Beta3-adrenergic Receptor Gene Research Articles

A single-nucleotide polymorphism of the beta 2-adrenergic receptor gene can predict pathological complete response to taxane- and platinum-based neoadjuvant chemotherapy in breast cancer.

BackgroundGermline genetic polymorphisms in certain genes are associated with the response to anthracycline- and taxane-based neoadjuvant chemotherapy in breast cancer (BC). This translational study aims to evaluate the potential role of rs1042713 in the beta 2-adrenergic receptor (ADRB2) gene in predicting pathological complete responses (pCRs) to taxane- and platinum-based neoadjuvant chemotherapy in locally advanced breast cancer (LABC).Materials and methodsThe distribution frequencies of rs1042713 were genotyped in LABC patients who received taxane- and platinum-based neoadjuvant chemotherapy. Associations between tumor-relevant biomarkers, genotypes and pCRs were evaluated using Student’s t-test for continuous variables and Chi-square or Fisher’s exact test for categorical variables. For univariate analysis, the relationship between the rs1042713 polymorphism and pCR was analyzed by Chi-square or Fisher’s exact test. The modified ORs with their 95% CIs were calculated by a multivariate logistic regression analysis to explore the association between genotype and pCR.ResultsThere was a significant correlation of the rs1042713 genotype with estrogen receptor (ER) status (P=0.008). Significant differences were detected in the rs1042713 genotypes of pCR and non-pCR patients (P=0.046). The pCR rate was 18.2% in patients with ADRB2 rs1042713 AA genotypes and 38.7% in AG+GG genotypes. Women carrying the AG+GG (OR=2.91, 95% CI: 1.02–8.29, P=0.046) genotype had a higher pCR rate than those with the AA genotype.Conclusionrs1042713, which is located in the ADRB2 gene, could predict pCR to taxane-and platinum-based neoadjuvant chemotherapy in LABC. This finding suggests that rs1042713 could play a potential role as a predictive marker in clinical settings.

Parental Depressive Symptoms Potentiate the Effect of Youth Negative Mood Symptoms on Gene Expression in Children with Asthma.

Depressive symptoms in parents and in youths have been found to relate to disease comorbidity processes in children, including greater disease-related impairment and poorer clinical outcomes. The current study sought to assess whether coming from a family characterized by more depressive symptoms on average would potentiate the effects of changes in youths' own negative mood on the expression of two receptor genes relevant to asthma that are the primary targets of asthma medication, such that the combination of low child negative mood in the context of greater parental depressive symptoms would relate to the lowest levels of gene expression. One-hundred-twenty youths with diagnosed asthma and their parents participated every 6months for 2years. Parents reported on their depressive symptoms, children reported negative mood symptoms, and youths completed blood draws from which expression of Glucocorticoid Receptor (GR) and Beta2 Adrenergic Receptor (β2-AR) genes was extracted. Multilevel linear modeling revealed significant interactions between average levels of parental depressive symptoms and changes in youths' negative mood symptoms predicting gene expression, such that youths expressed significantly less GR and β2-AR during times when they experienced more negative mood symptoms, but this was only true if they came from families with higher levels of average parental depressive symptoms. The current study identifies novel and biologically-proximal molecular signaling patterns that connect depressive symptoms to pediatric asthma while also highlighting the important role of family environment for biological processes that may operate within depression comorbidity.

Gene\u2013diet-related factors of hyperglycaemia in postmenopausal women

As ageing and increased body fat are the signs of insulin resistance, we have studied whether the presence of Pro12Ala and C1431T of peroxisome proliferator-activated receptor gamma 2 gene and Trp64Arg of beta 3-adrenergic receptor gene may predispose to the hyperglycaemia development in postmenopausal women, who have never undergone hypoglycaemic treatment. The distributions of selected allele and genotype frequencies were determined by the PCR–RFLP method in normo- and hyperglycaemic, who have never been diagnosed and treated for diabetes mellitus were measured. The amount of body fat and lean body mass (LBM) were assessed by the bioimpedance method and nutritional habits by 7-day dietary recall. There were no differences between the distribution of genotypes and the allele frequencies of the Pro12Ala, C1431T and Trp64Arg polymorphisms in normo- and hyperglycaemic women. Hyperglycaemic women were characterized by visceral obesity, hypertension, higher serum insulin and triglycerides, higher intake of fat and lower consumption of complex carbohydrates and B vitamins. Normoglycaemic women with Pro12Pro polymorphism acquired higher energy from dietary fat (p < 0.0276) and lower energy from carbohydrates (p < 0.0480) than normoglycaemic Ala12 carriers. Subjects with Pro12Pro polymorphism and LBM > 58% of total body mass or with Trp64Trp and normal triglycerides have higher chance of normoglycaemia. Genotyping for Pro12Ala and Trp64Arg polymorphism in postmenopausal women may have the clinical benefit of predicting hyperglycaemia, thereby contributing to the prevention of diabetes mellitus development in the future. However, not only the genetic background but also the dietary habits (intake of fat, carbohydrates and B vitamins) determine the risk of hyperglycaemia.

Supplementation with trans fatty acid at 1% energy did not increase serum cholesterol irrespective of the obesity-related genotypes in healthy adult Japanese.

The excessive intake of trans fatty acids increases serum low-density lipoproteincholesterol and reduces high-density lipoprotein-cholesterol. We studied the effects of 1% energy trans fatty acid supplementation on serum lipid concentrations in healthy adult Japanese with different obesity-related gene polymorphisms. A randomized, double-blind, parallel trial was conducted in 53 healthy adults. The volunteers consumed one cookie containing either 1% energy or <0.01% energy (control) of trans fatty acids every day for 4 weeks, and a blood sample was then obtained after overnight fasting. The single nucleotide polymorphisms of the fat mass- and obesity-associated gene rs9939609 and beta-3 adrenergic receptor rs4994 were genotyped. The mean trans fatty acid intake of the control and trans fatty acid groups corresponded to 0.28% and 1.31 % energy, respectively. There were no significant differences in serum cholesterol (total, low-density lipoprotein and high-density lipoprotein) or triacylglycerol between the control and trans fatty acid groups. The responses of serum cholesterol, triacylglycerol, glucose, insulin and hemoglobinA1c were also independent of the fat mass- and obesity-associated gene and beta-3 adrenergic receptor gene variants. Our findings indicate that supplementation with 1% energy trans fatty acids has little effect on serum cholesterol in healthy adult Japanese, regardless of genotype of fat mass- and obesity-associated gene or beta-3 adrenergic receptor. More systematic studies, with respect to dietary trans fatty acid intakes above those used here, may be warranted to determine the tolerable upper level of dietary trans fatty acid.

Beta-2 adrenergic receptor (ADRB2) gene polymorphism Arg16Gly as risk factor for osteoporosis

Searchable abstracts of presentations at key conferences in endocrinology ISSN 1470-3947 (print) | ISSN 1479-6848 (online)

Beta2-adrenergic receptor gene haplotypes and bronchodilator response in Egyptian patients with chronic obstructive pulmonary disease

PurposeChronic obstructive pulmonary disease (COPD) is a multi-factorial disorder caused by environmental determinants and genetic risk factors. Understanding the genetic predisposition of COPD is essential to develop personalized treatment regimens. Beta2-adrenergic receptor (ADRB2) gene polymorphisms have been implicated in the pathogenesis of obstructive pulmonary diseases. This study was conducted to assess the genetic association between Arg16Gly and Gln27Glu polymorphisms and COPD in the Egyptian patients, and to analyze their impact on the clinical outcome and therapeutic response. Patients/methodsThe study population included 115 participants (61 COPD patients and 54 healthy controls) were genotyped for the Arg16Gly (rs1042713) and Gln27Glu (rs1042714) polymorphisms. Pulmonary function test was done and repeated in patients after salbutamol inhalation. ResultsThe Gly16 and Gln27 alleles represented 57% and 70% of the whole study population, and only 3 haplotypes were detected; Arg16/Gln27, Gly16/Gln27, and Gly16/Glu27. Genotypes and haplotypes homozygous for Arg16 and Gln27 were more likely to develop COPD (p<0.05). However, individuals carrying Glu27 allele conferred protection against COPD development (p=0.002). Furthermore, Arg16 genotypes and haplotypes were significantly associated with higher grades of dyspnea, more COPD symptoms and frequent exacerbations. In contrast, patients carrying Glu27 allele had better bronchial airway responsiveness to β2-agonists. ConclusionsOur findings suggested that the ADRB2 gene polymorphisms may have vital role in COPD risk, severity, and bronchodilator response among Egyptian population. Larger epidemiological studies are needed for results validation.

Polymorphisms in Beta-2 Adrenergic Receptor Gene and Association with Tuberculosis.

Genetic susceptibility for tuberculosis in human has been previously demonstrated. Polymorphisms in genes involved in immune responses may alter the susceptibility of individuals to tuberculosis. Polymorphisms of beta-2 adrenergic receptor (ADRB2) gene can be possibly an important risk factor in tuberculosis. In this study, the association between rs1042713 (Arg16Gly +46A>G) and rs1042714 (Gln27Glu +79C>G) polymorphisms in ADRB2 gene and tuberculosis was evaluated. Genotype distributions of the rs1042713 (Arg16Gly +46A>G) and rs1042714 (Gln27Glu +79C>G) polymorphisms in ADRB2 gene in 106 patients with pulmonary tuberculosis and 88 healthy subjects were studied by PCR-RFLP method in an Iranian population. The frequency of rs1042713*G and rs1042714*G alleles in ADRB2 gene in tuberculosis patients was significantly different from healthy controls [odds ratio (OR)0.176, 95% confidence interval (CI) 0.065-0.48, P value<0.001 and OR0.45, 95% CI 0.247-0.825, P value=0.009, respectively]. There were no significant differences in haplotype analysis between the patients and control subjects. The association was reported between rs1042713 and rs1042714 polymorphisms in ADRB2 gene and tuberculosis for the first time. rs1042713*G and rs1042714*G polymorphisms in ADRB2 gene makes people more susceptible to develop the disease.

Association of β-Adrenergic Receptor Gene Polymorphisms With Acute Coronary Syndrome and Cardiovascular Risk Factors in an Arab Population.

We evaluated the association between beta-adrenergic receptor genes (ADRB1 and ADRB2) polymorphism, cardiovascular risk, and acute coronary syndrome (ACS) in individuals from an Arab ethnicity. A total of 388 Qatari participants were assessed and genotyped for ADRB1 (rs1801252 & rs1801253) and ADRB2 (rs1042718 & rs1042713) polymorphisms using allele-specific PCR. Minor allele frequencies (MAF) in each single-nucleotide polymorphisms (SNPs) did not show statistically significant difference between cases and controls. A higher proportion of patients with ACS had homozygous minor alleles (GG) for rs1801253 (28.8% vs 17.1%; P = .019) compared with controls. Among cases with ACS, there was an association of minor allele frequency (G) for rs1801253 with severe coronary artery stenosis (0.485 vs 0.428; P = .04) than that of insignificant stenosis (<50% stenosis). There was a 3-fold increased risk of significant coronary stenosis in patients with diabetes mellitus (DM) and carrier of rs1801253 genotypes with dominant model (P = .01) and recessive model (P = .05). There is a possible synergic association between DM, carrier of ADRB1 (Arg389Gly) variants, and significant coronary artery stenosis among Arabs. Further prospective studies with larger sample sizes are warranted to support our findings.

Impact of the Arg 16 allele of the B2AR gene on the effect of withdrawal of LABA in patients with moderate to severe asthma

Introduction: Long-acting beta agonists (LABAs) are effective for controlling asthma, however questions about their safety have led to concerns over use. Genetic polymorphisms at the 16 amino acid position of the beta-2 adrenergic receptor gene (B2AR) may be associated with increased risk. Methods: A randomized, double blind study was conducted in patients with moderate to severe asthma being treated with combined inhaled corticosteroids/LABA (ICS/LABA), comparing the effect of LABA continuation versus withdrawal on asthma outcomes among patients stratified by B2AR genotype (Arg/Arg vs. Gly/Gly at the 16th amino acid position). Results: 67 participants (31 Arg/Arg, 36 Gly/Gly) were randomized to receive fluticasone alone (F) or continue combined fluticasone/salmeterol (F/S) after a run-in period on F/S. Among Gly/Gly subjects, those in the F/S treatment group showed improvement in AM PEFR (+ 8.4 L/s) whereas those receiving F alone experienced a reduction in AM PEFR over the study period (−14.4 L/s), (p = 0.06). There was no significant difference in morning peak expiratory flow rate (AM PEFR) in Arg/Arg participants randomized to receive F/S (−15.7L) vs F alone (−5.6 L/s) (p = 0.61). There was no significant difference in exacerbations in the Arg/Arg subjects treated with F/S compared with those treated with F (p = 0.65). Conclusions: Withdrawal of LABA therapy in asthmatics with the Arg/Arg genotype at the 16th amino acid position of B2AR did not lead to significant improvement in AM PEFR. LABA withdrawal in the Gly/Gly genotype however led to a borderline significant decline in AM PEFR.

P02. Beta-2 adrenergic receptor (ADRB2) gene polymorphisms as risk factors for reduced bone mineral density

P02. Beta-2 adrenergic receptor (ADRB2) gene polymorphisms as risk factors for reduced bone mineral density

(283) Beta2-adrenergic receptor gene polymorphisms and haplotypes associate with chronic pain in sickle cell disease

(283) Beta2-adrenergic receptor gene polymorphisms and haplotypes associate with chronic pain in sickle cell disease

ADRB2 Polymorphism and Salbutamol Responsiveness in Northern Indian Children with Mild to Moderate Exacerbation of Asthma.

The primary objective was to determine the association between beta-2 adrenergic receptor (ADRB2) gene polymorphism (rs1042713, c.46A>G, p.Arg16Gly) and the response to inhaled salbutamol in North Indian children aged 5 to 15 years, with mild to moderate exacerbation of asthma. This cross-sectional study was done at a tertiary-care hospital in Northern India from June 2011 to May 2013. 120 children with asthma with mild to moderate exacerbation underwent spirometry at baseline and after administration of three doses of salbutamol. An increase in FEV1 =15% was considered as positive response. Blood samples from these children were analysed for ADRB2 polymorphism (p.Arg16Gly). 94 non-asthmatic adult controls were also studied to determine the prevalence of ADRB2 polymorphism. In asthmatic children, the frequency of AA, GG, AG genotypes were 24.2%, 24.2% and 51.7% compared to 20.2%, 20.2% and 59.6%, respectively in the non-asthmatic adults. Salbutamol responsiveness showed no correlation with the studied ADRB2 polymorphism (p= 0.55). A trend towards greater bronchodilator responsiveness amongst AA genotype, compared to GG genotype was observed (Median change in percent predicted FEV1 14.5% and 7.5%, respectively). No correlation was found between salbutamol responsiveness and ADRB2 genotype in Northern Indian children with asthma with mild-to moderate exacerbation.

An association and meta-analysis study of 4 SNPs from beta-2 adrenergic receptor (ADRB2) gene with risk of asthma in children.

Although various case-control studies have been conducted to investigate the relationship between ADRB2 gene polymorphisms and asthma risk in different population groups, the results have been conflicting and inconclusive. We performed a case-control study to investigate the association of 4 SNPs in the ADRB2 gene with risk of asthma in children, and then conducted a meta-analysis by combining the previous studies. A total of 340 patients and 340 age-matched healthy controls were recruited. All of the subjects were genotyped using the PCR-based invader assay. The case-control study was performed to define the contribution of rs1042713, rs1042714, rs1800888, and rs1042711 to the predisposition of asthma. Additionally, we further conducted a meta-analysis of the study findings together with those of previously reported studies. No significant association was found between the polymorphisms rs1042713, rs1042714, rs1800888, and rs1042711 and asthma in the current case-control study. The meta-analysis confirmed that there was no positive association of these SNPs with asthma in children in Asia, South America, Europe and the overall population. None of the four polymorphisms in ADRB2 gene were associated with a risk of asthma in a current children population.

The influence of clinical and genetic factors on left ventricular wall thickness in Ragdoll cats

ObjectivesTo investigate the effect of various genetic and environmental modifiers on left ventricular (LV) wall thickness in a cohort of cats genotyped for the myosin binding protein C3 mutation (MYBPC3). AnimalsSixty-four Ragdoll cats. MethodsAll cats were screened for HCM with echocardiography and genotyping for the HCM-associated MYBPC3:R820W mutation. Cats were also genotyped for previously identified variant polymorphisms of the angiotensin-converting enzyme (ACE) and cardiac beta-adrenergic receptor (ADRB1) genes. Plasma N-terminal pro-B-type natriuretic peptide and cardiac troponin I were also measured. Associations were evaluated between genotype (MYBPC3 negative/positive, and ACE and ADRB1 negative/heterozygous/homozygous), patient factors (body weight, age and sex) and echocardiographic measurements of LV wall thickness. ResultsMale cats had greater maximum wall thickness (LVmax; 5.8 mm, IQR 5.1–6.4 mm) than females (4.7 mm, IQR 4.4–5.3 mm, p = 0.002). Body weight positively correlated with LVmax (ρ = 0.604, p < 0.001). The MYBPC3:R820W-positive cats had a greater LVmax (5.44 mm, IQR 4.83–6.28 mm) than the negative cats (4.76 mm, IQR 4.36–5.32 mm, p = 0.001). Also, the ACE polymorphism genotype was associated with LVmax: the homozygous cats (5.37 mm, IQR 5.14–6.4 mm) had greater LVmax than the heterozygous cats (4.73 mm, IQR 4.41–5.55 mm, p = 0.014). Only the MYBPC3 genotype and body weight were independently associated with wall thickness in multivariable analysis. ConclusionsThis study provides evidence that the MYBPC3:R820W mutation is independently associated with LV wall thickness in Ragdoll cats. Body weight is also independently associated with maximum LV wall thickness, but is not currently accounted for in HCM screening. In addition, other genetic modifiers may be associated with variation in LV wall thickness in Ragdolls.

Beta 2-adrenergic receptor gene association with overweight and asthma in children and adolescents and its relationship with physical fitness

ObjectiveTo investigate the association of Arg16Gly and Gln27Glu polymorphisms of β2-adrenergic receptor gene (ADRB2) with the occurrence of asthma and overweight and the gene's influence on anthropometric, clinic, biochemical and physical fitness variables in children and adolescents. MethodsSubjects were evaluated for allelic frequencies of the β2-adrenergic receptor gene, height, weight, body mass index (BMI), BMI Z-score, waist circumference (WC), pubertal stage, resting heart rate (HRres), blood pressure (BP), total cholesterol (TC), glucose, insulin, high density lipoprotein (HDL-C), low density lipoprotein (LDL-C), triglyceride (TG), Homeostasis Metabolic Assessment (HOMA2-IR), Quantitative Insulin Sensitivity Check Index (QUICKI) and maximal oxygen uptake (VO2max). The participants were divided in four groups: overweight asthmatic (n=39), overweight non-asthmatic (n=115), normal weight asthmatic (n=12), and normal weight non-asthmatic (n=40). ResultsRegarding the Gln27Glu polymorphism, higher total cholesterol was observed in usual genotype individuals than in genetic variant carriers (p=0.04). No evidence was found that the evaluated polymorphisms are influencing the physical fitness. The Arg16 allele was found more frequently among the normal weight asthmatic group when compared to the normal weight non-asthmatic group (p=0.02), and the Glu27 allele was more frequently found in the overweight asthmatics group when compared to the normal weight non-asthmatic group (p=0.03). ConclusionsThe association of Arg16 allele with the occurrence of asthma and of the Glu27 allele with overweight asthmatic adolescents evidenced the contribution of the β2-adrenergic receptor gene to the development of obesity and asthma.

The influence of bisoprolol on lipids metabolism in patients with heart failure and systolic dysfunction depending on beta1-adrenergic receptor gene polymorphism

Purpose: To investigate the influence of bisoprolol using on lipids metabolism depending on Ser49Gly and Arg389Gly β1-adrenergic gene polymorphism in patients with severe chronic heart failure (CHF).

Association of polymorphisms in the beta-2 adrenergic receptor gene with fracture risk and bone mineral density.

SummarySignaling through the beta-2 adrenergic receptor (B2AR) on the osteoblast influences bone remodeling in rodents. In the B2AR gene, three polymorphisms influence receptor function. We show that these polymorphisms are not associated with fracture risk or bone mineral density in the UCP, Rotterdam Study, and GEFOS cohorts.IntroductionSignaling through the beta-2 adrenergic receptor (B2AR) on the osteoblast influences bone remodeling in rodents. In the B2AR gene, three polymorphisms are known to influence receptor function in vitro and in vivo (rs1042713, rs1042714, and rs1800888). We examined the role of these polymorphisms in the B2AR gene on human bone metabolism.MethodsWe performed nested case–control studies to determine the association of these polymorphisms with fracture risk in the Utrecht Cardiovascular Pharmacogenetics (UCP) cohort and in three cohorts of the Rotterdam Study. We also determined the association of these polymorphisms with bone mineral density (BMD) in the GEFOS Consortium. UCP contains drug-dispensing histories from community pharmacies linked to national registrations of hospital discharges in the Netherlands. The Rotterdam Study is a prospective cohort study investigating demographics and risk factors of chronic diseases. GEFOS is a large international collaboration studying the genetics of osteoporosis. Fractures were defined by ICD-9 codes 800–829 in the UCP cohort (158 cases and 2617 unmatched controls) and by regular X-ray examinations, general practitioner, and hospital records in the Rotterdam Study (2209 cases and 8559 unmatched controls). BMD was measured at the femoral neck and lumbar spine using dual-energy X-ray absorptiometry in GEFOS (N = 32,961).ResultsMeta-analysis of the two nested case–control studies showed pooled odds ratios of 0.98 (0.91–1.05, p = 0.52), 1.04 (0.97–1.12, p = 0.28), and 1.16 (0.83–1.62, p = 0.38) for the associations between rs1042713, rs1042714, and rs1800888 per minor allele and fractures, respectively. There were no significant associations of the polymorphisms and BMD in GEFOS.ConclusionIn conclusion, polymorphisms in the beta-2 adrenergic receptor gene are not associated with fracture risk or BMD.

Are beta2-Adrenergic Receptor Gene Single-Nucleotide Polymorphisms Associated with Polycystic Ovary Syndrome? a Pharmacogenetic Study

Study background: Polycystic ovary syndrome (PCOS) is a common complex condition in women associated with reproductive, metabolic and psychological features. Evidences from studies on women with PCOS and on an experimental rat PCO model suggest that the sympathetic regulatory drive to the ovary may be unbalanced (hyperactivity). The aim of this study was to investigate polymorphism codon 16, 27,113 and 164 of beta2 adrenergic receptor in polycystic ovary syndrome (PCOS). Methods: 100 patients with PCOS from Infertility Center of Valie Asre, Imam Khomeini Hospital Complex participated in this study for the first time between May 2014-2015. All women aged 20-40 years and had a body mass index (BMI) were under 28. Results: Our results show that women with PCOS had polymorphism only in codon 164 with 44.4% (P< 0.002), that represents a significant difference between the study and control groups. Conclusion: Therefore Beta2 adrenergic receptor gene polymorphism (Thr164Ile) associates withpolycystic ovary syndrome. The ratio of heterozygotes to homozygotes shows a significant difference between the two groups.

ADRB2 polymorphisms predict the risk of myocardial infarction and coronary artery disease.

Recently, the rs1042713 G > A and rs1042714 C > G polymorphisms in the beta-2 adrenergic receptor (ADRB2) gene were shown to be related to atherosclerosis diseases. Therefore, we performed a systemic meta-analysis to determine whether the two functional polymorphisms are related to the risk of myocardial infarction (MI) and coronary artery disease (CAD). We identified published studies that are relevant to our topic of interest. Seven case-control studies, with a total of 6,843 subjects, were incorporated into the current meta-analysis. Our analysis showed a higher frequency of rs1042713 G > A variant in patients with MI or CAD compared to healthy controls. A similar result was also obtained with the rs1042714 C > G variant under both the allele and dominant models. Ethnicity-stratified subgroup analysis suggested that the rs1042714 C > G variant correlated with an increased risk of the two diseases in both Asians and Caucasians, while rs1042713 G > A only contributes to the risk of two diseases in Asians. In the disease type-stratified subgroups, the frequencies of both the rs1042713 G > A and rs1042714 C > G variants were higher in the cases than in the controls in both the MI and CAD subgroups. Collectively, our data contribute towards understanding the correlation between the rs1042713 G > A and rs1042714 C > G polymorphisms in ADRB2 and the susceptibility to MI and CAD.

A population-based case-control study to evaluate the role of codon 164 of beta 2-adrenergic receptor gene polymorphism in Iranian PCOS patients

A population-based case-control study to evaluate the role of codon 164 of beta 2-adrenergic receptor gene polymorphism in Iranian PCOS patients