中国北方汉族人群支气管哮喘患者β2肾上腺素能受体基？…

探讨中国北方汉族人群β２肾上腺素能受体（β２ＡＲ）１６、２７和１６４位点基因多态性与支气管哮喘的相关性。方法采用等位基因特异性聚合酶链反应方法,对５８例哮喘缓解期患者进行β２ＡＲ基因多态性分析检测,并与８９名正常者进行对照。结果（１）中国北方汉族人群β２ＡＲ基因１６、２７、１６４位点多态性分布频率与英美高加索人群不同;（２）哮喘组人群β２ＡＲ基因１６位点多态性分布频率显示,精氨酸／精氨酸基因型占２     

Association between beta2-adrenergic receptor genetic polymorphisms and total serum IgE in asthmatic patients of Chinese Han nationality

BACKGROUND: beta(2)-Adrenergic receptor (beta(2)-AR) polymorphisms occurring at amino acid position 16 (Arg-Gly) and 27 (Gln-Glu) are known to be functionally relevant and also disease-modifying in subjects with asthma. It has been found in Caucasoid asthmatic patients that the Gln27 genotype beta(2)-AR was associated with an increase in total serum IgE levels. The association between beta(2)-AR genetic polymorphisms and total serum IgE in asthmatic patients of Chinese Han nationality remains to be established. OBJECTIVES: It was the aim of this study to investigate the association between beta(2)-AR genetic polymorphisms and total serum IgE in asthmatic patients of Chinese Han nationality. METHODS: All 59 asthmatic patients investigated (27 males and 32 females, aged between 16 and 60 years) were people of Chinese Han nationality. They were tested for their total serum IgE levels with the enzyme-linked immunosorbent assay test, and beta(2)-AR genetic polymorphisms were tested with the polymerase chain reaction allele-specific oligonucleotide hybridization assay. RESULTS: There was a significant difference of serum IgE levels among three beta(2)-AR 27 loci groups (p < 0.0001), with the highest IgE level [(1.24 +/- 0.25) x 10(6) IU/l] in the Gln/Gln group and the lowest IgE level [(0.48 +/- 0.06) x 10(6) IU/l] in the Glu/Glu group. No polymorphism of beta(2)-AR 16 loci was found to be associated with total serum IgE (p > 0.05). CONCLUSIONS: Our research suggested that in asthmatic patients of Chinese Han nationality, the beta(2)-AR genetic polymorphism at 27 loci could be associated with serum IgE levels and it might therefore play an important role in the determination of phenotypes of bronchial asthma.     

β2-肾上腺素能受体多态性/单倍型与支气管哮喘表型的相关性

目的 研究β2-肾上腺素能受体基因的多态性/单倍型与支气管舒张剂的反应性及血清免疫球蛋白E的负对数(lgIgE)间的关系.方法 2006年2月至2007年2月采用DNA测序法测定了201例哮喘患者(哮喘组)和276名健康对照者(健康对照组)的β2-AR基因5个位点(-47、-20、46、79、252)的基因型并确定其单倍型.统计学处理采用SPSS 11.5软件.以拟和优度的x2检验计算各位点基因型频率是否符合Hardy-Weinberg平衡.5个位点基因型的频率比较采用卡方检验,位点间的连锁不平衡采用确切概率法,不同基因型及单倍型与定量指标间的比较采用方差分析.如果方差分析有统计学意义,则用LSD方法对各组间的值进行两两比较.结果 哮喘组中Arg16Arg16基因型患者的支气管舒张剂反应性为(13±4)L,与Arg16Gly16基因型[(7±3)L]及G1y16Gly16基因型[(7±3)L]比较差异有统计学意义(F=81.55,P＜0.01);在哮喘组6种单倍型中,单倍型Arg16Gln27/Arg16Gln27的△FEV1最高[(13.4±3.5)L],与其他种单倍型[Gly16Gln27/Gly16Gln27(6.4±0.6)L、Gly16Glu27/Gly16Glu27(7.6±3.1)L、Gly16Gln27/Gly16Glu27(6.9±3.5)L、Gly16Gln27/Arg16Gln27(7.2±3.3)L及Gly16Glu27/Arg16Gln27(7.9±2.7)L]比较差异有统计学意义(F=32.55,P＜0.01);哮喘组中Gln27Gln27基因型患者的血清lgIgE为(2.51±0.33)IU/L,与Gln27Glu27基因型患者的血清lgIgE[(2.30±0.82)IU/L]比较差异有统计学意义(F=3.89,P＜0.05);哮喘组中单倍型Gly16Glu27/Arg16Gln27的血清lglgE最低[(2.13±0.15)IU/L],与其他4种单倍型[Arg16Gln27/Arg16Gln27为(2.56±0.14)IU/L、Gly16Glu27/Gly16Glu27为(2.40±0.16)IU/L、Gly16Gln27/Gly16Glu27为(2.54±1.26)IU/L、Gly16Gln27/Arg16Gln27为(2.48±0.48)IU/L]比较差异有统计学意义(F=3.56,P＜0.01).结论 依据所研究的哮喘表型,无论是β2-AR基因的多态性,还是单倍型均可能影响疾病的表现.     

β_2-肾上腺素能受体基因多态性与新疆维吾尔族患者支气管哮喘间的关系研究

目的 :探讨 β2 肾上腺素能受体 (β2 adrenergicreceptor,β2 AR) 16 ,2 7位点基因多态性与新疆维吾尔族支气管哮喘患者及其临床表型间的关系。方法 :采用序列特异引物聚合酶链反应 (sequencespecificprimers polymerasechainreaction ,SSP PCR)技术检测 12 3例维吾尔族哮喘组患者β2 AR16和 2 7位点基因多态性 ,并与 89例正常组进行对照 ,统计分析 β2 AR16和 2 7位点基因型与哮喘病情严重度的关系。应用UniCAP变应原检测系统 (SWEDENPHARMACIAUniCAPSystems)测定血清嗜酸性粒细胞阳离子蛋白(ECP)、血清总免疫球蛋白E(T IgE)和特异性IgE抗体 (Phadiatop)水平肺功能测定 ,记录 1s用力呼气容量占预计值百分比 (FEU1 % )及最大峰流速 (PEF)。结果 :新疆维吾尔族人群 β2 AR基因 16位点多态性分布以杂合子所占比率较高 ;2 7位点多态性分布以纯合子所占比率较高 ;16 ,2 7位点多态性分布频率与北方汉族人群不同。亦与英、美高加索人群不同。Gly16纯合子基因型的频率在哮喘组明显高于正常对照组的频率 (13 0 1%vs 10 11% ,P <0 0 5 ) ,而且在夜间哮喘组的频率较非夜间哮喘组明显增高 (30 6 %vs 14 9% ,P <0 0 1) ,β2 AR16位点基因多态性在重度哮喘组Gly Gly基因型分布频率明显高于轻度哮喘和中?     

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 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.     

Tachyphylaxis to beta2-agonists in Spanish asthmatic patients could be modulated by beta2-adrenoceptor gene polymorphisms

BACKGROUND: The study of determinants of asthma is a subject of much interest currently, especially the pharmacogenetic aspects of asthma management. Genetic polymorphisms affecting amino-acids at positions 16 and 27 within beta(2)-adrenoceptor (beta(2)AR) gene have been implicated in the asthma phenotypes and influence on the variability observed in response to use of bronchodilator agents used in the treatment of asthma. Whether these polymorphisms alter the bronchoprotection response to beta(2)-agonist treatment in Spanish asthmatic population is unknown. The aim of this study was to investigate whether genetic polymorphisms within beta(2)AR gene modulate the clinical outcomes of the individual response to beta(2)-agonist therapy and the development of desensitization in Spanish asthmatic patients. METHODS: In a prospective, case-control study were included 80 asthmatic patients. Based on the standard criteria, patients were classified into two groups: patients with tachyphylaxis and good responders to beta(2)-agonist therapy. DNA samples were genotyped for the Arg(16)Gly and Glu(27)Gln alleles within the beta(2)AR gene as well as in 64 control samples from blood donors. RESULTS: Arg(16) allele was slightly more frequent within the group with tachyphylaxis (P=0.039), whereas Gly(16) allele carriers were overrepresented within the group of good responders (59.7%, P=0.028). On the other hand, the allele frequency of Gln(27) and the proportion of Gln(27) carriers was higher within the group with tachyphylaxis (P=0.010 and 0.049, respectively) and Glu(27) allele carriers were overrepresented within the group of good responders (P=0.026). The Arg(16) and Gln(27) alleles were in strong linkage disequilibrium across this locus, resulting in the occurrence of disease haplotype. CONCLUSIONS: The predisposition to develop tachyphylaxis in our population seems to be linked to the Arg(16) and Gln(27) alleles and to the Arg(16)/Gln(27) risk haplotype (positive association between the presence of the Arg(16) and Gln(27) alleles and tachyphylaxis). The Arg(16) allele is perhaps overrepresented due to the strong linkage disequilibrium between both polymorphisms. The presence of the Glu(27) allele seems to be a protective factor against tachyphylaxis in this cohort study.     

Variants in the human beta 1-, beta 2-, and beta 3-adrenergic receptor genes are not associated with morbid obesity in children and adolescents

AIM: beta-adrenergic receptors (beta-ARs) are of key importance for the regulation of lipolysis and thermogenesis by catecholamines. Genetic defects in expression or function of beta(1)- beta(2)- and/or beta(3)-AR could affect energy homeostasis and predispose an individual towards the development of obesity. We therefore investigated the possible association of polymorphisms in the beta-adrenergic receptor genes with early onset obesity. METHODS: Frequencies of the following variants were assessed in extremely obese children and healthy underweight controls: Gly/Ser in codon 49 and Arg/Gly in codon 389 of the beta(1)-AR, Arg/Gly in codon 16 and Gln/Glu in codon 27 of the beta(2)-AR, Trp/Arg in codon 64 of the beta(3)-AR. RESULTS: The Ser49 allele in the beta(1)-AR gene was found at a frequency of 0.131 in obese and 0.136 in lean subjects (p = 0.835), while the Gly389 allele in the beta(1)-AR had a frequency of 0.319 in obese and 0.328 in lean subjects (p = 0.802). Gly16 in the beta(2)-AR was found with a frequency of 0.590 in obese and 0.611 in lean subjects (p = 0.591) and the Glu27 allele in the beta(2)-AR had a frequency of 0.380 in obese and 0.420 in lean subjects (p = 0.298). CONCLUSION: We did not detect significant differences for allele and carrier frequencies of individual polymorphisms. Together with previously obtained data on genotype distribution of a beta(3)-AR variant in the same study group, no significant differences were found between obese and lean subjects for the distribution of individuals with variants in none, one, two or all three beta-ARs. Our data make it unlikely that polymorphisms in beta-ARs are involved in the pathogenesis of early onset obesity.     

β(2) -adrenoreceptor polymorphisms in asthmatic and non-asthmatic schoolchildren from colombia and their relationship to treatment response

Asthma is a chronic and recurrent disease. Its high prevalence around the world is the result of a complex interaction between genetic and environmental factors. The genetic aspects of susceptibility, severity, and response to treatment in asthma are of great scientific interest. The purpose of the study was to establish the relationship between the Gln27Glu and Arg16Gly alleles of the β(2) -adrenergic receptor (ADRB2) gene with respect to the susceptibility to and severity of asthma, as well as the response to treatment in mestizo schoolchildren. 109 schoolchildren with asthma diagnosis and 137 asymptomatic controls were genotyped for the Arg16Gly and Gln27Glu alleles of the ADRB2 gene by minisequencing. Allele, genotype, and haplotype frequencies of the ADRB2 gene between asthmatic and non-asthmatic as well as demographic, clinical, and spirometric variables among asthmatic patients according to their genotype were compared. ADRB2 gene expression was determined by real-time quantitative PCR. No statistical differences were found in allele, genotype, and haplotype frequencies of the ADRB2 gene between cases and controls. We did not find differences between asthmatic patients classified according to their ADRB2 genotypes and haplotypes when evaluating demographic, clinical, and spirometric variables. The ADRB2 genotype and haplotype are not associated with spirometric responses or ADRB2 gene expression after administration of a β-(2) agonist plus a glucocorticoid. These results suggest that in the group of mestizo schoolchildren studied, the Arg16Gly and Gln27Glu polymorphisms are not markers of susceptibility or severity of asthma and do not affect ADRB2 gene expression during the rescue therapy.     

Polymorphisms in beta-adrenergic receptor genes in the acquired long QT syndrome

INTRODUCTION: Sympathetic activation is a trigger for life-threatening arrhythmias in many patients with the congenital long QT syndrome (LQTS), and an increase in heart rate has been reported just prior to torsades de pointes in patients with drug-associated (acquired) LQTS (aLQTS). We compared the frequencies of five recognized nonsynonymous coding region polymorphisms in genes encoding the beta1-adrenergic and beta2-adrenergic receptors (AR) in 93 patients with aLQTS and 3 control groups: an ethically diverse set of individuals from middle Tennessee (n = 71), a subset of the Polymorphism Discovery Resource obtained from National Human Genome Research Institute (n = 89), and patients who tolerated QT-prolonging drugs without aLQTS (non-aLQTS group; n = 66). METHODS AND RESULTS: Polymerase chain reaction-restriction fragment length polymorphism was used to screen for Ser49Gly and Gly389Arg (beta1-AR) and Thr164Ile (beta2-AR). For Arg16Gly and Gln27Glu, polymorphic sites 33 nucleotides apart in the beta2-AR, single-stranded conformational polymorphism was used to distinguish among the 4 possible haplotypes and 10 possible genotypes. Allele frequencies were similar among the 4 groups at the 2 beta1-AR sites. The uncommon Ile164 variant in beta2-AR was slightly more frequent in patients (3.2%) than in any of the 3 control groups (0.6% to 2.3%). At the 16-27 neighboring sites in the beta2-AR, one haplotype (Arg16/Glu27) was not detected, as in previous studies; hence, only 6 genotypes were present. There were fewer Gly16/Gln27 homozygotes in the non-aLQTS group (1.5%) than in two other control groups or the aLQTS group (8.5% to 10%). CONCLUSION: None of the five common nonsynonymous coding region polymorphisms in the beta-AR genes predict drug-associated torsades de pointes, although the Gly16/Gln27 haplotype may be a risk factor.     

Influence of beta-2 adrenergic receptor gene polymorphism on the hemodynamic response to propranolol in patients with cirrhosis

The beta-2-adrenergic receptor (beta(2-)-AR) has several single-nucleotide polymorphisms. These influence the functional response to adrenergic stimulation; genotypes homozygous for Gly16-Glu27 or Gly16-Gln27 alleles (Gly16-Glu/Gln27 haplotypes) are associated with enhanced response, whereas genotypes homozygous for Arg16-Gln27 alleles (Arg16-Gln27) show a decreased response. We hypothesized that gene polymorphisms at the beta2-AR may influence the hemodynamic response to propranolol in patients with cirrhosis. The beta2-AR gene polymorphisms were determined by direct sequencing of the polymerase chain reaction (PCR) products in 48 patients with cirrhosis. All patients also had hepatic and systemic hemodynamic studies before and after propranolol administration. Prevalence of Gly16-Glu/Gln27 haplotypes was 29.1%, Arg16-Gln27 haplotype was 16.7%, and 54.2% were compound heterozygotes. Patients with cirrhosis with Gly16-Glu/Gln27 haplotypes had a greater decrease in heart rate, cardiac index, and hepatic blood flow after propranolol administration than those with Arg16-Gln27 haplotype. However, the HVPG response to propranolol was similar in both groups, whereas estimated hepatic sinusoidal resistance increased significantly in Gly16-Glu/Gln27 haplotypes but not in Arg16-Gln27 (+27.1 +/- 17.8% vs -17.9 +/- 13.9%, P = .042), suggesting that unopposed vasoconstrictive activity at the intrahepatic circulation hinders the fall in HVPG despite enhanced hemodynamic response to propranolol in Gly16-Glu/Gln27 haplotypes. In conclusion, beta2-AR gene polymorphisms influence the response to beta-blockade. However, HVPG reduction cannot be predicted from polymorphism analysis. Patients with the Gly16-Glu/Gln27 haplotypes may benefit from the association of hepatic vasodilators to propranolol therapy.     

Beta-adrenergic receptor genes are associated with arterial stiffness in black and white adults: the Bogalusa Heart Study

BACKGROUND: Sympathetic nervous activity, which is regulated by the beta-adrenergic receptor (beta-AR), is an important determinant of the arterial wall-stiffening process. This study examines the genetic influence of beta-AR gene polymorphisms (beta(1)-AR Arg389Gly, beta(2)-AR Arg16Gly, and beta(3)-AR Trp64Arg) on arterial stiffness in black and white young adults. METHODS: The study cohort included 366 black and 891 white adults, aged 19 to 44 years, enrolled in the Bogalusa Heart Study. Aorta-femoral pulse-wave velocity (af-PWV) was measured by echo-Doppler in a subsample (n = 614). RESULTS: Pulse pressure and heart rate were significantly associated with af-PWV in both races, but not with the three polymorphisms. The af-PWV values differed significantly among the beta(1)-AR Arg389Gly genotype groups in whites (P = .007) and in the total sample (P = .005), with those who were homozygous for Gly389 showing higher values than those who were homozygous for Arg389, after adjusting for cardiovascular risk factors. The beta(3)-AR Arg64 allele was associated with higher af-PWV values in blacks (P = .022) and in the total sample (P = .015). The beta(2)-AR Arg16 allele was associated with af-PWV only in blacks (P = .020). In multivariate regression analysis for the total sample, age, pulse pressure, heart rate, beta(1)-AR Arg389Gly, beta(3)-AR trp64Gly, and smoking status were, in descending order, associated with af-PWV. Furthermore, af-PWV values significantly increased with the increasing number of beta(1)-AR Gly389, beta(2)-AR Arg16, and beta(3)-AR Arg64 alleles (P for trend = .0003). CONCLUSIONS: These results indicate that the beta-AR gene polymorphisms influence arterial stiffness in black and white young adults in an additive manner.     

Roles of Genotypes of β2-Adrenergic Receptor in the Relationship Between Eosinophil Counts and Lung Function in Taiwanese Adolescents

To examine the roles of genetic polymorphism of the β₂-adrenergic receptor (β₂AR) in the relationship between eosinophil (EOS) counts and eosinophil cationic protein (ECP) counts and lung function, we recruited a random sample from the 1996 nationwide survey of asthma prevalence in middle school children. A total of 149 subjects—42 asthmatic children, 38 asthmatics in remission (no reported attack for more than 12 months), and 69 nonasthmatics—completed a physical evaluation, pulmonary function test, and determination of EOS, ECP, and β₂AR genotypes at amino acids 16 and 27. Asthmatic children had higher EOS and ECP than did nonasthmatics. No association was found between asthma and β₂AR genotypes. Lung function was significantly and inversely correlated with EOS but not with ECP in asthmatic children. By genotype, an inverse correlation between lung function and EOS was found in asthmatic children with Arg16Arg or Gln27Glu. A nonsignificant but similar inverse correlation was found in asthmatic children with Arg16Gly or Gln27Gln. However, a nonsignificant but positive correlation was found in asthmatic children with Gly16Gly. In conclusion, we suggest that EOS is a better clinical indicator of airway inflammation than ECP when children are not having an asthma attack. The association between an increase of EOS and lower lung function can be differentiated by β₂AR genotypes at amino acid 16.     

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.     

The effect of polymorphisms of the beta(2)-adrenergic receptor on the response to regular use of albuterol in asthma

Inhaled beta-adrenergic agonists are the most commonly used medications for the treatment of asthma although there is evidence that regular use may produce adverse effects in some patients. Polymorphisms of the beta(2)-adrenergic receptor (beta(2)-AR) can affect regulation of the receptor. Smaller studies examining the effects of such polymorphisms on the response to beta-agonist therapy have produced inconsistent results. We examined whether polymorphisms at codon 16 (beta(2)-AR-16) and codon 27 (beta(2)-AR-27) of the beta(2)-AR might affect the response to regular versus as-needed use of albuterol by genotyping the 190 asthmatics who had participated in a trial examining the effects of regular versus as needed albuterol use. During the 16-wk treatment period there was a small decline in morning peak expiratory flow in patients homozygous for arginine at B(2)-AR-16 (Arg/Arg) who used albuterol regularly. This effect was magnified during a 4-wk run out period, during which all patients returned to using as-needed albuterol, so that by the end of the study Arg Arg patients who had regularly used albuterol had a morning peak expiratory flow 30. 5 +/- 12.1 L/min lower (p = 0.012) than Arg/Arg patients who had used albuterol on an as needed basis. There was no decline in peak flow with regular use of albuterol in patients who were homozygous for glycine at beta(2)-AR-16. Evening peak expiratory flow also declined in the Arg/Arg patients who used albuterol regularly but not in those who used albuterol on an as-needed basis. No significant differences in outcomes between regular and as-needed treatment were associated with polymorphisms at position 27 of the beta(2)-AR. No other differences in asthma outcomes that we investigated occurred in relation to these beta(2)-AR polymorphisms. Polymorphisms of the beta(2)-AR may influence airway responses to regular inhaled beta-agonist treatment.     

新疆维吾尔族人β2肾上腺素能受体基因多态性与原发性高血压的相关性

目的探讨β₂肾上腺素能受体（β₂-AR）基因Arg16Gly和Gln27Glu多态性在新疆维吾尔族人原发性高血压（EH）发病中的作用。方法应用TaqMan技术检测了367例新疆维吾尔族EH患者及408例正常血压对照者Arg16Gly和Gln27Glu多态性。结果 Arg16Gly和Gln27Glu多态性在新疆维吾尔族群体中分布均符合Hardy-Weinberg平衡;Arg16GlyGG、AG、AA基因型频率和Gln27GluGG、CG和CC基因型频率在EH组和正常血压组间差异无统计学意义（P>0.05）。EH组和正常血压组间Arg16Gly及Gln27Glu位点的G等位基因频率分别为46.0%、42.5%和22.3%、24.5%,差异无统计学意义（P>0.05）。结论β₂-AR基因Arg16Gly和Gln27Glu多态位点可能不是新疆维吾尔族人群原发性高血压的遗传易感指标。     

beta2-adrenergic receptor polymorphisms and salbutamol-stimulated energy expenditure

The beta-adrenergic system is involved in the control of energy metabolism and expenditure. The beta2-adrenergic receptor (beta2-AR) gene shows polymorphisms that have been associated with obesity in several studies. In vitro and in vivo studies suggest differences in beta2-AR-mediated function between these polymorphisms. The aim of this study was to investigate the influence of genetic variation in codon 16 of the beta2-AR gene on energy metabolism in humans. Thirty-four subjects were recruited [Gly16Gly (n = 13), Gly16Arg (n = 16), or Arg16Arg (n = 5)]. The beta2-AR was stimulated with two doses of salbutamol (50 and 100 ng/kg fat-free mass per minute) after blockade of the beta1-adrenergic receptors with atenolol. Energy expenditure and plasma substrate and hormone concentrations were measured. The increase in energy expenditure (DeltaEE) was significantly different among groups in which the Arg16Arg group showed the lowest increase (P < 0.05 vs. Gly carriers). In a multiple regression model, variations in the increase in nonesterified fatty acid concentration during salbutamol infusion (partial r = 0.51) and the polymorphism contributed significantly to the variation in DeltaEE. Thirty-five percent of the variation in DeltaEE was explained by these two factors. We conclude that subjects with the Arg16Arg polymorphism of the beta2-AR gene have a reduced thermogenic response to beta2-adrenergic stimulation. Although this relatively small study needs confirmation, the findings support a role for this polymorphism in the development and maintenance of overweight and obesity.     

Suppressive effect of the Gly389 allele of the beta1-adrenergic receptor gene on the occurrence of ventricular tachycardia in dilated cardiomyopathy.

Beta-1-adrenergic receptor (beta1-AR) blockers reduce both the incidence of sudden death and the ventricular volume in heart failure. In vitro, the Gly389 variant of beta1-AR mediates less adenylyl cyclase activities than the Arg389 variant, so Arg389Gly polymorphism was investigated with regard to the genesis, progression, or arrhythmogenesis of dilated cardiomyopathy (DCM). Allele and genotype frequencies of the Arg389Gly polymorphism were determined in 163 DCM patients and 157 age- and sex-matched controls. There were no differences in genotype and allele frequencies between patients and controls. Echocardiograms, left ventriculograms and 24h-Holter electrocardiograms were evaluated in the DCM patients and none of the clinical indices, other than ventricular tachycardia (VT), differed among the 3 genotypes. The Gly389 allele was more frequent in the VT(-) group than in the VT(+) group (0.46 vs 0.24, p=0.001). In univariate analysis, the odds ratio for VT in patients carrying 1 or 2 copies of the Gly389 allele was 0.29 ([95% confidence interval, 0.13-0.64], p=0.002), when compared with the Arg389 homozygotes. The Gly389 variant supressed the occurrence of VT in DCM, suggesting that this allele confers a decreased risk of sudden death.     

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.     

Polymorphism of the beta(2)-adrenoceptor in COPD in Chinese subjects.

STUDY OBJECTIVES: To assess the frequencies of three polymorphisms at amino acid positions 16, 27, and 164 of the beta(2)-adrenoceptor (beta(2)-AR) gene and their effects on COPD patients. DESIGN: Prospective, case-control study PATIENTS: Sixty-five patients with COPD and 41 healthy subjects were included. MEASUREMENTS: Polymorphisms of the beta(2)-AR coding block were delineated using an allele-specific polymerase chain reaction (PCR) approach. The allele-specific PCR technique was verified by direct dideoxy sequencing of PCR products. Pulmonary function tests were performed in all patients. RESULTS: The Arg16 beta(2)-AR polymorphism was less prevalent in COPD patients than in healthy populations (p = 0.01). A significant correlation (p < 0.018) between the Gln27 beta(2)-AR polymorphism and FEV(1) percent predicted value was found. Patients with the Gln27 polymorphism had a higher percentage of low FEV(1) percent predicted than did patients with the GlnGlu and GluGlu variants. CONCLUSIONS: The polymorphism of Gly16 may increase the patient's susceptibility to the development of COPD. The Gln27 beta(2)-AR polymorphism may be associated with the severity of COPD in a Chinese population.