Gly Allele Research Articles

Polymorphism of FGFR4 in cancer development and sensitivity to cisplatin and radiation in head and neck cancer

The aim of this study was to investigate the predisposition of the FGFR4 Gly/Arg polymorphism for development of head and neck squamous cell carcinoma (HNSCC) and, furthermore, to examine if the FGFR4 Arg(388) allele can be associated with resistance to chemo- and radiotherapy. When analysing 110 tumour biopsies a significant 1.7-fold increased risk to develop HNSCC in individuals carrying the Gly(388) allele (p=0.026) was found. Moreover a 2-fold increased risk for males harbouring the Gly(388) allele (p=0.031) to develop HNSCC was detected. In 39 HNSCC cell lines the role of the Arg(388) allele for radiation and cisplatin sensitivity was investigated. Our results show no role of the Arg(388) allele for the radiosensitivity (p=0.996) but indicate a tendency to increased cisplatin sensitivity (p=0.141). When screening the transmembrane and kinase domains in the FGFR4 gene a novel mutation, probably generating a truncated protein lacking exons 14-18, was found in six of eight selected cell lines. Taken together, we have here identified a marker that predicts the risk to develop HNSCC and possibly the sensitivity to cisplatin as well as a novel mutation in the FGFR4 gene.

Limitations of Genetic Findings That Are Not in Hardy-Weinberg Equilibrium

We thank Drs. Body and Schwinn for their critical remarks on our study.1To clarify, our double-blinded, placebo-controlled trial was primarily designed to test the hypothesis that the perioperative administration of bisoprolol would reduce the incidence of cardiovascular complications in patients with or at risk for coronary artery disease undergoing surgery with spinal nerve block. However, because single nucleotide polymorphisms of the β-adrenergic receptor genes may act as disease modifiers,2biologically important nonsynonymous coding variants of the β-adrenergic receptor were determined in our study population. This analysis showed that carriers of at least one Gly allele of the β1-adrenergic receptor polymorphism Arg389Gly experienced a higher number of adverse events than Arg homozygotes.1Drs. Body and Schwinn raised concerns with respect to genotyping errors based on the observed deviation from Hardy-Weinberg equilibrium for this particular polymorphism in our trial. Genotyping error is indeed one of the many possible sources of Hardy-Weinberg disequilibrium. To exclude this possibility in our trial, we have carefully regenotyped all patients for the Arg389Gly polymorphism using internal controls for wild-type, heterozygous, and mutant genotypes for each amplification process. As reported in our publication, from the 189 patients, who consented to genotyping, 186 could be unequivocally identified and confirmed by regenotyping by three independent individuals. In three patients (notably without a primary outcome), genotyping was not possible, and these patients were excluded from genotype-related outcome analysis. Our genotyping platform was further meticulously validated by bidirectional sequencing of DNA samples for the Arg389Gly polymorphism from 12 randomly selected patients of this particular study and from many other patients not related to this study. Bidirectional sequencing is regarded as the standard of genotyping and as by far more reliable than any other genotyping platform.Although testing for Hardy-Weinberg equilibrium is used as some quality-control measure, particularly in case–control gene association studies, it cannot be used to detect genotyping error.3,4Genotyping errors are generally small and do not generate sufficient deviations from Hardy-Weinberg equilibrium to be detected. In the case of a reduced number of observed heterozygous patients, as may occur in the presence of poor amplification of one of the alleles, large samples sizes are necessary to detect deviations from Hardy-Weinberg equilibrium. For example, with the Gly389 allele of the Arg389Gly polymorphism with a reported allele frequency of 0.27 and an error rate of 0.05, more than 8,000 patients would be necessary to detect deviation from Hardy-Weinberg with a power of 0.80 at an α level of 0.05. Increasing the error rate to 0.15 reduces the sample size to the still considerably high patient number of 944. Therefore, testing for Hardy-Weinberg equilibrium is an unreliable tool to identify genotyping errors. Conversely, the presence of Hardy-Weinberg equilibrium does not rule out that genotyping errors might have occurred. Hence, it seems unlikely that genotyping error is the source of the Hardy-Weinberg disequilibrium observed in our study. Because approximately 10% of all genotype–phenotype association studies show deviation from Hardy-Weinberg equilibrium, the results of our trial cannot be considered “abnormal.”5Rather, as outlined in the discussion of our findings,1a selection bias (population stratification) may have occurred because of inclusion and exclusion criteria of this randomized trial. A mortality bias (different survival of marker genes) due to varying genetic and environmental background (e.g. , response to cardiovascular medication) in this elderly study population at the end of life expectancy may have also caused this disequilibrium. Of note, Hardy-Weinberg disequilibrium that is caused by most interesting biologic phenomena typically results in excess homozygosity, as observed in our study.1However, we agree with Drs. Body and Schwinn that violation of Hardy-Weinberg equilibrium in our study population implies a selected rather than a random sample, invalidating direct comparisons with other populations. Therefore, we share their view that our results should be regarded with caution. Our findings should be confirmed in future prospective larger-scale clinical trials, specifically designed and adequately powered to detect genotype-specific differences in cardiovascular outcome in patients with or at risk of coronary artery disease.*University Hospital Zurich, Zurich, Switzerland. michael.zaugg@usz.ch

Job Stress, Gene Polymorphism of β 2-AR, and Prevalence of Hypertension

To study the interactive effect of job stress and genetic susceptibility (or gene polymorphism) on hypertension. A cross-sectional epidemiological study was conducted in 452 workers from a thermal power plant in China. Extrinsic effort, occupational reward, and over-commitment were measured. Hypertensive patients were defined by three phases of screening, reexamination, and final diagnosis. beta2-AR genotypes and allele frequencies at amino acid positions 16 (beta2-AR-16: Arg-->Gly) and 27 (beta2-AR-27: Gln-->Glu) were identified by PCR-RFLP. Job stress was related with the prevalence of hypertension in males (P < 0.05), whereas no significant relationship was found in females (P > 0.05). Differences in genotypes and allele frequencies of the beta2-AR-16 were statistically significant between the hypertension and control groups (P < 0.05), whereas those of beta2-AR-27 were not (P > 0.05). The prevalence of hypertension was higher in individuals carrying Gly16 allele than in those carrying Arg16 allele of the high job stress group (P < 0.01 or 0.05). High job stress and polymorphism of beta2-AR-16 have an interactive effect on the prevalence of hypertension in male workers.

P1-71 CARDIAC TISSUE APOPTOSIS INDUCED BY CARDIOPLEGIC SOLUTION OF CORONARY ARTERY BYPASS GRAFTING PATIENTS WITH THE COMPENSATORY EFFECT OF IGF-1 SURVIVAL SIGNALING ACTIVATION

artery disease (CAD), we seek to evaluate the association of Gly1057Asp of IRS-2 with CAD in Taiwanes. Methods: Patients receiving coronary angiography were enrolled. Mild CAD is defined as presence of significant stenosis (diameter stenosis>50%) in none or one coronary artery and severe CAD in two or three. Gly1057Asp of IRS2 are determined by polymerase chain reaction and restriction fragment length polymorphism and confirmed by DNA sequencing. Results: 481 patients were enrolled. 207 patients have severe CAD. The Gly allele frequency is 66.2% in patients with severe CAD and 54.0% in mild CAD (p<0.001). The Gly/Gly genotype frequency is 44.0% in patients with severe CAD and 31.4% in mild CAD (p<0.001). The risk of severe CAD increases according to the dosage of Gly allele(odds ratio for Gly/Asp genotype 1.944 [1.074∼3.519]; Gly/Gly genotype 3.237 [1.741∼6.019]; p for trend<0.0001) after adjustment for other risk factors. There is interaction of Gly1057Asp of IRS-2 and type 2 DM associating individuals with severe CAD. Presume the risk for severe CAD in non-diabetics with Arg/Arg genotype is 1, the risk is 1.88 (odds ratio), 0.59∼5.93 (95% confidence interval) (p=0.285) in diabetics with Arg/Arg genotype; 2.36 (1.23∼4.51)(p=0.009)in non-diabetics with Gly/Gly or Gly/Arg genotype; and 5.64 (2.76∼11.52)(p<0.001)in diabetcis with Gly/Gly or Gly/Asp. Conclusion: Gly1057 allele of IRS-2 alone or interacting with type 2 DM associates with CAD in Taiwanese.

Association between a β2-adrenergic receptor polymorphism and elite endurance performance

The Arg16Gly single nucleotide polymorphism of the human β 2-adrenoceptor ( ADRB2) gene was evaluated in a case-control study that included 313 white male elite endurance athletes and 297 white male sedentary controls (SCs) recruited in a multicenter project from North America, Finland, and Germany. The groups were matched by country of origin. The elite endurance athletes were required to have a maximum oxygen uptake ≥75 mL·kg −1·min −1 (mean [SD], 79.0 [3.5]), whereas SC subjects had to be sedentary with a measured maximum oxygen uptake ≤50 mL·kg −1·min −1 (40.1 [7.0]). Polymerase chain reaction technique was used to amplify the single nucleotide polymorphism–containing region in codon 16 of the ADRB2 gene. ADRB2 genotypes were in Hardy-Weinberg equilibrium in both groups. Genotypes did not differ between countries or sports of the athletes. The χ 2 analysis for the genotype distribution showed a significant difference between the 2 cohorts ( P = .030), suggesting a positive association between the tested Arg16Gly polymorphism and endurance performance. Comparing carriers vs non-carriers for the 2 alleles, an excess of Gly allele carriers was seen in the SC group ( P = .009), indicating an unfavorable effect of the Gly allele with respect to the performance status. In conclusion, we found suggestive evidence that the Arg16Gly polymorphism in the gene encoding for the β 2-adrenergic receptor may associate with endurance performance status in white men.

Association of β-adrenoceptor polymorphisms with cardiac autonomic modulation in Japanese males

The beta1- and beta2-adrenergic receptors (ARs) coexist in the human heart and control sympathetic responses. Several functional genetic variations in the beta-AR genes (ADRB1 or ADRB2) have been identified and implicated as causes of hypertension and cardiovascular disease. We assessed the relationship between 4 representative genetic polymorphisms of beta-AR (Ser49Gly and Arg389Gly in beta1-AR, Arg16Gly and Gln27Glu in beta2-AR) and autonomic nervous system (ANS) function in healthy young Japanese males. One hundred forty-nine subjects were genotyped for each beta-AR polymorphism and underwent evaluation of ANS function by power spectral analysis of heart rate variability (HRV) during supine rest and in a standing position. The low-frequency (LF; <0.15 Hz) and high-frequency (HF; >0.15 Hz) components of HRV were quantified by frequency domain analysis and expressed in absolute and normalized units. The beta2-AR Arg16 homozygous group had a significantly lower diastolic and mean blood pressure than the Gly16 group in both Arg16Gly individual and Gln27Glu polymorphism combined diplotype-based analyses. In a supine rest position, subjects homozygous for the beta2-AR Arg16 allele had significantly lower HRV sympathetic indices (LF [%] and LF/HF ratio) but higher HRV parasympathetic indices (HF [%]) than the Gly16 allele carriers. Meanwhile, the beta2-AR Glu27 allele was significantly associated with higher HRV LF power than were Gln27 homozygous subjects. In the analysis of gene-gene interaction, the effects of the beta2-AR Arg16 homozygotes on HRV were more apparent in the presence of the beta1-AR Gly389 allele. No independent associations were observed between the beta1-AR Ser49Gly or Arg389Gly genotypes and HRV indices. The Arg16Gly polymorphism of the beta2-AR is related to the modulation of sympathovagal balance, and beta2-AR Glu27 allele carriers potentially have increased autonomic activity. Thus, beta-AR genotype-related differences in basic receptor function cause phenotypic differences in cardiac ANS function.

Adrenergic Receptor Genotype but Not Perioperative Bisoprolol Therapy May Determine Cardiovascular Outcome in At-risk Patients Undergoing Surgery with Spinal Block

Neuraxial blockade is used as primary anesthetic technique in one third of surgical procedures. The authors tested whether bisoprolol would protect patients at risk for cardiovascular complications undergoing surgery with spinal block. The authors performed a double-blinded, placebo-controlled, multicenter trial to compare the effect of bisoprolol with that of placebo on 1-yr composite outcome including cardiovascular mortality, nonfatal myocardial infarction, unstable angina, congestive heart failure, and cerebrovascular insult. Bisoprolol was given orally before and after surgery for a maximum of 10 days. Adrenergic receptor polymorphisms and safety outcome measures of bisoprolol therapy were also determined. A total of 224 patients were enrolled. Spinal block could not be established in 5 patients. One hundred ten patients were assigned to the bisoprolol group, and 109 patients were assigned to the placebo group. The mean duration of treatment was 4.9 days in the bisoprolol group and 5.1 days in the placebo group. Bisoprolol therapy reduced mean heart rate by 10 beats/min. The primary outcome was identical between treatment groups and occurred in 25 patients (22.7%) in the bisoprolol group and 24 patients (22.0%) in the placebo group during the 1-yr follow-up (hazard ratio, 0.97; 95% confidence interval, 0.55-1.69; P = 0.90). However, carriers of at least one Gly allele of the beta1-adrenergic receptor polymorphism Arg389Gly showed a higher number of adverse events than Arg homozygous (32.4% vs. 18.7%; hazard ratio, 1.87; 95% confidence interval, 1.04-3.35; P = 0.04). Perioperative bisoprolol therapy did not affect cardiovascular outcome in these elderly at-risk patients undergoing surgery with spinal block.

The Arg389Gly β1-adrenergic receptor gene polymorphism and susceptibility to faint during head-up tilt test

To investigate the association of the Gly389 allele with positive head-up tilt test (HUT) in a Mexican Mestizo population. 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. 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.

Studies of associations between the Arg389Gly polymorphism of the β1‐adrenergic receptor gene (ADRB1) and hypertension and obesity in 7677 Danish white subjects

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. 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. 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. 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.

Studies of the associations between functional β2-adrenergic receptor variants and obesity, hypertension and type 2 diabetes in 7,808 white subjects

Functional and common Arg16Gly and Gln27Glu polymorphisms have been identified in ADRB2, the gene encoding the beta2-adrenergic receptor. These variants have previously been examined for association with obesity, hypertension and diabetes with inconclusive results. We investigated both of these variants in 7,808 unrelated, middle-aged white people for their association with obesity in a case-control study, quantitative trait analysis and meta-analysis. Moreover, both variants were investigated for their potential influence on measures of hypertension and type 2 diabetes by case-control and quantitative trait analyses. The present study did not find consistent evidence for an association of these beta2-adrenergic receptor variants with obesity or hypertension; neither did the quantitative trait analyses show any effect of the variants on obesity-related traits. However, both the Gly allele of the Arg16Gly variant and the Glu allele of the Gln27Glu variant showed nominal association with systolic blood pressure. Furthermore, there was a nominal association of the Arg16 allele frequency and genotype distribution with type 2 diabetes; however, no influence on quantitative biochemical phenotypes related to type 2 diabetes was found. A nominal association of the Arg/Gly genotype with the metabolic syndrome was also observed (p=0.003). Logistic regression analyses provided no evidence of a synergistic or an additive effect of these variants on obesity, hypertension or diabetes. After studying 7,808 middle-aged white subjects, we were unable to demonstrate any consistent associations between two common amino acid polymorphisms of the beta2-adrenergic receptor and obesity, hypertension or type 2 diabetes.

High Plasma Norepinephrine Levels Associated with .BETA.2-Adrenoceptor Polymorphisms Predict Future Renal Damage in Nonobese Normotensive Individuals

Renal injury is common in obesity and hypertension. In the present study, we examined relationships between renal function alterations, plasma norepinephrine (NE), and beta2-adrenoceptor polymorphisms in a longitudinal design over 5 years. In 219 nonobese, normotensive men with entry-normal renal function, we measured serum blood urea nitrogen (BUN), creatinine, creatinine clearance, plasma NE, homeostasis model assessment of insulin resistance (HOMA-IR), body mass index (BMI), total body fat mass, and blood pressure (BP) annually for 5 years. beta2 (Arg16Gly, Gln27Glu)-adrenoceptor polymorphisms were determined. The subjects were stable in body weight and BP (<10%) for 5 years. High plasma NE was defined as > or =mean+1 SD at entry. Thirty-seven subjects had entry-high plasma NE and 182 were entry-normal. Entry-high plasma NE subjects had significantly greater total body fat mass and plasma NE and significantly lower creatinine clearance at entry and throughout the study. Increases in BMI, fat mass, BP, plasma NE, BUN, and creatinine, as well as the reduction in creatinine clearance in the 5 years, were significantly greater in entry-high NE subjects. These subjects had significantly higher frequencies of the Gly16 allele of beta2-adrenoceptor polymorphisms. Throughout the study, subjects carrying the Gly16 allele had higher plasma NE, HOMA-IR, and fat mass, and significantly greater reductions in creatinine clearance. Plasma NE at entry was a determinant variable for changes in BUN, creatinine, and creatinine clearance over the 5-year period in multiple regression analysis. In conclusion, high plasma NE at entry, associated with the Gly16 allele of the beta2-adrenoceptor polymorphisms, predict renal function deterioration (seen in elevations of BUN and creatinine and reduction of creatinine clearance) over a 5-year period accompanying further heightened sympathetic nerve activity and deterioration of insulin resistance.

β-2-Adrenergic receptor gene polymorphism confers susceptibility to Graves disease

Graves disease (GD) is an autoimmune disorder with genetic predisposition. The polymorphisms 47A-->G (Arg16Gly) and 79C-->G (Gln27Glu) of the adrenergic beta-2 receptor (ADRB2) gene in the 5q32 region affect the functional reaction to adrenergic stimulation, which contributes to the regulation of immunological response. The -367T-->C polymorphism within the 5'-leading regulatory sequence affects ADRB2 transcriptional activity. The aim of the present study was to investigate whether ADRB2 gene variants are associated with susceptibility to GD. All polymorphisms were studied in Polish GD patients (n=300) and healthy control subjects without a family history of autoimmune disorders (n=301). Genotypes were determined by the MassARRAY system (Sequenom, San Diego, CA). Gly16 and Gln27 allele frequencies were 61.4% and 55.2% among healthy controls, almost the same as previously reported in 4441 white participants of a cardiovascular health study. We found a higher risk of GD in Gln27 carriers (CC or CG genotypes) than in Glu27 homozygous (GG genotype) participants (OR=1.99, 95% CI: 1.27-3.12, p=0.003, pcorr=0.03). The frequency of the 79GG protective genotype was significantly smaller in the GD patients without symptoms of Graves ophthalmopathy compared to controls (10% vs 22%, OR=0.41, 95% CI: 0.234-0.706, p=0.0017, pcorr=0.015). We didn't find any association of -367T--> or 47A-->G genotypes/alleles with Graves disease, however, haplotype analysis has shown a significant difference in haplotype distribution between patients and controls (the global p=0.001) with increased -367T/47A/79C haplotype frequency in GD patients compared to controls (34% vs 25%, p=0.00073, pcorr=0.0044). In conclusion, Gln27 carriers (79CC or 79GC genotypes) have increased risk of Graves disease. Our results suggest that ADRB2 plays a role in susceptibility to Graves disease in humans.

β1-ADRENERGIC RECEPTOR GENE MODULATES THE EFFECT OF HEART RATE ON ARTERIAL STIFFNESS: THE BOGALUSA HEART STUDY.

Introduction Heart rate and sympathetic nervous activity are important determinants of arterial stiffness. However, whether the relationship between heart rate and arterial stiffness is modulated by β1-adrenergic receptor (β1-AR) gene variation is not known. This study examines the genetic modulation by β1-AR gene polymorphism (Arg389Gly) on the effect of heart rate on arterial stiffness in young adults. Methods The study cohort included 183 blacks and 502 whites aged 19 to 44 years enrolled in the Bogalusa Heart Study. Aortofemoral pulse wave velocity (af-PWV) was measured by echo-Doppler. Results Heart rate was significantly associated with af-PWV in blacks, whites, and the total sample. However, there was no difference in heart rate between carriers and noncarriers of Gly389 allele in both blacks and whites. Carriers versus noncarriers of the Gly389 allele showed higher values of af-PWV (5.29 m/sec vs 5.19 m/sec, p Conclusions β1-AR gene modulates arterial stiffness and its association with heart rate in young adults.

한국 여성 노인에서 α -Adducin, Angiotensinogen, ACE 유전자다형성 및 나트륨 섭취수준에 따른 혈압의 비교

Gene polymorphisms that are associated with sodium homeostasis in the body, such as α-adducin (ADD1, Gly460Trp), angiotensinogen (AGT, Met235Thr), and angiotensin converting enzyme (ACE, Ins/Del) may increase the risk for the development of hypertension. The purpose of this study was to elucidate the relationship between the singular and combined effects of ADD1, AGT, ACE genotypes, and blood pressure in elderly population. Moreover, we examined the interaction of sodium intake and polymorphisms of aforementioned genes and their effects on blood pressure. Among one hundred and nine female subjects, aged 60 and over (mean 75.9 yr), the major alleles for ADD1, AGT, and ACE polymorphisms in the studied population were Gly (66.1%), Thr (64.2%), Ins (83.5%), respectively. Analysis on the combined effects of genetic variation showed that subjects who were both ADD1 Trp/Trp and ACE Del/Del homozygotes had significantly higher systolic blood pressure (p=0.01). Similarly, ACE Del/Del homozygotes who had AGT Met allele had significantly higher diastolic blood pressure (p＜0.001). However, in single-gene analyses, no association was found between any specific genotype and blood pressure. In subjects with low sodium intake, ADD1 Trp/Trp homozygotes had significantly higher systolic blood pressure than subjects who had ADD1 Gly allele (138 mmHg vs. 127 mmHg, p=0.03). There was no difference in blood pressure between ADD1 Trp/Trp and ADD1 Gly/Gly or Gly/Trp, in subjects with high sodium intake. In summary, this study shows that interactions between the ADD1, AGT and ACE genes influence systolic and diastolic blood pressure in elderly subjects, and dietary sodium intake can modulate the effects of ADD1 Gly460Trp polymorphisms on systolic blood pressure.<BR>

β2-Adrenergic receptor polymorphisms and treatment-induced regression of left ventricular hypertrophy in hypertension

Although blood pressure is considered the major determinant of left ventricular hypertrophy in hypertension, genetic variability is increasingly being considered among the factors influencing this complication. beta(2)-Adrenergic receptors (beta(2)ARs) are up-regulated in hypertension and largely polymorphic within the human population. Recently, we have shown that the Glu27 beta(2)AR variant is strongly associated with cardiac hypertrophy in hypertension. The objective of this study is to verify whether this polymorphism also affects hypertrophy regression in response to antihypertensive therapy. In a prospective follow-up study we screened 970 hypertensive patients of Caucasian descent for the Gly16Arg, Gln27Glu, and Thr164Ile beta(2)AR polymorphisms and left ventricular echocardiographic hypertrophy and assigned selected patients to enalapril or atenolol to assess left ventricular hypertrophy regression after 2-year follow-up. Results were stratified according to treatment and the Glu27Gln polymorphism of the beta(2)AR. In cells with stable overexpression of the Glu27 or Gln27 variant of beta(2)AR, we also explored the implications of this polymorphism on hypertrophy-related intracellular signal transduction. Among hypertensive patients, the Gly16 allele was found in 63% of patients and the Glu27 allele was found in 40.6%. Both polymorphisms were in linkage disequilibrium, as expected. Four hundred forty-one hypertrophic hypertensive patients completed the 2-year follow-up. At baseline, patients carrying at least 1 allele of the Glu27 variant presented with a larger cardiac size despite similar blood pressure levels (142.9 +/- 22.5 g/m(2) in Glu27 carriers versus 138.2 +/- 18.4 g/m(2) in Gln27 carriers, P < .02). Blood pressure normalization was achieved by both drugs. At follow-up, compared with the Gln27 patients, the Glu27 patients showed a larger reduction in hypertrophy when treated with enalapril (percent change in left ventricular mass, -6.3% +/- 7.7% in Glu27 carriers versus -2.18% +/- 7.9% in Gln27 carriers; P < .05) but not with atenolol therapy (-2.8% +/- 8.9% in Glu27 carriers versus -2.4% +/- 8.8% in Gln27 carriers, P = not significant). In in vitro studies the activation of p38 and extracellular signal-regulated kinase (ERK-) 1/2 (data not shown) and the activity of the atrial natriuretic factor (ANF) promoter after isoproterenol (INN, isoprenaline) stimulation were larger in Glu27 beta(2)AR overexpressing cells than in Gln27 beta(2)AR overexpressing cells (fold difference compared with unstimulated cells, 9.7 +/- 2.9 for Glu27 beta(2)AR versus 4.2 +/- 0.3 for Gln27 beta(2)AR; P < .05). The Glu27 variant of beta(2)AR enhances hypertension-induced left ventricular hypertrophy. In these patients angiotensin-converting enzyme inhibitors are more efficient than beta-blockers in reducing cardiac size.

β 2-Adrenoceptor Polymorphisms Relate to Obesity Through Blunted Leptin-Mediated Sympathetic Activation

Obesity is a growing public health problem. It has been reported that beta2-adrenoceptor polymorphisms are associated with obesity. This study examines the associations of beta2-adrenoceptor polymorphism with relationships between plasma norepinephrine (NE) and leptin to evaluate further the mechanisms of obesity. In 329 normotensive (BP <140/90 mm Hg) men with a wide range of BMI (17.0 to 36.5 kg/m2), we measured BMI, total body fat mass, waist-to-hip ratio (W/H), BP, plasma NE, leptin, and the beta2-(Arg16Gly, Gln27Glu) adrenoceptor polymorphisms. The subjects consisted of 206 nonobese (BMI <25 kg/m2) and 123 overweight or obese (BMI >or=25 kg/m2) men. Overweight or obese subjects had a significantly higher frequency of Gly16 and Glu27 alleles compared with nonobese subjects. The subjects carrying Gly16 or Glu27 alleles regardless of BMI had greater total fat mass, W/H and plasma leptin compared with those without the Gly16 or Glu27 alleles, indicating that Gly16 and Glu27 alleles of the beta2-adrenoceptor gene are related to obesity and fat mass. Only in the nonobese subjects who carried the Gly16 and Glu27 alleles was there a high plasma NE level, but similar in overweight or obese subjects. To evaluate leptin-mediated sympathetic activation, we performed linear regression analyses between plasma leptin and NE. In groups with and without the Gly16 or Glu27 alleles, plasma leptin correlated with NE, but the slope in the group carrying the Gly16 or Glu27 allele was significantly lower than that without the Gly16 or Glu27. The findings demonstrate a strong and significant association of the Gly16 and Glu27 alleles with obesity. Lower slopes between leptin and NE in the subjects carrying these beta2-adrenoceptor polymorphisms indirectly indicate a blunted leptin-mediated sympathetic nerve activity. We propose that the beta2-adrenoceptor polymorphisms related to blunted leptin-mediated sympathetic activation offers further proof for the mechanisms of obesity.

Adrenergic Receptor Polymorphisms Associated with Resting Heart Rate: The HyperGEN Study

The association between polymorphisms in the beta1, beta2 and alpha2B adrenergic receptor (ADR) genes (ADRB1, ADRB2 and ADRA2B) and resting heart rate was examined in white and African-American participants of the HyperGEN Study. All analyses were adjusted for age, sex, body mass index, alcohol use, smoking status and daily exercise within strata of race, hypertension status and beta-blocker use. The Ser49Gly polymorphism of the beta1 ADR was associated with resting heart rate in hypertensive African-Americans and hypertensive whites taking beta-blockers, with carriers of the Gly allele having a higher mean resting heart rate by 2.7 and 4.4 beats per minute (bpm), respectively. The Arg389Gly polymorphism of the beta1 ADR was associated with lower heart rate in the normotensive African-American sample. A beta1 haplotype (Ser49Gly-Arg389Gly) was modestly associated with resting heart rate in the hypertensive African-Americans. The alpha2B C/A polymorphism was associated with heart rate in hypertensive whites, and both whites and African-Americans taking beta-blockers, with carriers of the A allele having a higher mean resting heart rate. In summary, each of the ADR gene polymorphisms was associated with heart rate in at least one stratum studied, but there was no consistent association from which one would infer a large genetic contribution to heart rate.

Association Between Nonspecific Airway Hyperresponsiveness and Arg16Gly β2-Adrenergic Receptor Gene Polymorphism in Asymptomatic Healthy Japanese Subjects

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.To determine whether polymorphism of the beta(2)-AR gene (Arg16Gly and Gln27Glu) might influence nonspecific AHR in asymptomatic healthy Japanese subjects.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.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).This study indicates that a specific beta(2)-AR polymorphism at codon 16 might be a genetic determinant of AHR, as judged by methacholine-induced bronchoconstriction in asymptomatic healthy subjects.

The β2-adrenoceptor gene and hypertension: is it the promoter or the coding region or neither?

The β2-adrenoceptor gene and hypertension: is it the promoter or the coding region or neither?

β2-Adrenergic Receptor Genetic Variants and Risk of Sudden Cardiac Death

Sympathetic activation influences the risk of ventricular arrhythmias and sudden cardiac death (SCD), mediated in part by the beta2-adrenergic receptor (B2AR). We investigated whether variation in the B2AR gene is associated with SCD risk. In this study, 4441 white and 808 black Cardiovascular Health Study (CHS) participants were followed up prospectively for SCD and genotyped for B2AR Gly16Arg and Gln27Glu polymorphisms. The study was replicated in 155 case and 144 control white subjects in a population-based case-control study of SCD, the Cardiac Arrest Blood Study (CABS). In CHS, Gly16 and Gln27 allele frequencies were 62.4% and 57.1% among white and 50.1% and 81.4% among black participants. Over a median follow-up of 11.1 years, 156 and 39 SCD events occurred in white and black participants, respectively. The Gln27Glu variant was associated with SCD risk (P=0.008 for general model). SCD risk was higher in Gln27 homozygous participants than in Glu27 carriers (ethnicity-adjusted hazard ratio [HR], 1.56; 95% confidence interval [CI], 1.17 to 2.09; P=0.003). The increased risk did not differ significantly between white (HR, 1.62; 95% CI, 1.18 to 2.23) and black (HR, 1.23; 95% CI, 0.61 to 2.48) participants, although the confidence interval was wide in blacks. In the CABS replication study, Gln27 homozygous participants similarly had higher SCD risk than Glu27 carriers (odds ratio, 1.64; 95% CI, 1.02 to 2.63; P=0.040). Gly16Arg was not associated with SCD risk in either study. Gln27 homozygous individuals have an increased risk of SCD in 2 study populations. Our findings suggest that B2AR plays a role in SCD in humans. Study of genetic variation within the B2AR gene may help identify those at increased SCD risk.