ADRB2 Polymorphisms Research Articles

ADRB2 and LEPR Gene Polymorphisms: Synergistic Effects on the Risk of Obesity in Japanese

The objective of the present study was to validate a recently reported synergistic effect between variants located in the leptin receptor (LEPR) gene and in the β-2 adrenergic receptor (ADRB2) gene on the risk of overweight/obesity. We studied a middle-aged/elderly sample of 4,193 nondiabetic Japanese subjects stratified according gender (1,911 women and 2,282 men). The LEPR Gln223Arg (rs1137101) variant as well as both ADRB2 Arg16Gly (rs1042713) and Gln27Glu (rs1042714) polymorphisms were analyzed. The primary outcome was the risk of overweight/obesity defined as BMI ≥25 kg/m(2), whereas secondary outcomes included the risk of a BMI ≥27 kg/m(2) and BMI as a continuous variable. None of the studied polymorphisms showed statistically significant individual effects, regardless of the group or phenotype studied. Haplotype analysis also did not disclose any associations of ADRB2 polymorphisms with BMI. However, dimensionality reduction-based models confirmed significant interactions among the investigated variants for BMI as a continuous variable as well as for the risk of obesity defined as BMI ≥27 kg/m(2). All disclosed interactions were found in men only. Our results provide external validation for a male specific ADRB2-LEPR interaction effect on the risk of overweight/obesity, but indicate that effect sizes associated with these interactions may be smaller in the population studied.

Multilocus Analyses of Seven Candidate Genes Suggest Interacting Pathways for Obesity‐Related Traits in Brazilian Populations

We investigated whether variants in major candidate genes for food intake and body weight regulation contribute to obesity-related traits under a multilocus perspective. We studied 375 Brazilian subjects from partially isolated African-derived populations (quilombos). Seven variants displaying conflicting results in previous reports and supposedly implicated in the susceptibility of obesity-related phenotypes were investigated: β2-adrenergic receptor (ADRB2) (Arg16Gly), insulin induced gene 2 (INSIG2) (rs7566605), leptin (LEP) (A19G), LEP receptor (LEPR) (Gln223Arg), perilipin (PLIN) (6209T > C), peroxisome proliferator-activated receptor-γ (PPARG) (Pro12Ala), and resistin (RETN) (-420 C > G). Regression models as well as generalized multifactor dimensionality reduction (GMDR) were employed to test the contribution of individual effects and higher-order interactions to BMI and waist-hip ratio (WHR) variation and risk of overweight/obesity. The best multilocus association signal identified in the quilombos was further examined in an independent sample of 334 Brazilian subjects of European ancestry. In quilombos, only the PPARG polymorphism displayed significant individual effects (WHR variation, P = 0.028). No association was observed either with the risk of overweight/obesity (BMI ≥ 25 kg/m2), risk of obesity alone (BMI ≥ 30 kg/m2) or BMI variation. However, GMDR analyses revealed an interaction between the LEPR and ADRB2 polymorphisms (P = 0.009) as well as a third-order effect involving the latter two variants plus INSIG2 (P = 0.034) with overweight/obesity. Assessment of the LEPR-ADRB2 interaction in the second sample indicated a marginally significant association (P = 0.0724), which was further verified to be limited to men (P = 0.0118). Together, our findings suggest evidence for a two-locus interaction between the LEPR Gln223Arg and ADRB2 Arg16Gly variants in the risk of overweight/obesity, and highlight further the importance of multilocus effects in the genetic component of obesity.

1-Adrenergic Receptor Polymorphisms and Response to -Blockade in the African-American Study of Kidney Disease and Hypertension (AASK)

This study focuses on the relationship between β(1)-adrenergic receptor (ADRB1) polymorphisms and blood pressure response to the β-blocker metoprolol among African Americans with early hypertensive nephrosclerosis. Participants from the African-American Study of Kidney Disease and Hypertension (AASK) trial were genotyped for ADRB1 polymorphisms: Ser49Gly and Arg389Gly. Cox proportional hazards models were used to determine the relationship between ADRB1 polymorphisms and time to reach a mean arterial pressure (MAP) of ≤107 mm Hg in the first year after randomization, adjusted for other predictors of blood pressure response. In the Ser49Gly model, Ser49/Gly49 individuals were less responsive compared to Ser49/Ser49 only among the more obese (body mass index (BMI) ≥39 kg/m(2)) participants (P < 0.05 for genotype × BMI interaction). The hazard ratio (HR) with a BMI of 39 kg/m(2) was 0.68 (95% confidence interval (CI) 0.46-0.99). In the Arg389Gly model, participants with Arg389 were less likely to respond to metoprolol: HR: 0.68 (95% CI 0.50-0.93). In addition, women were less responsive to metoprolol compared to men: HR: 0.78 (95% CI 0.60-0.995). Ser49/Gly49 was predictive of blood pressure response to metoprolol only among more obese African Americans with early hypertensive nephrosclerosis. In contrast to other studies suggesting increased short-term responsiveness to β-blockers with Arg389, Arg389 individuals were less responsive in this study analyzing blood pressure over a 1-year period. This may be partly explained by decreased agonist-promoted desensitization with Arg389. However, gender, physiological adaption to stress, interactions between genes and between genes and the environment, as well as study in other patient populations need to be considered.

Pharmacogenetics of β2-Agonists

Short-acting β2-agonists (SABAs) and long-acting β2-agonists (LABAs) are both important for treatment of asthma and chronic obstructive pulmonary disease (COPD) because of their bronchodilator and bronchoprotective effects. However, the use of these agonists, at least for asthma, has generated some controversy because of their association with increased mortality. Pharmacogenetics is the study of genetically determined variation in response to medications, which might prove useful for target therapies in highly responsive patients, especially for more expensive therapies or those with increased risk of side effects. Variation in response to both SABAs and LABAs has been observed in patients with polymorphisms in the β2 adrenoceptor gene (ADRB2). This review summarizes results from various studies on the possible relationship between ADRB2 polymorphisms and the bronchodilator or bronchoprotective effects of inhaled β2-agonists. By assessing the ADRB2 genotype, the hope is that it will be possible to predict the responsiveness to chronic administration of β2-agonists. Genetic testing, however, is of limited usefulness at this stage for ADRB2 because the common variants identified thus far account for only a small proportion of the variation observed for given responses. Carefully performed and adequately powered clinical trials continue to be important for achieving the goal of pharmacogenetic approaches to therapy.

Promoter Polymorphisms in the β-2 Adrenergic Receptor Are Associated With Drug-Induced Gene Expression Changes and Response in Acute Lymphoblastic Leukemia

We investigated whether genetic polymorphisms in the promoter region of the proapoptotic β-2 adrenergic receptor gene (ADRB2) influence treatment-induced changes in ADRB2 expression in leukemia cells and response to chemotherapy. The ADRB2 promoter region was genotyped in germline DNA from 369 children with acute lymphoblastic leukemia (ALL). For 95 of the patients, sufficient RNA was available before and after in vivo treatment to assess treatment-induced gene expression changes in ALL cells. After treatment, the median ADRB2 mRNA expression was ninefold lower in leukemia cells of patients who ultimately relapsed as compared with patients who remained in continuous complete remission (CCR). Polymorphisms in the ADRB2 promoter were significantly linked to methotrexate (MTX)-induced upregulation in ADRB2 gene expression in ALL cells. Moreover, the ADRB2 promoter haplotype was significantly related to early treatment response in 245 children with ALL who received uniform treatment. We conclude that germline polymorphisms in ADRB2 are linked to the antileukemic effects of ALL chemotherapy.

Relation of ADRB1, CYP2D6, and UGT1A1 Polymorphisms With Dose of, and Response to, Carvedilol or Metoprolol Therapy in Patients With Chronic Heart Failure

The response to beta blockers in patients with heart failure could be associated with the genotype of drug-metabolizing enzymes and/or drug targets. The purpose of the present study was to determine whether specific genetic polymorphisms in ADRB1 (encoding the beta1-adrenergic receptor), CYP2D6, and UGT1A1 correlated with dose of, or response to, metoprolol or carvedilol treatment in patients with heart failure. A cohort of patients with heart failure (n = 93), characterized as responders or nonresponders to metoprolol (n = 19) or carvedilol (n = 74) therapy, was retrospectively identified. Individual genotyping was performed for a panel of polymorphisms in the ADRB1, CYP2D6, and UGT1A1 genes. Univariate and multivariate analyses were performed to compare the genotype to the metoprolol or carvedilol response status and dose. A nonresponse was identified in 10 of 19 patients taking metoprolol and 32 of 74 patients taking carvedilol. None of the polymorphisms in ADRB1, CYP2D6, and UGT1A1 were associated with a response or nonresponse. However, a significant relation between the carvedilol (but not metoprolol) dose and the ADRB1 and CYP2D6 genotype was observed. Patients homozygous for the ADRB1 389Gly variant or who were CYP2D6 poor metabolizers achieved a significantly higher dose of carvedilol (p = 0.01 and p = 0.02, respectively). In conclusion, polymorphisms in ADRB1, CYP2D6, and UGT1A1 were not associated with a response to metoprolol or carvedilol therapy in our cohort of patients with heart failure. The ADRB1 and CYP2D6 genotype, alone and in haplotype, were significantly associated with the dose of carvedilol.

Association between β‐adrenoceptor gene polymorphisms and relative response to β2‐agonists and anticholinergic drugs in Japanese asthmatic patients

Whether beta(2)-adrenoceptor gene (ADRB2) polymorphisms are associated with airway responsiveness to beta(2)-agonist medications remains controversial, partly due to factors that may confound pharmacogenetic associations, including age, cigarette smoking and airway remodelling. To overcome these problems, we performed an analysis using parameters that reflected the specific bronchodilator response to beta(2)-agonists. The increases in FEV(1) after inhalation of procaterol hydrochloride (Delta FEV(1) procaterol) or oxitropium bromide (Delta FEV(1) oxitropium), and after sequential inhalation of procaterol and oxitropium (total airway reversibility), were measured in 81 Japanese patients with moderate to severe asthma. Approximately 3 kb of the DNA sequence of the coding and 5'-flanking regions of ADRB2 were genotyped by direct sequencing and PCR-restriction fragment length polymorphism assay. The mean age of the participants was 54 years, and 38 (47%) were smokers. Although Delta FEV(1) procaterol and Delta FEV(1) oxitropium adjusted for predicted FEV(1) were not associated with ADRB2 polymorphisms, the ratio of Delta FEV(1) procaterol to total airway reversibility was significantly associated with the ADRB2 A46G genotype (P < 0.05). Patients who were homozygous for the A46 allele (arginine at amino acid 16) were more responsive than carriers of the G46 (glycine 16) allele (P = 0.008). Multivariate linear regression analysis showed that Delta FEV(1) procaterol was correlated with the number of A46 alleles (P = 0.014), and also with total airway reversibility (P < 0.001) and smoking index in current smokers (P = 0.009). The ADRB2 A46G polymorphism was associated with a relatively greater bronchodilator responsiveness to beta(2)-agonists even in elderly asthmatic patients and smokers.

Genetic Covariance Between γ-Glutamyl Transpeptidase and Fatty Liver Risk Factors: Role of β2-Adrenergic Receptor Genetic Variation in Twins

Plasma levels of gamma-glutamyl transpeptidase (GGT) are associated with risk factors for nonalcoholic fatty liver disease (NAFLD), such as dyslipidemia, insulin resistance (IR), and hypertension. Limited data exist on whether there is genetic covariance between plasma levels of GGT and NAFLD risk factors. Variants of beta2-adrenergic receptor gene (ADRB2) have been associated with dyslipidemia, IR, and hypertension, but its effect on GGT secretion is not known. We estimated the heritability of GGT using a twin-study design and examined the genetic covariance between GGT levels, IR, hypertension, levels of low-density lipoproteins and triglycerides, and ADRB2 variants. We studied phenotypes of 362 twins; the heritabilities of increased GGT activity and genetic covariance with NAFLD risk factors were estimated by variance-component methodology. ADRB2 genotype associations with plasma GGT activity were examined using generalized estimating equations to account for intra-twinship correlations. GGT activity was heritable at 49% +/- 8% of the twin cohort and had significant covariance with IR; insulin, triglyceride, and uric acid levels; and diastolic blood pressure. In generalized estimating equation models, the most common haplotype of ADRB2 was significantly associated with plasma GGT activity. Five single nucleotide polymorphisms in ADRB2 were associated with levels of GGT; ADRB2 haplotypes displayed pleiotropic effects on GGT and triglyceride levels. In a twin study, GGT shared genetic codetermination with traits of metabolic syndrome. The ADRB2 gene had pleiotropic effects on plasma levels of GGT and triglycerides, indicating linked pathways (eg, adrenergic) between genetic susceptibility to NAFLD and metabolic syndrome.

BETA1 (ARG389GLY, SER49GLY)- AND BETA2 (ARG16GLY)-ADRENOCEPTOR POLYMORPHISMS ARE RELATED TO LEFT VENTRICULAR HYPERTROPHY USING ECG IN MIDDLE-AGED, NORMOTENSIVE SUBJECTS: PP.22.358

Objective: Left ventricular hypertrophy (LVH) accompanying elevated sympathetic nervous activity (SNA) is more common in hypertensive and obese people. Elevated SNA is an important mechanism in cardiovascular complications and cardiac morbidity and mortality. β2-adrenoceptor (ADRB2) polymorphisms are closely linked to hypertension and obesity, and β1-adrenoceptor (ADRB1) play roles directly with the heart. We evaluated the relationships between ADRB1 polymorphisms, ADRB2 polymorphisms and LVH. Methods: In 215 nonobese, normotensive Japanese men, ADRB1 polymorphisms (Arg389Gly, Ser49Gly), ADRB2 polymorphisms (Arg16Gly, Gln27Glu), BMI, BP, heart rates (HR), total body fat-mass, waist-to-hip ratio (W/H), plasma norepinephrine (NE), insulin, leptin and ECG were measured. LVH was determined by the Sokolow-Lyon voltage criteria. Results: Twenty-four subjects (11.2%) showed LVH on ECG. Subjects with LVH had higher NE, BP levels and HR compared to those without LVH (all P < 0.05), but BMI, fat-mass, W/H, insulin and leptin were similar. Subjects with LVH had higher frequencies of Gly389 or Gly49 alleles of ADRB1 polymorphisms (χ2 = 49.94, P = 0.002; χ2 = 11.43, P = 0.001, respectively), and Gly16 or Glu27 alleles of ADRB2 polymorphisms (χ2 = 9.59, P = 0.002; χ2 = 3.12, P = 0.059, respectively). Distributions of Gly389 and Gly49 alleles of ADRB1 polymorphisms and Gly16 and Glu27 alleles of ADRB2 were 39.5%, 27.9%, 74.4% and 11.2%, respectively. Subjects with Gly389 or Gly49 had higher frequencies of LVH, higher NE and HR (all P < 0.05), whereas BMI, fat-mass, W/H, BP, insulin and leptin were similar. Subjects with Gly16 had higher frequencies of LVH and greater BMI, fat-mass, systolic BP, NE and insulin compared to those without Gly16 allele (all P < .05). In multiple regression analysis, plasma NE was a significant determinant for systolic BP and LVH in all subjects. Conclusions: Subjects carrying Gly389 and Gly49 alleles of ADRB1 polymorphisms and Gly16 allele of ADRB2 polymorphisms had higher frequency of LVH accompanying high plasma NE. ADRB1 polymorphisms might relate to LVH directly through elevated SNA, but ADRB2 polymorphisms might relate to LVH through obesity and hypertension associated with elevated SNA and insulin resistance.

Common genetic variation of β1- and β2-adrenergic receptor and response to four classes of antihypertensive treatment

Varying results have been reported on the association of beta-adrenergic receptor polymorphisms with blood pressure (BP) response to beta-blockers. We investigated the influence of ADRB1 Ser49Gly and Arg389Gly, and ADRB2 Gly16Arg and Glu27Gln polymorphisms on ambulatory BP response to bisoprolol and three other antihypertensive drug monotherapies in a placebo-controlled, double-blind, cross-over study with 233 moderately hypertensive men. ADRB1 Ser49Ser homozygotes tended to have a better ambulatory BP response to bisoprolol but the difference was statistically nonsignificant. ADRB1 Arg389Arg homozygotes did not show better BP response to bisoprolol than the other genotypes. There were no significant associations of ADRB2 polymorphisms with BP responses to any of the study drugs. The results from this controlled study in hypertensive men do not support clinical use of common polymorphisms in ADRB1 and ADRB2 in predicting BP responses to beta-blockers or to three other antihypertensive drugs.

Adrenergic-β2 receptor polymorphism and athletic performance

The focus of this review is to evaluate the influence of beta(2)-adrenergic receptor (ADRB2) polymorphism on human physiological function and in turn on athletic performance. A narrative review is conducted on available literature using MedLine, Pubmed and the Cochrane Library to document the location and function of ADRB2 receptors, and specifically to address the influence of genetic polymorphisms on cardiovascular, respiratory, metabolic and musculoskeletal systems and athletic performance. Search terms included ADRB2, endurance and polymorphism. Previous literature exploring the genetic composition of athletes has proposed that alterations in the genetic structure result in an enhancement in their capacity to achieve successful aerobic phenotypes such as a higher VO(2max) and increased fat oxidation. Polymorphism of the Gly16Glu27 haplotype is believed to promote positive aerobic phenotypes and regulate optimal lipolysis. Greater knowledge of the ADRB2 polymorphism can aid in understanding the specific phenotypes that are altered, which may influence performance. Until the interaction between fatigue and athletic performance is better understood, the development of appropriate training principles to enhance genetically polymorphic aerobic phenotypes remains complicated. Following the review, there is still no distinctive evidence for the predictive ability of the polymorphism of ADRB2 genotype for the purpose of identifying potential elite athletes.

Genetic Polymorphisms of ADRB2 and IL10 May Be Associated with the Risk of IgE Sensitization to Digestive Powders in Exposed Medical Personnel

Background: It has been reported that pancreatic extracts may induce IgE-mediated respiratory allergy in medical personnel. The aim of the study was to identify genetic factors associated with IgE sensitization to digestive powders containing pancreatic extract. Methods: This case-control study was performed on 153 subjects routinely exposed to digestive powder and on 123 nonexposed controls working in Ajou University Hospital. Skin prick testing was performed using 4 commonly used digestive powders and α-amylase. Serum specific IgE levels were measured by ELISA. Three single nucleotide polymorphisms, ADRB2 46A>G, IL10 –1082A>G and IL4 –589T>C, were genotyped using the single base extension method. Results: The positive rate of serum specific IgE to digestive powder was significantly higher in the 41 (26.8%) exposed personnel with work-related respiratory symptoms than in controls (24.4 vs. 5.4%, p = 0.012). Thirty-nine (25.5%) of the 153 exposed personnel were found to have an allergy to digestive powder, as determined by a positive skin prick test and/or a high serum specific IgE level to digestive powder. The ADRB2 46A>G and IL10 –1082A>G polymorphisms were found to be significantly associated with the development of an allergy to digestive powder in exposed medical personnel by multiple logistic regression analysis after controlling for age, atopy and job type (pharmacist or nurse; p = 0.035 and p = 0.027, respectively). Conclusion: These results suggest that the genetic polymorphisms ADRB2 46A>G and IL10 –1082A>G are genetic factors that increase IgE sensitization to pancreatic extracts in medical personnel occupationally exposed to digestive powders.

19 DARK CHOCOLATE ATTENUATES THE POST-PRANDIAL INCREASE IN HVPG IN PATIENTS WITH CIRRHOSIS AND PORTAL HYPERTENSION

were observed between PH-S and PH-P. According to response to propranolol prophylaxis status, and ADRB2 polymorphisms (SNP) a significant higher ADRB2 activity was observed in non-responder PH patients. This activity was more pronounced when any of the ADRB2 SNP was present in both, responder and non-responder patients (Fig. 1). Conclusions: Non-responder PH patients to propranolol prophylaxis show a most reactive ADRB2 to adrenergic stimulus compared with responders, in both groups, native or polymorphic patients.

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.

Very important pharmacogene summary ADRB2

The beta2-adrenergic receptor (beta2-AR) is a member of the G-protein-coupled adrenergic receptor family with seven transmembrane segments. Similar to other members of this receptor family, beta2-AR specifically binds and is activated by the endogenous class of ligands known as catecholamines, and epinephrine in particular. The gene encoding this receptor, ADRB2, was cloned by Kobilka et al. in 1987 and is localized to chromosome 5q31–q32, a region that has been linked with asthma and asthma related phenotypes [1,2]. ADRB2 consists of a single exon of 2015 nucleotides, which encodes a 413 amino acid protein. This review highlights the genetic polymorphisms in ADRB2 and the pivotal role of beta2- AR in the regulation of the cardiac, pulmonary, vascular, endocrine, and central nervous systems. ADRB2 is abundantly expressed in bronchial smooth muscle cells and activation of the resulting receptor leads to bronchodilation. In addition, this gene is expressed in cardiac myocytes and vascular smooth muscle cells. Activation of beta2-AR in these cells causes an increase in the rate and force of heart contractions. Intracellular signaling upon beta2-AR activation is largely affected through a trimer of G proteins coupled to adenylate cyclase, to produce cyclic adenosine monophosphate. This, in turn, activates protein kinase A, leading to the phosphorylation and down-regulation of proteins including beta2-AR itself (please refer to PharmGKB β-agonist and β-blocker Pathway for further details: https://www.pharmgkb.org/do/serve?objId=PA2024&objCls=Pathway#). Beta2-AR is the target of clinically important drugs for asthma and cardiovascular conditions including hypertension and congestive heart failure (CHF). Beta-receptor agonists (e.g. albuterol, salmeterol) and antagonists (e.g. carvedilol and propranolol) are among the most commonly prescribed medications in the treatment of asthma and cardiovascular disease, respectively. Although some beta-blockers are ‘selective’ for the beta1-AR (e.g. metoprolol and atenolol), these also antagonize the beta2-AR at higher concentrations. A number of genetic polymorphisms in the ADRB2 gene have been described which affect gene expression, the function of the resulting receptor, and response to beta2-agonists.

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.

Polymorphism of the ADRB2 Gene and Response to Inhaled Beta- agonists in Children with Asthma: A Meta-analysis

Background. About 9% of children have asthma, corresponding to almost 6.8 million children in the USA and 1.1 million in the UK. Asthma exacerbations are the leading cause of pediatric emergency room visits and impose a large burden on the individual, family, and society. There is mounting evidence that therapeutic failure of inhaled beta-agonists is associated with polymorphisms of the β2-adrenergic receptor gene (ADRB2); specifically, mutations leading to amino acid changes at positions 16 and 27, which alter down-regulation of the β2-adrenergic receptor (β2AR), induce resistance to the smooth-muscle relaxing effect of β2-adrenergic agonists. Methods. We conducted a meta-analysis to examine the association between ADRB2 polymorphisms and the response to inhaled β2-adrenergic agonists in children with asthma. We included all published studies until November 2008, in which asthmatic children underwent testing for acute bronchodilator response, defined as ≥ 15% improvement in forced expiratory volume in 1 second (FEV1) and single nucleotide polymorphism (SNP) genotyping for positions 16 and/or 27 of the β2AR. Individual and summary odds ratios were calculated using a random effects model. Results. We identified three case-control or family-based studies involving 960 asthmatic children (692 children with negative β2-bronchodilator response, defined as < 15% improvement in FEV1 and 268 children with positive bronchodilator response). We found a significant association between favorable therapeutic response to inhaled β2-adrenergic agonists in asthmatic children and the Arg/Arg phenotype at position 16 of the β2AR [OR = 1.77; 95% CI (1.01; 3.1); p = 0.029], compared with the Arg/Gly or Gly/Gly phenotypes. The beneficial effect of Arg at position 16 of the β2AR was most pronounced in African-American asthmatic children [OR = 3.54; 95% CI (1.37, 9.13)]. There was no association between clinical response to β2-agonists and polymorphism at amino acid position 27 of the β2AR (OR = 1.04; 95% CI [0.76,1.42]). Conclusions. Failure of bronchodilator response to inhaled beta-agonists in asthmatic children is associated with the Gly allele (Arg/Gly and Gly/Gly genotypes) at position 16 of the β2-adrenergic receptor. Genetic typing for β2AR polymorphism may help identify children with drug-resistant asthma.

Influence of β 2-adrenoceptor gene polymorphisms on β 2-adrenoceptor expression in human lung

Background The aim of the present study was to establish whether polymorphisms, especially those within the promoter region, of the β 2-adrenoceptor gene ( ADRB2) influence β 2-adrenoceptor expression in human lung. Methods The density of β-adrenoceptors in human lung tissue ( n = 88) was determined by saturation binding using the radioligand, iodinated cyanopindolol. Discrimination of β 1- and β 2-adrenoceptors was determined using the highly selective β 1-adrenoceptor antagonist, CGP20712A. Genotype was determined at 5 positions of ADRB2 previously reported as polymorphic. Potential influences of single nucleotide polymorphisms (SNPs) within the promoter region (−367, −47) and coding block (46, 79, 491) of ADRB2 on β 2-adrenoceptor expression were investigated. Results The density of β 2-adrenoceptors was variable among the 88 lung preparations studied ranging from 17 to 177 fmol/mg protein (mean ± S.E.M., 72 ± 4 fmol/mg protein). There was no influence of genotype on β 2-adrenoceptor expression for any of the polymorphisms studied except at position 491. The polymorphism at position 491C > T, leading to a change from thr to ile at amino acid 164, is uncommon. Preparations genotyped as heterozygous (126 ± 15 fmol/mg protein; n = 5) expressed significantly ( P = 0.0005) higher levels of β 2-adrenoceptor than those that were homozygous (69 ± 4 fmol/mg protein; n = 83). Conclusion With the exception of position 491, these data indicate that polymorphisms of ADRB2 do not influence β 2-adrenoceptor expression in human lung.

Role ofADRB2 gene polymorphism in asthma and response to β2-agonists in Polish children

The aims of this study were: (1) to find associations of asthma with single-nucleotide polymorphisms (SNPs) within the ADRB2 gene: Arg16Gly, Gln27Glu, -1023 G/A, -367 T/C, -47 C/T ; (2) to define linkage disequilibrium in the gene region, basing on the analyzed SNPs; and (3) to analyze the importance of ADRB2 polymorphism for response to bronchodilator drugs in children diagnosed with bronchial asthma. We compared 113 asthmatic children and 123 healthy subjects from the Polish population. Genotyping was performed by PCR-RFLP. We found an association of the A allele of -1023A/G ADRB2 polymorphism with asthma (P = 0.024). No significant associations with other SNPs were detected. Moderate linkage was found between Gln27Glu and -47C/T polymorphisms in linkage disequilibrium analysis (D' = 0.85, r(2) = 0.429, LOD = 31.97). No significant differences were found in haplotype frequencies in comparison to the control group, implicating that they are not associated with susceptibility to asthma in the analyzed population. There was no significant correlation between the analyzed SNPs of the ADRB2 gene and the response to beta(2)-agonists. This is the first report providing suggestive evidence for association of -1023A/G ADRB2 polymorphism with an increased risk of asthma. The analyzed SNPs may not play a major role in response to beta(2)-agonists in asthmatic children.