Beta3-adrenergic Receptor Gene Research Articles

Beta-1 and beta-2 adrenergic receptor polymorphism and association with cardiovascular response to orthostatic screening

Variation in the beta-1 and beta-2 adrenergic receptor genes (ADRB1 and ADRB2, respectively) may influence cardiovascular reactivity including orthostatic stress. We tested this hypothesis in a head-up tilt (HUT) screening protocol in healthy young adults without history of syncope. Following brachial arterial catheter insertion, 120 subjects (age 18–40, 72 females, Caucasian) underwent 5min 60° HUT. Polymorphisms tested were: Ser49/Gly and Arg389/Gly in ADRB1; and Arg16/Gly, Gln27/Glu, and Thr164/Ile in ADRB2. Three statistical models (recessive, dominant, additive) were evaluated using general linear models with analysis for each physiologic variable. A recessive model demonstrated a significant association between Arg16/Gly and: absolute supine and upright HR; HUT-induced change in cardiac index (CI), stroke index (SI) and systemic vascular resistance (SVR); and supine and upright norepinephrine values. Blood pressure was not influenced by genotype. Fewer associations were present for other polymorphisms: Ser49/Gly and the change in SI (dominant model), and Arg389/Gly and supine and HUT norepinephrine (additive model). We conclude that in this population, there is a robust association between Arg16/Gly and HUT responses, such that 2 copies of Arg16 increase supine and upright HR, and greater HUT-induced decreases in CI and SI, with greater increases in SVR and norepinephrine. ADRB1 gene variation appears to impact SI and plasma NE levels but not HR. Whether ADRB2 gene variation is ultimately disease-causing or disease-modifying, this study suggests an association between Arg16/Gly and postural hemodynamics, with sympathetic noradrenergic activity affected in a similar direction. This may have implications in the development of orthostatic disorders.

Identification of beta-1 adrenergic receptor polymorphisms in cats

In human beings, genetic polymorphisms within the beta-1 adrenergic receptor (ADRB1) gene have been associated with variable pharmacologic responses to beta blocker therapy. Beta-blockers are commonly given to cats with heart disease, particularly hypertrophic cardiomyopathy, a common cause of feline heart disease. We hypothesized that polymorphisms are present in the feline ADRB1 gene, which could result in an altered pharmacologic response to beta-blocker therapy. We sequenced the feline ADRB1 gene in 42 cats of five breeds. We identified three polymorphisms within the ADRB1 gene. Two polymorphisms did not change the amino acid produced and are unlikely to be clinically significant. A third polymorphism identified was an AA/CC substitution at the 830–831 base pair sites. This alteration changed the amino acid produced from proline to glutamine at position 277 and computer modeling predicts an altered protein structure. Further study is warranted to determine if this polymorphism alters response to beta blocker therapy.

Association of beta 2 -adrenergic receptor gene polymorphisms and nocturnal asthma in Saudi patients

BACKGROUND AND OBJECTIVES:Two polymorphisms of beta2-adrenergic receptor (β2-AR) gene, namely the substitution from arginine (Arg) to glycine (Gly) at codon 16 and from glutamine (Gln) to glutamic (Glu) at codon 27, are linked with functional changes in the β2-AR in the respiratory system even though they are not deemed to be susceptibility genes for asthma per se. The objective of this study was to investigate this association in a subset of asthmatic patients, namely those with nocturnal asthma.METHODS:The β2-AR gene polymorphisms at codon 16 and 27 were assessed in 40 patients clinically diagnosed with nocturnal asthma and 96 normal controls. Genomic DNA was obtained from whole blood and genotyping was carried out by a PCR based restriction fragment length polymorphism technique.RESULTS:There was a statistically significant difference in genotype frequencies at codon 16 (Arg/Gly) between nocturnal asthmatic patients and normal control subjects (P < 0.05). However, there was no statistically significant difference in allele frequencies between the two groups. In addition, there was a significant association between Arg16-Gly genotype with nocturnal asthma compared to homozygous Gly16 (codominant model P = 0.0033, OR = 3.69: 95% CI: 1.49-9.12). However, there were no statistically significant differences in genotype and allele frequencies at codon 27 (Gln/Glu) between the normal control and nocturnal asthmatic groups (χ2 = 1.81, P = 0.41). The results also indicate that linkage disequilibrium existed between the β2-AR codon 16 and β2-AR codon 27 polymorphism (|D´| = 0.577). The data for all haplotypes did not show a statistically significant association.CONCLUSION:We present the genotype and allele frequencies of β2-AR gene polymorphisms in normal Saudi subjects and nocturnal asthmatic patients. There was a significant difference in genotype frequencies at codon 16 (Arg/Gly). However, our study indicates a poor association of individual single nuceotide polymorphisms with nocturnal asthma.

Association of BMI with the Beta3 Adrenergic Receptor Gene Mutation: A Meta-Analysis

The beta3 adrenergic receptor (ADRB3) is a part of the adrenergic system, which is known to play a key role in energy metabolism. The relationship between the Trp64Arg variant of ADRB3 and body mass index (BMI) has been widely examined; however, the results of these studies have been inconsistent. Therefore, we performed a meta-analysis of the relationship between an ADRB3 variant and BMI in 2008. Our results suggested that the Trp64Arg variant of ADRB3 was associated with BMI in East Asians, but not Europeans. Additionally, our report showed the importance of meta-analyses in the field of genetic association studies for common traits. In 1995, Yoshida et al. reported that the Trp64Arg variant of ADRB3 was related to difficulty in weight loss. The decrease in body weight in obese subjects with the mutation was lower than that in obese subjects without the mutation following a 3 month combined low-calorie diet and exercise regimen. However, subsequent studies have yielded inconsistent results. Accordingly, further studies are needed to reliably assess and interpret gene-phenotype associations with this ADRB3 variant.

The effect of beta1-adrenergic receptor gene polymorphism on prolongation of corrected QT interval during endotracheal intubation under sevoflurane anesthesia

BackgroundThe hemodynamic responses to endotracheal intubation are associated with sympathoadrenal activity. Polymorphisms in the beta1-adrenergic receptor (β1AR) gene can alter the pathophysiology of specific diseases. The aim of this study is to investigate whether the Ser49Gly and Arg389Gly polymorphism of the β1AR gene have different cardiovascular responses during endotracheal intubation under sevoflurane anesthesia.MethodsNinety-one healthy patients undergoing general anesthesia were enrolled. Patients underwent slow inhalation induction of anesthesia using sevoflurane in 100% oxygen. Vecuronium 0.15 mg/kg was given for muscle relaxation. Endotracheal intubation was performed by an anesthesiologist. The mean arterial pressure (MAP), heart rate (HR), and the corrected QT (QTc) interval were measured before induction, before laryngoscopy, and immediately after tracheal intubation. Genomic DNA was isolated from the patients' peripheral blood and then evaluated for the β1AR-49 and β1AR-389 genes using an allele-specific polymerase chain reaction method.ResultsNo differences were found in the baseline values of MAP, HR, and the QTc interval among β1AR-49 and β1AR-389, respectively. In the case of β1AR-49, the QTc interval change immediately after tracheal intubation was significantly greater in Ser/Ser genotypes than in Ser/Gly genotypes. No differences were observed immediately after tracheal intubation in MAP and HR for β1AR-49 and β1AR-389.ConclusionsWe found an association between the Ser49 homozygote gene of β1AR-49 polymorphism and increased QTc prolongation during endotracheal intubation with sevoflurane anesthesia. Thus, β1AR-49 polymorphism may be useful in predicting the risk of arrhythmia during endotracheal intubation in patients with long QT syndrome.

ASSOCIATION OF ARG16GLY POLYMORPHISM OF THE BETA-2 ADRENERGIC RECEPTOR (B2AR) GENE WITH SYSTOLIC HYPERTENSION IN A LATIN-AMERICAN POPULATION FROM COLOMBIA: PP.21.319

Objective: Beta-2 adrenergic receptor (B2AR) gene is among the candidate genes most widely studied in hypertension. In particular, Arg16Gly (46 A–>G rs1042713) a non-synonymous coding polymorphism of the B2AR, has been reported to be associated with hypertension with inconclusive results. The aim of the present study was to test the association between this polymorphism and essential hypertension in a Latin American population. Methods: A total of 800 individuals aged 30–65 years were recruited for the study. They constituted a random and representative sample of the general population of the city of Medellin (Colombia). Arg16Gly polymorphism was repeatedly genotyped (forward and backward, genotype accuracy >99%), using automated DNA sequencer 3730XL (ABI Prism). Blood pressure (BP) levels were defined by the average of four conventional sitting BP measurements (2007 ESH-ESC Guidelines) made at five min intervals by two trained physicians. All measurements were performed in the left arm at the heart level after 5 min rest using a standard mercury sphygmomanometer. Systolic hypertension was defined as a systolic (S)BP at or above 140 mmHg. Results: Allelic distribution of the Arg16Gly polymorphism was in Hardy-Weinberg equilibrium. In the logistic regression analysis, systolic hypertension was considered as the dependent variable and only individuals not under antihypertensive treatment were included (n = 599). After adjustment for age, sex, diabetes, BMI and smoking (independent variables), individuals homozygous for Gly16 (Gly/Gly genotype) had a higher significant risk of systolic hypertension (89% increase in odds of having systolic hypertension) when compared to the individuals with other genotypes (Arg/Arg or Arg/Gly) [odds ratio (OR) = 1.89; 95% confidence interval (CI) = 1.18–3.03; p = 0.008]. See table Conclusions: These results support the hypothesis that polymorphisms in the ADRB2 gene are involved in the modulation of blood pressure levels in humans. In particular, the presence of a Glycine homozygous genotype of the Arg16Gly polymorphism is associated with an increased risk of systolic hypertension in subjects of Latin-American origin.

Evaluation of the Influence of the Codon 16 Polymorphism of the Beta-2 Adrenergic Receptor Gene on the Incidence of Arterial Hypotension and Ephedrine Use in Pregnant Patients Submitted to Subarachnoid Anesthesia

The beta-2 adrenergic receptor gene has several polymorphisms. Recent studies have demonstrated the clinical importance of the latter. The objective of the present study was to evaluate the influence of the Arg16Gli polymorphism on the incidence of arterial hypotension and ephedrine use in pregnant patients submitted to subarachnoid block for Cesarean section. Healthy parturients (ASA I and II) were submitted to subarachnoid anesthesia for elective Cesarean section (n = 50). Ephedrine was administered in cases of arterial hypotension. The incidence of arterial hypotension and the required dose of ephedrine to correct the arterial pressure were compared between the different genotypes identified. The most prevalent genotype was Arg16Gli (60%, n = 30) followed by Gli16Gli (26%, n = 13) and Arg16Arg (14%, n = 7). No differences were observed regarding the basic characteristics of the genotypes. In comparison to the Arg16Arg genotype, the Gli16Gli presented a 3.95-fold increase in the hazard ratio of arterial hypotension (95%CI 0.86-18.11; p = 0.076), whereas the Arg16Gli presented a 4.83-fold increase (95%CI 1.13-20.50; p = 0.033). The parturients with the Arg16Arg needed, on average, 6.4 +/- 8.5 mg of ephedrine to correct the arterial hypotension, whereas those with the Arg16Gli needed 19.5 +/- 15.9 mg (p = 0.0445; 95%CI 0.3325-25.78) and the ones with the Gli16Gli genotype, 19.2 +/- 14.3 (p = 0.0445, 95%CI 0.3476-25.26). The results show that the genetic variant Arg16Arg presents a lower incidence of arterial hypertension and that lower doses of ephedrine were necessary to reestablish normal arterial pressure in the patients with this genetic profile. We conclude that the Arg16Arg genotype confers better pressure stability to the parturients submitted to subarachnoid anesthesia for Cesarean section.

Beta2-adrenergic receptor gene polymorphisms as systemic determinants of healthy aging in an evolutionary context

The Gln 27Glu polymorphism but not the Arg 16Gly polymorphism of the beta2-adrenergic receptor (ADRB2) gene appears to be associated with a broad range of aging-associated phenotypes, including cancers at different sites, myocardial infarction (MI), intermittent claudication (IC), and overall/healthy longevity in the Framingham Heart Study Offspring cohort. The Gln 27Gln genotype increases risks of cancer, MI and IC, whereas the Glu 27 allele or, equivalently, the Gly 16Glu 27 haplotype tends to be protective against these diseases. Genetic associations with longevity are of opposite nature at young-old and oldest-old ages highlighting the phenomenon of antagonistic pleiotropy. The mechanism of antagonistic pleiotropy is associated with an evolutionary-driven advantage of carriers of a derived Gln 27 allele at younger ages and their survival disadvantage at older ages as a result of increased risks of cancer, MI and IC. The ADRB2 gene can play an important systemic role in healthy aging in evolutionary context that warrants exploration in other populations.

Beta-adrenergic receptor gene polymorphisms and cardiovascular reactivity to stress in Black adolescents and young adults.

Cardiovascular reactivity to stress and beta-adrenergic receptor (beta-AR) function may contribute to the development of hypertension. As Black Americans have an increased risk of hypertension, we evaluated associations between beta(1)-AR (Arg389Gly) and beta(2)-AR (Arg16Gly, Gln27Glu) gene variants and cardiovascular reactivity in 500 Black youth. Heart rate, preejection period, total peripheral resistance, and blood pressure reactivity were measured during cold and psychological stress. The Arg389Gly polymorphism in the beta(1)-AR was associated with preejection period reactivity in males but not in females. The Arg16Gly polymorphism in the beta(2)-AR was associated with diastolic blood pressure reactivity only during video game stress. An association between the Gln27Glu polymorphism in the beta(2)-AR and vascular reactivity depended on sex. Thus, specific patterns of associations emerged between genetic variations in beta-ARs and cardiovascular reactivity in young Blacks.

Polymorphisms in theACEandADRB2Genes and Risks of Aging-Associated Phenotypes: The Case of Myocardial Infarction

Multiple functions of the beta2-adrenergic receptor (ADRB2) and angiotensin-converting enzyme (ACE) genes warrant studies of their associations with aging-related phenotypes. We focus on multimarker analyses and analyses of the effects of compound genotypes of two polymorphisms in the ADRB2 gene, rs1042713 and rs1042714, and 11 polymorphisms of the ACE gene, on the risk of such an aging-associated phenotype as myocardial infarction (MI). We used the data from a genotyped sample of the Framingham Heart Study Offspring (FHSO) cohort (n = 1500) followed for about 36 years with six examinations. The ADRB2 rs1042714 (C-->G) polymorphism and two moderately correlated (r(2) = 0.77) ACE polymorphisms, rs4363 (A-->G) and rs12449782 (A-->G), were significantly associated with risks of MI in this aging cohort in multimarker models. Predominantly linked ACE genotypes exhibited opposite effects on MI risks, e.g., the AA (rs12449782) genotype had a detrimental effect, whereas the predominantly linked AA (rs4363) genotype exhibited a protective effect. This trade-off occurs as a result of the opposite effects of rare compound genotypes of the ACE polymorphisms with a single dose of the AG heterozygote. This genetic trade-off is further augmented by the selective modulating effect of the rs1042714 ADRB2 polymorphism. The associations were not altered by adjustment for common MI risk factors. The results suggest that effects of single specific genetic variants of the ADRB2 and ACE genes on MI can be readily altered by gene-gene or/and gene-environmental interactions, especially in large heterogeneous samples. Multimarker genetic analyses should benefit studies of complex aging-associated phenotypes.

Role of Beta-Adrenergic Receptor Gene Polymorphisms in the Long-Term Effects of Beta-Blockade with Carvedilol in Patients with Chronic Heart Failure

Beta-blockers are mainstay of current treatment of heart failure (HF). Beta-adrenergic receptors (AR) single nucleotide gene polymorphisms (SNPs) may influence the sensitivity and density of beta-AR. We assessed the relation between three common beta-AR SNPs and the response to carvedilol administration. We studied 183 consecutive patients with chronic HF due to ischemic or nonischemic cardiomyopathy, a LV ejection fraction (LVEF) < or = 0.35, not previously treated with beta-blockers. Each patient underwent gated-SPECT radionuclide ventriculography, cardiopulmonary exercise testing and invasive hemodynamic monitoring at baseline and after 12 months of carvedilol administration at maintenance dosages. The beta1-AR gene Arg389Gly and the beta2-AR gene Arg16Gly SNPs were not related to the response to carvedilol administration. Homozygotes for the Glu27Glu allele showed a greater increase in the LVEF, compared to the other patients (+13.0 +/- 12.2% versus +7.1 +/- 8.1% in the Gln27Gln homozygotes, and 8.3 +/- 11.4% units in the Gln27Glu heterozygotes; p = 0.022 by ANOVA). Glu27Glu homozygotes also showed a greater decline in the pulmonary wedge pressure both at rest and at peak exercise. Gln27Glu SNP was selected amongst the determinants of the LVEF response to carvedilol at multivariable analysis, in addition to the cause of cardiomyopathy, baseline systolic blood pressure and the dose of carvedilol administered. Beta1-AR Arg389Gly and beta2-AR Arg16Gly SNPs are not related to the response to carvedilol therapy. In contrast, the Gln27Glu SNP is a determinant of the LVEF response to this agent in patients with chronic HF.

The relationship between birthweight and longitudinal changes of blood pressure is modulated by beta-adrenergic receptor genes: the Bogalusa Heart Study.

This study examines the genetic influence of β-adrenergic receptor gene polymorphisms (β2-AR Arg16Gly and β3-AR Trp64Arg) on the relationship of birthweight to longitudinal changes of blood pressure (BP) from childhood to adulthood in 224 black and 515 white adults, aged 21–47 years, enrolled in the Bogalusa Heart Study. Blacks showed significantly lower birthweight and frequencies of β2-AR Gly16 and β3-AR Trp64 alleles and higher BP levels and age-related trends than whites. In multivariable regression analyses using race-adjusted BP and birthweight, low birthweight was associated with greater increase in age-related trend of systolic BP (standardized regression coefficient β = −0.09, P = .002) and diastolic BP (β = −0.07, P = .037) in the combined sample of blacks and whites, adjusting for the first BP measurement in childhood, sex, age, and gestational age. Adjustment for the current body mass index strengthened the birthweight-BP association. Importantly, the strength of the association, measured as regression coefficients, was modulated by the combination of β2-AR and β3-AR genotypes for systolic (P = .042 for interaction) and diastolic BP age-related trend (P = .039 for interaction), with blacks and whites showing a similar trend in the interaction. These findings indicate that the intrauterine programming of BP regulation later in life depends on β-AR genotypes.

Probable Role of Beta 2-Adrenergic Receptor Gene Haplotype in Toluene Diisocyanate-Induced Asthma

PurposeA genetic polymorphism of the beta 2-adrenergic receptor is a major factor associated with the asthmatic phenotype. The association of this polymorphism with toluene diisocyanate (TDI)-induced asthma has not been investigated. We examined 103 TDI-induced asthma patients (TDI-OA), 60 asymptomatic exposed controls (AEC), and 263 unexposed healthy controls (NC) in order to identify beta 2-adrenergic receptor gene (ADRB2) polymorphisms and the possible association with TDI-induced asthma.MethodsSingle nucleotide polymorphisms (SNPs) of ADRB2 were genotyped by direct sequencing. Serum-specific IgE and IgG levels were measured using an enzyme-linked immunosorbent assay. Phenotypes and clinical patient parameters were compared.ResultsSNPs were identified (-47 T>C, -20 T>C, Arg16Gly A>G, Gln27Glu C>G, Leu134Leu G>A, Arg175Arg C>A) during ADRB2 screening (from -231 to 793 bp). No significant differences in allelic and genotypic frequencies were noted for any of the six ADRB2 SNPs. The Arg16Gly A>G, Leu134Leu G>A, and Arg175Arg C>A SNPs and haplotype 1 [TTACGC] were significantly associated with specific IgE antibodies to the TDI-human serum albumin (HSA) conjugate in TDI-exposed subjects (P<0.05). Exposed workers with the ADRB2 ht1/ht1 homozygote had a significantly higher TDI-HSA conjugate-specific IgE sensitization rate than did those with the null ht1 haplotype (odds ratio, 15.40; 95% confidence interval, 1.81-131.06).ConclusionsADRB2 polymorphisms may affect IgE-specific sensitization to TDI-HSA conjugate in TDI-exposed workers.

An insertion/deletion variant of a thymine base in exon 2 of the porcine beta 3‐adrenergic receptor gene associated with loin eye muscle area

An insertion/deletion variant of a thymine base (T5 and T6) in exon 2 of porcine beta 3-adrenergic receptor (ADRB3) gene has been described. In the current study, we made an association study between the ADRB3 polymorphisms and production traits in 735 Duroc pigs. The allele frequencies for the T5 and T6 alleles in our study population were 0.433 and 0.567, respectively. Any associations between ADRB3 genotype and average daily weight gain during test period, or backfat thickness and intramuscular fat content were not detected in either sex. However the size of the loin eye muscle area (EMA) was significantly associated with ADRB3 genotypes in gilts. T6-homozygous gilts had a higher mean of EMA (40.6 +/- 0.6 cm(2)) than T5-homozygous (38.1 +/- 0.4 cm(2), P = 0.002) and heterozygous (38.8 +/- 0.3 cm(2), P = 0.034) gilts. This association was not detected in males. In addition, a multiple traits animal model best linear unbiased predictor (BLUP) analysis revealed that the T6-homozygous genotype had positive effects on breeding value of EMA. Accordingly, we suggest that ADRB3 polymorphism has the potential to be an important genetic marker for prediction of EMA in Duroc pigs.

Beta-2 adrenergic receptor gene polymorphisms Gln27Glu, Arg16Gly in patients with heart failure

Background -Beta-2 adrenergic receptor gene polymorphisms Gln27Glu, Arg16Gly and Thr164Ile were suggested to have an effect in heart failure. We evaluated these polymorphisms relative to clinical characteristics and prognosis of alarge cohort of patients with heart failure of different etiologies.Methods -We studied 501 patients with heart failure of different etiologies. Mean age was 58 years (standard deviation 14.4 years), 298 (60%) were men. Polymorphisms were identified by polymerase chain reaction-restriction fragment length polymorphism.Results -During the mean follow-up of 12.6 months (standard deviation 10.3 months), 188 (38%) patients died. Distribution of genotypes of polymorphism Arg16Gly was different relative to body mass index (χ2 = 9.797;p = 0.04). Overall the probability of survival was not significantly predicted by genotypes of Gln27Glu, Arg16Gly, or Thr164Ile. Allele and haplotype analysis also did not disclose any significant difference regarding mortality. Exploratory analysis through classification trees pointed towards a potential association between the Gln27Glu polymorphism and mortality in older individuals.Conclusion -In this study sample, we were not able to demonstrate an overall influence of polymorphisms Gln27Glu and Arg16Gly of beta-2 receptor gene on prognosis. Nevertheless, Gln27Glu polymorphism may have a potential predictive value in older individuals.

Genetic variations of the beta2-adrenergic receptor gene are associated with essential hypertension in Xinjiang Kazakans

Objective The aims of the present study were to investigate the associations of 46 A>G, 79 C>G, 491 C>T and 659 C>G genetic variants of the human beta 2-adrenergic receptor (β2-AR), ADRB2, gene with essential hypertension (EH) in Xinjiang Kazakans population.Methods A gender-matched case-control (271 hypertensive cases and 267 normotensive controls) study was used to investigate the associations of the four variations in the coding region of ADRB2 with EH. The genotypes of the variants were identified by the polymerase chain reaction and restriction fragment length polymorphism (PCR-RFLP) methods. Results 46 A>G, 79 C>G and 659 C>G polymorphisms were common in the Kazakan population, but 491 C>T was a mutation (frequency of T allele was only 0.003) and only found in EH group. The frequency distributions of genotypes and alleles for 659 C>G between the EH and control groups was significantly different (P G and 79 C>G polymorphisms were not statistically different. Logistic regression analysis suggested that the G allele of 659 C>G polymorphism was a risk factor for hypertension (minor allele vs common homo; odds ratio, 13.240, 95% CI, 4.052-43.274; P G were significantly higher than those in the CC group, but no significant difference of blood pressure were found between common homo and minor allele for 46 A>G and 79C>G polymorphisms. Haplotype analysis showed that two hyplotypes, H1: 46A­79C­491C­523C(48%)and H5:46A­79C­491C­659G, were associated with EH.Conclusion ADRB2 genetic variants may play independent roles in the molecular genetic mechanism of EH in Xinjiang Kazakans population (J Geriatr Cardiol 2010; 7:52-57).

Associations of β2‐adrenergic receptor genotypes and haplotypes with wheezing illness in Taiwanese schoolchildren

Increasing attention was focused on the beta2-adrenergic receptor gene (ADRB2), whose genetic variability has been implicated as a risk factor for asthma-related phenotypes. However, only a few studies reported the associations by utilizing haplotypic approaches. We therefore examined the relationship of childhood wheezing illness with polymorphisms at codons 16 and 27, and evaluated the influence of polymorphisms individually and in combination as haplotypes. We conducted a genetic case-control study comprising 215 wheezing children and 183 nonwheezing controls, all of whom were selected from 2524 fourth- to ninth-grade schoolchildren in southern Taiwan. All participants were homozygous at the ADRB2 Thr164 locus. After controlling for possible confounders, ADRB2 Glu27 allele was significantly associated with wheezing illness in all genetic models, but the risks on Arg16Gly genotypes were inconclusive. Estimated frequencies for the three main hyplotypes were Arg16/Gln27 57.2%, Gly16/Gln27 35.3%, Gly16/Glu27 7.4% in wheezing children, and Arg16/Gln27 56.3%, Gly16/Gln27 32.2%, Gly16/Glu27 10.4% in controls. The protective effect of Gly16/Glu27 haplotype remained relative to all other ADRB2 haplotypes [adjusted relative risk (aRR) = 0.58; 95% confidence interval (CI) 0.35-0.97]. As compared with children without Gly16/Glu27 haplotype, those with Gly16/Glu27 haplotype had a significantly lower risk for wheezing illness (aRR = 0.56; 95% CI 0.33-0.99). The copy numbers of Gly16/Glu27 haplotype also showed a clear dose-response relationship on the decreased risks. No significant association was found with the prevalence of wheezing illness for other haplotypes. We concluded that ADRB2 Glu27 allele and Gly16/Glu27 haplotype were significantly protective factors for wheezing illness in Taiwanese schoolchildren.

Characterization of a de novo translocation t(5;18)(q33.1;q12.1) in an autistic boy identifies a breakpoint close to SH3TC2, ADRB2, and HTR4 on 5q, and within the desmocollin gene cluster on 18q

We have recently reported the identification of a de novo balanced translocation t(5;18)(q33.1;q12.1) in a boy with autism. Here we discuss the identification of the breakpoints on chromosomes 5 and 18, and subsequent genomic and candidate gene analyses. The 18q breakpoint lies between desmocollin genes DSC1 and DSC2. The chromosome 5 breakpoint lies at the 3' end of the SH3TC2 gene and distal to beta-adrenergic receptor gene ADRB2 and serotonin receptor gene HTR4. We hypothesized that the transcription of one (or more) of these genes is affected by the translocation by position effect. Looking at allele-specific gene expression for the genes at the 5q locus, we were able to determine that ADRB2 is expressed from both the normal and derivative alleles. Due to the lack of expression in available tissues or lack of available informative transcribed SNPs, we were unable to exclude the involvement of SH3TC2 and HTR4 due to position effect. However, we determined that both DSC1 and DSC2 are only transcribed from the normal chromosome 18 in lymphocytes from the proband. This monoallelic expression of DSC2 may put the patient at risk for arrythmogenic right ventricular cardiomyopathy. Desmocollin genes encode cell-adhesion molecules, and are also highly expressed in brain regions, and thus may also be important for normal neuronal functioning. While a role for SH3TC2, ADRB2, and HTR4 as putative candidate genes for autism cannot be discounted, a role for the desmocollin genes at the 18q breakpoint should also be considered.

Altered Beta-2 Adrenergic Receptor Gene Expression in Human Clinical Hypertension

The beta-2 adrenergic receptor is involved in mediating vasodilatation via neurohumoral and sympathetic nervous system pathways. Alterations in beta-2 adrenergic receptor gene expression (mRNA transcription) may contribute to the hypertensive phenotype. Human gene expression in clinical phenotypes remains largely unexplored due to ethical constraints involved in obtaining human tissue. We devised a method to obtain normally discarded internal mammary artery tissue from coronary artery bypass graft patients. We then investigated differences in hypertensive and normotensive participants' beta-2 adrenergic receptor gene expression in this tissue. We collected arterial tissue samples from 46 coronary artery bypass patients in a surgical setting. Using 41 of the samples, we performed TaqMan real-time polymerase chain reaction (RT-PCR) and used the delta delta cycle threshold (DeltaDeltaCt) relative quantitation method for determination of fold-differences in gene expression between normotensive and hypertensive participants. The beta-2 adrenergic receptor target was normalized to glyceraldehyde-phosphate dehydrogenase. Participants with hypertension had significantly less-expressed beta-2 adrenoceptor gene (2.76-fold, p<.05) compared to normotensive participants. After Bonferroni correction, gene expression did not differ by race, gender, type/dose of beta-blocker prescribed, positive family history of hypertension, or diagnosis of diabetes mellitus type 2. These data support the possibility of a molecular basis for impaired adrenoceptor-mediated vascular tone in hypertension. Modification and extension of this research is required.

Trp64Arg Polymorphism in Beta3-Adrenergic Receptor Gene Is Associated with Decreased Fat Oxidation Both in Resting and Aerobic Exercise in the Japanese Male

The purpose of our study was to investigate whether the Trp64Arg polymorphism in β3-AR gene and the −3826A/G polymorphism in the UCP1 gene were associated with the reduction in energy expenditure and fat oxidation both in resting and aerobic exercise in Japanese. Eighty-six nonobese young healthy Japanese were recruited. Energy expenditure was measured using indirect calorimetry. The subjects performed an aerobic exercise program at 60% of their maximal heart rate for 30 minutes. The level of fat oxidation at rest and aerobic exercise of the male subjects with Trp/Arg of the β3-AR gene was significantly lower than that of the Trp/Trp genotype. No difference in FO0−30 was observed in the female subjects. There was no association between UCP-1 polymorphism and energy expenditure during aerobic exercise. It was revealed that the Trp64Arg polymorphism in β3-AR gene is associated with reduction of fat oxidation both in resting and aerobic exercise in healthy, young Japanese males.