenergic receptor gene single-nucleotide polymorphisms are associated with rheumatoid arthritis in northern Sweden

The beta2-adrenergic receptor (beta2-AR) belongs to the group of G-protein-coupled receptors and is present on skeletal and cardiac muscle cells and on lymphocytes. The gene encoding beta2-AR (ADRB2) displays a moderate degree of heterogeneity in the human population and the distributions of single-nucleotide polymorphisms (SNPs) at amino acid positions 16, 27, and 164 are changed in asthma, obesity, and hypertension and in the autoimmune disease myasthenia gravis. An involvement of the beta2-AR has also been suggested in human rheumatoid arthritis (RA) and its animal model. We describe here an increased prevalence of the alleles Arg16 and Gln27 and a lower prevalence of homozygosis for Gly16 and Glu27 in patients with RA. Patients having the genotype combination GlyGly16-GlnGlu27 had higher levels of rheumatoid factor (RF) and a more active disease than other patients. Patients having the genotype Arg16-Gln27+ had higher levels of RF when compared to those having Arg16+Gln27+, and patients who were carriers of Gln27 had a more active disease than non-carriers of Gln27. Our results show an association of beta2-AR SNPs with RA in a population from the northern part of Sweden. Our study also confirms the strong linkage disequilibrium of genotypes at amino acid positions 16 and 27.     

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.     

The beta(2)-adrenergic receptor Arg16-gly polymorphism and interactions involving beta(2)- and beta(3)-adrenergic receptor polymorphisms are associated with variations in longitudinal serum lipid profiles: the Bogalusa Heart Study

We examined the effects of combined genotypes of the beta(2)-adrenergic receptor (AR) Arg(16)-Gly and beta(3)-AR Trp(64)-Arg polymorphisms on longitudinal serum total (T-C) and low-density lipoprotein cholesterol (LDL-C) profiles in 1,198 subjects examined multiple times (6,488 observations) from 1973 to 1996 in the Bogalusa Heart Study, at ages from 4.5 to 38 years. Within 5-year age groups, T-C was significantly (P <.05) higher in beta(2)-AR Arg(16)/Arg(16) homozygotes than in Gly(16) carriers among those 4 to 8 (171.4 +/- 30.0 v 161.5 +/- 27.7 mg/dL), 9 to 13 (167.7 +/- 28.6 v 162.4 +/- 27.4 mg/dL), and 14 to 18 (158.8 +/- 29.6 v 154.7 +/- 27.5 mg/dL) years of age, but not in those 19 to 23, 24 to 28, 29 to 33, or 34 to 38 years of age. The beta(3)-AR polymorphism was not associated with variation in either T-C or LDL-C. In multilevel polynomial growth curve models, the combination of the beta(2)-AR Arg(16)/Arg(16) genotype with either the beta(3)-AR Arg(64)/Arg(64) or Trp(64)/Arg(64) genotypes, denoted AA/AX, was associated with variation in longitudinal T-C (P <.01) and LDL-C (P <.01) profiles. The association between combined beta(2)/beta(3)-AR genotype and lipid profiles differed among race/sex groups, being most marked in black females, in whom the AA/AX combination was associated with higher T-C and LDL-C profiles across all ages. In White males, the AA/AX combination was most strongly associated with higher lipids in adults. In black males and white females, lipid profiles differed little between genotype groups. Our findings suggest that the beta(2)-AR Arg(16)-Gly genotype influences T-C and LDL-C levels in an age-specific manner, that it may interact with beta(3)-AR Trp(64)-Arg genotypes to influence longitudinal T-C and LDL-C profiles, and that the effect of combined beta(2)/beta(3)-AR genotypes on T-C and LDL-C profiles may differ among race/sex groups.     

Genotype Gly/Gly of the Arg16Gly polymorphism of the beta2-adrenergic receptor is associated with elevated fasting serum insulin concentrations, but not with acute insulin response to glucose, in type 2 diabetic patients

The beta(2)-adrenergic receptor (B2AR) is expressed in pancreatic beta-cells and modulates insulin secretion. The purpose of the present study was to evaluate the influence of the Arg16Gly variant allele of B2AR on insulin secretion in patients with type 2 diabetes. We used minimal model analysis of the frequently sampled insulin-modified intravenous glucose tolerance test (FSIGT) and polymerase chain reaction (PCR)-restriction fragment length polymorphism to examine differences of insulin secretion and insulin resistance among three genotypes. There were no significant differences in baseline clinical characteristics, HbA1c, uric acid, CRP or lipid profiles among the three groups. The Gly/Gly group had significantly higher levels of fasting insulin (38.2+/-4.7 pmol/l versus 23.6+/-3.5 pmol/l) and homeostasis model assessment of insulin resistance (HOMA-R) (1.90+/-0.19 versus 1.32+/-0.24), compared with the Arg/Arg group, but there were no significant differences in acute insulin response to glucose (AIRg) bolus, insulin sensitivity (Si), or glucose effectiveness (Sg) among the three genotypes. Several reports have speculated that the Gly16 allele of B2AR exhibits agonist-promoted downregulation, but our findings, elevated fasting insulin concentrations, and previous clinical studies of blood pressure and lypolysis are controversial. The direct mechanism by which the Gly16 allele of B2AR may influence insulin secretion of pancreatic beta-cells is unknown. Further studies of the expression of the allelic receptor in islet cells may help to resolve the role of B2AR in insulin secretion. However, increased sensitivity to catecholamine-induced lipolysis of the Gly allele promotes higher free fatty acids concentrations in the portal system, which could enhance the higher levels of fasting insulin.     

Beta 2-adrenergic receptor polymorphisms and haplotypes are associated with airways hyperresponsiveness among nonsmoking men

STUDY OBJECTIVE: To investigate the relationship of common single nucleotide polymorphisms (SNPs) of the beta(2)-adrenergic receptor (AR) gene at codons 16 and 27, and the intermediate phenotype of airways hyperresponsiveness. DESIGN: A case-control study in 543 white men (152 case patients and 391 control subjects), who were nested in an ongoing longitudinal cohort. SETTING: Subjects were selected from the Normative Aging Study, an ongoing longitudinal cohort of healthy aging. PARTICIPANTS: Case patients were defined as those having a positive response to methacholine challenge testing. Control subjects were selected among those who did not have a diagnosis of asthma and who had no response to methacholine. RESULTS: There was a trend for an association of the Arg16 SNP genotype with airways hyperresponsiveness (odds ratio, 1.25; 95% confidence interval, 0.96 to 1.64 [in an additive model]). In stratified analyses, the effect of the Arg16 variant was seen mainly among nonsmokers. Smokers had increased risks for airway hyperresponsiveness regardless of genotype at either SNP. Using a program to estimate haplotype frequencies, three common haplotypes were identified. Adjusting for age, baseline FEV(1), serum IgE level, and smoking status, the Gly16/Gln27 haplotype was negatively associated with airways hyperresponsiveness in the full complement of case patients and control subjects (score statistic, - 2.43; p = 0.02). The effect of the beta(2)-AR haplotypes was much stronger among lifelong nonsmokers, among whom the Gly16/Gln27 haplotype remained negatively associated with airways hyperresponsiveness (score statistic, - 3.114; p = 0.002), whereas the Arg16/Gln27 haplotype was positively associated with airways hyperresponsiveness (score statistic, 3.142; p = 0.002). No effects were seen among ever-smokers. CONCLUSIONS: In this cohort of middle-aged to older white men, beta(2)-AR polymorphisms were associated with airways hyperresponsiveness, particularly among lifelong nonsmokers. Our results illustrate an instance in which greater power is obtained by performing haplotype analyses as opposed to single SNP analysis.     

Gln27Glu polymorphism in the beta2 adrenergic receptor gene and lipid metabolism during exercise in obese women

BACKGROUND: The Glu27Glu genotype in the beta-2-adrenergic receptor (ADRB2) is associated with fat mass, body mass index and obesity in females. In our population, we previously found an association of higher body mass index (BMI) among women who reported more physical activity and carried the Glu27 allele as compared to non carriers with the same level of activity. OBJECTIVE: To examine the lipid metabolism differences, both at rest and during submaximal exercise in ADRB2 Glu27Glu vs Gln27Gln obese women. SUBJECTS: Eight obese women with the Glu27Glu genotype (age, 43+/-5 y; body mass index (BMI), 31.7+/-0.9 kg/m(2); percentage fat mass, 42.0+/-1.3; WHR, 0.83+/-0.02; and VO(2max), 21.6+/-0.9 ml/kg/min) were compared with seven obese women with the Gln27Gln genotype (age, 43+/-5 y; BMI, 33.9+/-1.3 kg/m(2); percentage fat mass, 41.6+/-1.2; WHR, 0.83+/-0.02; and VO(2max), 20.6+/-0.8 ml/kg/min). MEASUREMENTS: The ADRB2 polymorphism was identified by PCR-RFLP. Respiratory quotient was determined by indirect calorimetry at baseline, during 1 h of walking on a treadmill and 1 h after the exercise. Plasma triglycerides, glycerol, FFA, hydroxybutyrate, glucose and lactate were assayed by spectrophotometric methods. Insulin, leptin and progesterone were measured by radioimmunoassay. Adrenaline and noradrenaline were quantified by high performance liquid chromatography. RESULTS: The ADRB2 Glu27Glu subjects had lower plasma glycerol (P=0.047) and lower hydroxybutyrate (P=0.001) throughout the study than the Gln27Gln group. Plasma triglycerides (P=0.001), lactate (P<0.05) and serum insulin (P<0.05) remained higher in the Glu27Glu group vs the Gln27Gln group. The respiratory quotient (RQ) was higher in the Glu27Glu obese women along the study (P=0.046), and fat oxidation was significantly lower in this group during the recovery (P=0.048). The other variables did not differ statistically between groups. CONCLUSION: These data suggest that both lipolysis and fat oxidation promoted by an acute submaximal exercise intervention could be blunted in the polymorphic ADRB2 Glu27Glu group of our female obese population.     

β2肾上腺素能受体基因Gln27Glu多态性与新疆哈萨克族原发性高血压的相关研究

目的研究新疆哈萨克族人β2肾上腺素能受体(β2-AR)基因Gln27Glu多态性与原发性高血压(EH)的关系,旨在从分子水平探讨哈萨克族人EH易感的机制.方法采用人群为基础的病例-对照研究方法,选择600例30～60岁(373例EH患者与227例血压正常者)哈萨克族人为研究对象,采集外周血,采用经典蛋白酶K消化、饱和酚/氯仿抽提法提取外周血白细胞基因组DNA,应用聚合酶链反应-限制性片段长度多态性分析技术,检测所有对象的Gln27Glu基因型.观察该多态性的分布特征.结果该人群β2-AR基因Gln27Glu位点的3种基因型Gln/Gln、Gln/Glu、Glu/Glu分布频率分别为52.00%、42.00%、6.00%,符合Hardy-Weinberg平衡(P＞0.05).3种基因型的频率在EH组中分别为50.67%,43.70%,5.63%;在正常血压组中为54.19%,39.21%,6.60%,等位基因C、G分布频率分别为72.52%、27.48%和73.79%、26.21%,两组基因型及等位基因频率的分布均差异无统计学意义(P＞0.05).各基因型间年龄、体质指数、收缩压以及舒张压亦差异无统计学意义(P＞0.05).结论未发现新疆哈萨克族人β2-AR基因Gln27Glu多态性与EH相关关系,提示该多态性在哈萨克族人EH的发病机制中可能不起主要作用.     

The Trp64Arg polymorphism of the beta3-adrenergic receptor gene is associated with hypertension in men with type 2 diabetes mellitus

A missense mutation of the beta3-adrenergic receptor gene (ADRB3) resulting in a tryptophan/arginine exchange at position 64 (Trp64Arg polymorphism) has recently been associated with greater capacity to gain weight, a low resting metabolic rate, higher blood pressure, and an early onset of type 2 diabetes. These findings prompted us to examine the relationship between this mutation, blood pressure, and vascular complications in German patients with type 2 diabetes. White patients with type 2 diabetes mellitus (n = 417) were enrolled in the study. The Trp64Arg polymorphism of the ADRB3 gene was detected by polymerase chain amplification and subsequent restriction digest with BstN I. Stepwise logistic regression analysis of the entire study population revealed a significant interaction between gender and genotype (P = .019). We therefore performed separate analyses for men and women. There was a significant relationship between hypertension and the ADRB3 Trp64Arg variant in men (P = .015), but not in women. Furthermore, blood pressure levels in male patients with the minor allele had higher blood pressure levels (P < .05), despite a significantly greater number of antihypertensive medications (P = .01). There was no association between ADRB3 genotype and vascular complications in these patients. In conclusion, our data are compatible with a contribution of this genetic variant of ADRB3 to hypertension in male patients with type 2 diabetes. Further studies will be needed to determine the role of this polymorphism as a predictor of hypertension or vascular complications in patients with type 2 diabetes.     

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.     

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.