Impact of beta1-adrenergic receptor polymorphisms on susceptibility to heart failure, arrhythmogenesis, prognosis, and response to beta-blocker therapy

Beta1-adrenergic receptor polymorphisms have been implicated with inconsistent results in the pathogenesis, clinical presentation, and prognosis of patients with heart failure (HF). The impact of 2 functional polymorphisms (beta1-Arg389Gly and beta1-Ser49Gly) on HF susceptibility, arrhythmogenesis, and prognosis was evaluated in Brazilian outpatients. Genotyping at codons 389 and 49 was performed using polymerase chain reaction with restriction fragment length polymorphism analysis in 201 outpatients with systolic HF and 141 apparently healthy controls. Enrolled patients were followed up at the HF clinic, and vital status was evaluated using electronic hospital records, telephone contact, and a local death certificate database. Allele frequencies were similar between patients with HF and controls, with neither polymorphism related to HF susceptibility. The beta1-389Gly homozygotes had significantly less nonsustained ventricular tachycardia on Holter monitoring (17% vs 48% for Arg/Arg patients; p = 0.015) and improved HF-related survival, with no events after a median follow-up of 40 months (log-rank statistics = 0.025). The negative impact of beta1-389Arg allele on HF-related survival was substantially reduced using high-dose beta-blocker therapy (80% survival for high-dose vs 42% for low-dose beta blockers or nonusers; log-rank statistics = 0.0003). The beta1-Ser49Gly polymorphism was not associated with nonsustained ventricular tachycardia or HF prognosis. In conclusion, beta1-Arg389Gly and beta1-Ser49Gly polymorphisms had no influence on HF susceptibility. However, the Gly389 allele was associated with a lower prevalence of ventricular arrhythmias and better HF-related survival. A pharmacogenetic interaction is suggested because beta blockers were more effective in beta1-389Arg allele carriers.     

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.     

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.     

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.     

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     

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.     

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.     

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.     

β2肾上腺素能受体基因+46位Arg16/Gly多态性与新疆哈萨克族人群低密度脂蛋白胆固醇水平的关系

目的探讨β2肾上腺素能受体基因（β2-adrenergic receptor,β2-AR）＋46 A→G （Arg16/Gly）多态性在哈萨克族人群中的分布及其与血清低密度脂蛋白胆固醇（LDL-C）水平的关系.方法采集506例30～69岁哈萨克族人的遗传标本,采用聚合酶链反应-限制性酶切片段多态性（PCR-RFLP）技术分析β2-AR基因＋46A→G基因多态性,观察各基因型和等位基因的分布频率及其与血清LDL-C及血清总胆固醇（TC）水平的关系.结果 （1） 该人群β2-AR＋46位基因型频率为AA 0.310、AG 0.455、GG 0.235.A、G等位基因频率分别为0.538、0.462;分布符合Hardy-Weinberg定律.（2）GG型者的血清LDL-C水平明显高于其他两种基因型者,与AG型相比差异有统计学意义（P〈0.05）.（3）比较β2-AR＋46位3种基因型对血脂影响的性别差异,发现女性中GG型与其他2种基因型相比,其LDL-C平均水平最高（P〈0.05）.结论哈萨克族人群β2-AR基因存在＋46位A→G 多态性,其分布频率为AA 0.310、AG 0.455、GG 0.235.该人群尤其在女性中GG型者的血清LDL-C水平明显增高,GG基因型频率与血清LDL-C水平呈正相关.     

Association between beta2-adrenergic receptor genetic polymorphisms and nocturnal asthmatic patients of Chinese Han nationality

BACKGROUND: As a result of the finding that the mutation of Arg into Gly at beta(2)-adrenergic receptor (beta(2)-AR)16 loci could promote the downregulation effect triggered by the beta(2)-agonist, it was supposed that Gly16 might be associated with the downregulation of beta(2)-AR in patients with nocturnal asthma. OBJECTIVE: It was the aim of this study to analyze the association between beta(2)-AR genetic polymorphisms and nocturnal asthmatic patients of Chinese Han nationality. METHODS: A polymerase chain reaction allele-specific oligonucleotide hybridization assay was used to determine 16 and 27 loci alleles of beta(2)-AR genetic polymorphisms in 25 nocturnal asthmatic patients (nocturnal asthma group), 22 non-nocturnal asthmatic patients (non-nocturnal asthma group), and 72 healthy people (control group). All people investigated were of Chinese Han nationality. RESULTS: The distribution frequency of genotype Arg/Arg, Arg/Gly, and Gly/Gly at beta(2)-AR 16 loci was 12, 16 and 72% in the nocturnal asthma group; and 27, 41 and 32% in the non-nocturnal asthma group. There was a significant increase in the frequency of genotype Gly/Gly and allele Gly in the nocturnal asthma group compared with the non-nocturnal asthma group (p < 0.01). However, there was no significant difference in the frequency of genotype Gly/Gly and allele Gly in the non-nocturnal asthma group, compared with the control group. There was no significance in the frequency of the genotypes and alleles of beta(2)-AR 27 loci among the three groups (p > 0.05). CONCLUSION: The Gly16 polymorphism of beta(2)-AR was overrepresented in nocturnal asthmatic patients, correlated with nocturnal asthma, and therefore appeared to be an important genetic factor in the expression of this asthmatic phenotype.     

Job strain, job demands and adrenergic beta1-receptor-polymorphism: a possible interaction affecting blood pressure in men

BACKGROUND: Job strain and the Arg389Gly polymorphism in the adrenergic beta1-receptor gene have been linked to hypertension. We aimed to study whether there is an interaction between the Arg389Gly polymorphism and job strain and its components (job demand and decision latitude) in relation to blood pressure. METHODS: From the Malm? Diet and Cancer population cohort, 6095 individuals were randomly selected to be followed regarding cardiovascular risk factors. From this group, employed individuals with baseline data regarding work characteristics were included (1338 men and 1707 women). Determination of adrenergic beta1-receptor Arg389Gly polymorphism was possible in 1271 men and 1601 women, and these individuals formed the study group. RESULTS: Men with the combination of Arg389Arg and job strain were more often on antihypertensive medication (P = 0.04), whereas blood pressure was not significantly higher, in comparison with those without both of these two factors. The interaction term genotype x job strain was borderline significant for systolic blood pressure (P = 0.07) after adjustments for age, country of birth, and job status. The demand score showed significant interaction in men with genotype (P = 0.01 for systolic blood pressure and P = 0.009 for diastolic blood pressure) after adjustments for age, country of birth, job status, antihypertensive treatment, and BMI. Men with the Gly389 allele had lower blood pressure with increasing demand score (P = 0.001), whereas men homozygous for the Arg389 allele had lower blood pressure with increasing latitude score (P = 0.03). In women, those with job strain tended to have higher blood pressure than those without job strain, among carriers of Arg389Arg and Arg389Gly genotype. CONCLUSION: Men with job strain and the Arg389Arg polymorphism were more often on antihypertensive treatment than other men. Significant interactions between the Arg389Gly polymorphism and aspects of job stress are described, but the absolute blood pressure differences are small. Considering the commonness of the polymorphism, stress, and hypertension further studies are indicated.     

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.     

阻塞性睡眠呼吸暂停低通气综合征患者肾上腺素β_1受体基因多态性与其心血管系统并发症的关系

目的 探讨OSAHS患者肾上腺素β_1受体基因多态性与其心血管系统并发症的相关性.方法 采用聚合酶链反应-限制性片段长度多态性(PCR-RFLP)技术对2007年2月至12月山西医科大学第二医院经多导睡眠监测(PSG)诊断的192例OSAHS患者肾上腺素β_1受体Gly389Arg位点的基因多态性进行检测,分析该位点基因型(CC组、CG组及GG组)与OSAHS患者PSG监测参数及心血管事件的相关性.采用方差分析,x~2检验及t检验进行统计学分析.结果 不同基因型频率两两比较CC组明显高于CG和GG组,等位基因频率C明显高于G.CC组的睡眠时最低血氧饱和度(minSaO_2)明显低于GG和CG组,睡眠期间SaO_2低于90%的时间占总睡眠时间的百分比(T90)及最长呼吸暂停时间(Tmax)均较高.3组间窦性心动过缓的发生率差异无统计学意义(P>0.05),CC组高血压、冠状动脉粥样硬化性心脏病、心律失常及肺源性心脏病的发生率均明显高于CG组和GG组(P<0.05).结论 OSAHS患者肾上腺素β_1受体Gly389Arg位点的CC基因型可能与其心血管并发症的发生有关,C等位基因可能是易感基因.     

Beta2-adrenergic receptor polymorphisms at codon 16, cardiovascular phenotypes and essential hypertension in whites and African Americans

Beta2-adrenergic receptors (beta2-AR) contribute to cardiovascular regulation by influencing several functions and previous studies suggest that a decreased function of the beta2-AR may be involved in essential hypertension. Beta2-AR are polymorphic and certain polymorphisms of these receptors are of functional importance. We focus here on the Arg16-->Gly16 beta2-AR polymorphism, which shows enhanced agonist-promoted downregulation of the receptor and which, in two recent studies, yielded opposite results in terms of association with essential hypertension: an increased frequency of the Gly16 variant in African-Caribbean hypertensives and of the Arg16 variant in offspring of Norwegian white hypertensive parents. In the current study, we genotyped 243 subjects, including both African-American and white individuals, for codon 16 polymorphism and assessed blood pressure and cardiovascular function using impedance cardiography and pressor sensitivity to phenylephrine. We found similar patterns of cardiovascular function and expression of hypertension with the two genotypes of codon 16. There was no statistically significant difference in the overall allelic distribution of the two genotypes: among African-Americans, 51% of the hypertensives and 50% of the normotensives carried the Arg16 allele, whereas among the white subjects 40% of the hypertensives and 47% of the normotensives were carriers of the Arg16 allele. Although we observed a statistically significant increase in the Arg16/Gly16 heterozygotes in the African-American population, the Gly16 allele was not significantly increased in the African-Americans compared to whites. These findings indicate that the codon 16 polymorphisms are not associated with hypertension in a mixed American study population nor do they appear to substantially impact on a variety of hemodynamic variables.     

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.     

Role of beta1- and beta2-adrenoceptor polymorphisms in heart failure: a case-control study.

BACKGROUND: We hypothesised that the polymorphisms of the genes encoding for beta1- and the beta2-adrenoceptors may have a role in the pathogenesis of heart failure (HF). We therefore compared the polymorphisms of the beta1-adrenoceptor gene (Arg389Gly), the beta2-adrenoceptor gene (Arg16Gly, Gln27Glu) and their combinations in patients with HF and normal subjects living in the same area. METHODS AND RESULTS: A total of 256 cases with HF (left ventricular ejection fraction < or = 40%) and 230 normal subjects were enrolled. The beta1- and beta2-adrenoceptor gene polymorphisms were assessed by PCR, followed by restriction enzyme digestion. No differences were observed in the distribution of any of the three genotypes studied in patients with HF and normal subjects. An analysis of the genotype combinations showed a non-significant increase in the risk of HF associated with the Arg389Gly16Gln27 (odds ratio = 1.4; 95%CI 0.5-3.6) and Arg389Gly16 Glu27 (odds ratio = 1.2; 95%CI, 0.5-2.8) homozygous allele combinations. CONCLUSION: None of the three most common polymorphisms of beta-adrenoreceptors are associated with an increased risk of HF.     

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.     

Polymorphisms of insulin receptor substrate 1 and beta3-adrenergic receptor genes in gestational diabetes and normal pregnancy

Gestational diabetes mellitus (GDM) is considered an important risk factor for the development of type 2 diabetes mellitus. We studied possible relations between GDM and both insulin receptor substrate 1 (IRS-1) (Gly972Arg) and beta3-adrenergic receptor (ADRB3 Trp64Arg, beta3-AR) gene mutations, considered potential modifying factors in the etiology of type 2 diabetes mellitus. We evaluated the 2 gene mutations in late gestation in 627 pregnant women, all studied using the glucose challenge test, followed (in positive tests) by the oral glucose tolerance test (100 g, Carpenter and Coustan [J Obstet Gynecol. 1982;144:768-773] criteria) We diagnosed 309 women with GDM, 41 with gestational impaired glucose tolerance and 277 normal pregnant women. Age, family history of diabetes, prepregnancy body mass index, weight gain during pregnancy, plasma glucose levels, hemoglobin A1c, islet autoantibody levels, and insulin treatment during pregnancy were all evaluated. All pregnant women were genotyped for IRS-1 (Gly972Arg) and beta3-AR (ADRB3 Trp64Arg) polymorphisms. The frequency of IRS-1 gene polymorphism was significantly higher in women with GDM than in women with a normal glucose tolerance (NGT) (P = .039), and there was a significant trend (P = .032) in the increasing frequency of mutant allele Arg from NGT > gestational impaired glucose tolerance > GDM. The search for beta3-AR gene polymorphism showed no significant differences between women with GDM and women with NGT. The X-Arg genotype of IRS-1 was significantly associated with a positive family history of diabetes in NGT (P = .006) and neared significance in GDM (P = .057). Moreover, we found that NGT carriers of both polymorphisms had a higher prepregnancy body mass index than carriers of the IRS-1 variant alone (P = .0034), the beta3-AR variant alone (P = .039), or neither (P = .048), suggesting a possible synergistic effect of the 2 gene polymorphisms. These results suggest that the IRS-1 genetic polymorphism is involved in the occurrence of gestational diabetes, as well as type 2 diabetes mellitus.     

Autoantibodies Against beta(1)-Adrenoreceptors in Patients With Cardiac Rhythm Disorders. Prevalence and Possible Role in Development of Arrhythmia

AIM: To assess prevalence of autoantibodies against beta(1)-adrenoreceptors (beta(1)-AR) in patients with arrhythmias of various etiology. MATERIAL: Patients with arrhythmias (n=110, including 59 patients with primary [idiopathic] electrical abnormalities, 33 - with chronic myocarditis and dilated cardiomyopathy [DCM]; 18 - with ischemic heart disease [IHD]) and healthy control subjects (n=20). METHODS: Antibodies against beta(1)-AR were measured in blood serum by direct immunoassay. Synthetic fragment containing 26 amino acids of beta(1)-AR second loop was used as antigen. RESULTS: Patients with primary electrical abnormalities and chronic myocarditis/DCM had similar prevalence of beta(1)-AR (49.1% and 54.5%, respectively), what was significantly higher than in controls (10%) and in patients with IHD (16.6%). These results provided evidence for the possible presence of an autoimmune process in the genesis of idiopathic arrhythmias. Among patients with idiopathic arrhythmias beta(1)-AR were found in 40% (10 of 25) of patients with ventricular tachycardia (VT), 63.6% (14 of 22) of patients with ventricular extrasystoles (VE), 41.6% (5 of 12) of patients with atrial fibrillation (AF). Among patients with chronic myocarditis and DCM beta(1)-AR were found in 72.2% (13 of 18) of patients with VT, 28.5% (2 of 7) of patients with VE, 37.5% (3 of 8) of patients with AF. Among patients with idiopathic arrhythmias female sex and frequent respiratory viral diseases were more common in beta(1)-AR-positive compared with beta(1)-AR-negative patients. VT and left ventricular ejection fraction <40% were more common in beta(1)-AR-positive than beta(1)-AR-negative patients among those with chronic myocarditis and DCM.     

Beta1-adrenergic receptor gene polymorphisms and response to beta1-adrenergic receptor blockade in patients with essential hypertension

BACKGROUND: Studies suggest that the Ser49Gly and Arg389Gly polymorphisms in the beta1-adrenergic receptor might be of functional importance for the cardiovascular system. Both have been associated with altered receptor activity in vitro, and with hypertension and cardiac failure in vivo. HYPOTHESIS: The aim of this study was to test whether these polymorphisms were associated with the change in heart rate or blood pressure in patients with essential hypertension and left ventricular (LV) hypertrophy treated with the beta1-adrenergic receptor blocker atenolol. METHODS: Blood pressure and heart rate were measured in 101 hypertensive patients with echocardiographically verified LV hypertrophy, randomized in a double-blind study to treatment with either the beta1-adrenergic receptor blocker atenolol or the angiotensin II type I receptor antagonist irbesartan. Changes in blood pressure and heart rate were evaluated after 12 weeks. Beta1-adrenergic receptor genotyping was performed using polymerase chain reaction and restriction fragment length polymorphism. RESULTS: We found no significant associations between the changes in the measured variables and either of the two polymorphisms. However, carriers of the 49Gly allele showed a tendency toward a greater reduction in heart rate compared with patients with the Ser/Ser49 genotype (p = 0.06). CONCLUSIONS: The Ser49Gly and Arg389Gly beta1-adrenergic receptor polymorphisms do not seem to exert a major effect on the changes in heart rate and blood pressure during 12 weeks of treatment with atenolol in patients with essential hypertension and LV hypertrophy.