PMCCPMCCPMCC

Search tips
Search criteria 

Advanced

 
Logo of nihpaAbout Author manuscriptsSubmit a manuscriptHHS Public Access; Author Manuscript; Accepted for publication in peer reviewed journal;
 
Pharmacogenet Genomics. Author manuscript; available in PMC 2011 May 20.
Published in final edited form as:
PMCID: PMC3098753
NIHMSID: NIHMS287252

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.

ADRB2 variants

The ADRB2 gene has been resequenced in multiple populations and more than 80 polymorphisms have been identified, of which 45 single nucleotide polymorphisms (SNPs) and two insertion/deletion polymorphisms have been validated in more than one study [3,4]. Two of these nonsynonomous SNPs code for amino acid changes at positions 16 [arginine to glycine (Arg16Gly); rs1042713] and 27 [glutamic acid to glutamine (Glu27Gln); rs1042714], are common with minor allele frequencies (MAF) between 40–50% and have been well characterized in asthma pharmacogenetics [5]. In-vitro studies showed that the Gly16 isoform enhanced the agonist-stimulated down-regulation of beta2-AR, whereas the Glu27 variant did not regulate the expression of this receptor [6,7]. In addition to these common polymorphisms, other less common, nonsynonymous coding variants have also been reported in the ADRB2 gene. For example, the SNP rs1800888 encodes a Threonine to Isoleucine substitution at amino acid position 164 (Thr164Ile) and occurs with a MAF of 1–3%. The Ile164 isoform is three-to-four times less responsive to agonist-induced stimulation than carriers of the wild-type Thr164 [8,9]. Another rare, nonsynonymous variant resulting in a Valine to Methionine change at amino acid position 34 (Val34Met) in beta2-AR has a MAF less than 1% [10].

In-vivo studies of the genetic variants in ADRB2 suggest that these are not likely to be disease-causing variants but possibly serve as predictive markers for responsiveness to both agonists and antagonists. Moreover, three meta-analyses of the two common nonsynonymous SNPs in ADRB2 have concluded that these polymorphisms are not associated with the diagnosis of asthma [1113]. However, homozygotes of Arg16 treated with regular short acting beta-agonist (SABA) therapy tend to experience more adverse effects [14]. Furthermore, among the patients prescribed beta-blocker therapy after an acute coronary syndrome, those homozygous for both Arg16 and Gln27 were at higher risk for death in 3 years (3-year mortality rate of 20%) compared to the other diplotypes (3-year mortality rate of 6–11%) [15]. CHF patients with the Ile164 variant were at higher risk for death or heart transplantation in 1 year (event rate 76%) compared to those homozygous for Thr164 whereas others did not observe this finding [16,17].

Important Variants (for full mapping information, see http://www.pharmgkb.org/search/annotatedGene/adrb2/variant.jsp)

  1. ADRB2: Arg16Gly; 285A>G (rs1042713),
  2. ADRB2: Gln27Glu; 318C>G (rs1042714),
  3. ADRB2: Thr164Ile; 730C>T (rs1800888).

ADRB2: Arg16Gly; 285A >G (rs1042713)

Arg16Gly is encoded by a common nonsynonymous polymorphism in the ADRB2 gene. The estimated frequency of the Arg16 variant is 39.3% in White Americans, 49.2% in Black Americans and 51.0% among Chinese [10]. In-vitro studies using Chinese hamster fibroblasts showed that the Gly16 receptor had an enhanced agonist-promoted down-regulation relative to Arg16 [6]. Similar findings were reported for human smooth muscle cells [7]. Owing to the functional significance and the prevalence of the Arg16Gly variant, it has been the focus of many clinical studies on asthma and cardiovascular diseases. Three meta-analyses have shown that the Arg16Gly variant is not associated with asthma [1113]. However, the allele encoding Gly16 has been associated with nocturnal asthma and with severe asthma [12]. Pharmacogenetic studies have observed an association between this polymorphism and response to beta2-agonists. Several studies have shown that homozygotes of Arg16 are more likely to respond (more rapid response and increased forced expiratory volume in one second ) to albuterol (SABA) compared to homozygotes of Gly16 and heterozygotes [1820]. One study observed this association only in response to high doses of SABA [21]. Other investigations, however, found no association between this SNP and variable drug response [3,22,23] whereas some groups reported contradictory results [2426]. Individuals who are homozygous for Arg16 and receiving regular albuterol treatment reported to have decreased response, measured by lower morning peak flow rates, compared with those who were not receiving regular albuterol treatment, suggesting that regular albuterol therapy may not be appropriate for Arg16 homozygous asthma patients [27].

The Arg16Gly amino acid substitution has been shown to influence agonist-mediated vascular response. The allele encoding the Arg16 receptor was associated with enhanced isoproterenol-mediated vascular desensitization in a study involving 26 healthy volunteers [28]. This prospective study suggests that this isoform is an important determinant of the vascular response to stress [28]. In addition, effects of common beta2-AR haplotypes on vascular responses to a beta2-agonist have been studied in 35 healthy volunteers [29]. In this study, the Arg16 receptor showed higher sensitivity to terbutaline than the Gly16 isoform at baseline. After terbutaline treatment for 2 weeks, the extent of desensitization of venous beta2-AR differs by haplotype; Arg16Gln27Thr164 has the greatest desensitization whereas Gly16Glu27Thr164 showed the lowest desensitization [29]. However, these studies involved a small number of healthy volunteers who may have different physiology from that of patients with cardiovascular disease. In addition, this study did not randomize the treatment sequence to minimize the effects of the time. In another study, the Arg16 isoform was associated with higher peak oxygen consumption (peak VO2) compared to Gly16 in 118 heart failure patients [30]. However, in another cohort study of 199 patients with stable CHF, the Arg16 isoform was not associated with improvement of left ventricular ejection fraction and decrease in heart rate in response to a β-blocker [31]. In a cohort study with 171 idiopathic dilated heart failure patients, the Arg16 isoform was associated with lower risk of death or heart transplantation compared with the Gly16 [32]. However, these findings have not been replicated. In fact, studies have produced conflicting results regarding an association between beta2-AR haplotypes and death or heart transplantation in stable heart failure. Although homozygosity for Arg16Gln27 haplotype was associated with an increased risk of death or heart transplantation in a prospective cohort study involving 227 patients [33], no beta2-AR haplotypes were associated with the outcomes in another prospective cohort study of 637 patients [34]. The studies evaluating intermediate or clinical outcomes have relatively small sample sizes and have different rates of background medications such as angiotensin-converting enzyme inhibitors and β-blockers for heart failure, which may account in part for the conflicting results.

Association studies of the Arg16Gly substitution with type-2 diabetes mellitus [35,36] and risk factors such as obesity, hypertension and insulin resistance have also reported conflicting results. A nominal association with the Arg16 variant in type-2 diabetes was found in a case-control study of 7808 unrelated, middle-aged White populations [36]. In another study of 130 Taiwanese patients with type-2 diabetes matched 1 : 1 for sex, age, and body mass index (BMI), two copies of the Arg16 isoform was an independent risk factor for development of type-2 diabetes and was associated with earlier disease onset [37]. However, there are other studies reporting Gly16 as the risk variant. The affect of this polymorphism on insulin secretion was studied in a cohort of 47 Japanese type-2 diabetic patients. Gly16 homozygotes had significantly higher levels of fasting insulin and homeostasis model assessment of insulin resistance compared with the Arg16 homozygotes [38]. These findings are in agreement with similar studies where the Gly16 isoform was associated with higher insulin resistance in nonobese, normotensive Japanese individuals [39]. Likewise, conflicting associations have been reported for hypertension risk among type 2 diabetic patients, with some groups reporting increased risk of hypertension associated with Arg16 [40] and others reporting associations with the Gly16 isoform [41]. Finally, several studies have reported increased BMI correlated with the Arg16 isoform [4143], while other studies found a protective effect of the same allele [37,40]. A meta-analysis of 11 populations from earlier studies reported no association between the polymorphism encoding Arg16 and obesity [44].

Earlier studies have suggested that the Arg16Gly variant may be associated with cholesterol metabolism in certain populations. A study of 100 hypertriglyceridemia cases and 241 healthy controls, from a population of Chinese Han showed that controls who were homozygous for the Arg16 isoform had higher serum triglycerides. In hypertriglyceridemia patients, Arg16 homozygotes had higher serum total cholesterol and low-density lipoprotein cholesterol levels (207.27±28.62 vs. 184.46±41.38 mg/dl, P<0.05; 117.17±27.07 vs. 92.03±42.54 mg/dl, P<0.05) [45].

The impact of the Arg16Gly amino acid substitution on other cardiovascular outcomes such as sudden cardiac death, ventricular arrhythmias, myocardial infarction (MI), and stroke has also been studied. Case-control studies reported no association between this polymorphism and the above-mentioned phenotypic outcomes [46,47]. Although these case-control studies have relatively large sample sizes (495–5393), they may have been confounded by unmeasured factors. Overall, data on the association of the Arg16Gly isoform with clinical outcomes in cardiovascular diseases are not consistent. Therefore, more studies involving larger sample sizes and a better design are needed to define the roles of this polymorphism in cardiovascular diseases.

ADRB2: Gln27Glu; 318C >G (rs1042714)

Gln27Glu is encoded by a common nonsynonymous polymorphism (rs1042714) in the ADRB2 gene. The estimated frequency of the Glu isoform is 24.6% among Whites, 18.7% among Blacks, and 9% among Chinese [10]. Earlier studies have suggested that the Glu27 isoform do not down-regulate the expression of the beta2-AR [6,7]. Individuals who were homozygous for Glu27 had higher maximal venodilatation in response to isoproterenol than those who were homozygous for Gln27, suggesting that the Gln to Glu change is associated with increased agonist-mediated responsiveness [28]. Impact of the ADRB2 polymorphisms on vascular responses to iso-proterenol were studied with internal mammary arteries obtained from 96 patients undergoing coronary bypass surgery. The arteries from patients homozygous for Gly16 displayed reduced sensitivity to isoproterenol compared with those from patients carrying Arg16. Among the arteries from the Gly16 homozygotes, those from the patients homozygous for Glu27 showed isoproterenol sensitivity similar to the arteries from the Arg16 carriers [48]. Thus, overall data suggest that the ADRB2 polymorphisms may influence vascular responses to a beta2-agonist. In addition, the Gln27 receptor has been associated with increases in systolic blood pressure [49].

Several studies found that the beta2-AR mediated increases in heart rate and contractibility are not dependent on the amino acid changes at codons 16 and 27 [9]. The polymorphism encoding the Gln27Glu change was not associated with the increased risk of sudden cardiac death and ventricular arrhythmias in patients with coronary artery disease [46], nor is it associated with the risk of MI or ischemic stroke in patients who were pharmacologically treated for hypertension [47]. The polymorphism has also been studied in heart failure. In a prospective cohort study with 80 patients with heart failure, those homozygous for Gln27 were less likely to have improved left ventricular ejection fraction after carvedilol treatment compared to Glu27 carriers [50]. However, in another prospective cohort study with 199 heart failure patients, this variant was not associated with the improvement of left ventricular ejection fraction or decrease in heart rate in response to a β-blocker [31]. Nevertheless, the Gln27 isoform was associated with a lower risk of death or heart transplantation in idiopathic dilated heart failure [32]. In addition, the Gln17 isoform, in the presence of the Gly16 and Ile164 variants were associated with decreased risk of MI [49]. Thus, data on the role of this polymorphism in heart failure are conflicting. In a prospective cohort study involving 735 patients who were prescribed a β-blocker after an acute coronary syndrome, patients homozygous for Gln27 had higher mortality rate (16%) compared to those heterozygous and homozygous for Glu27 (11 and 6%, respectively). In addition, those homozygous for both Arg16 and Gln27 were at higher risk for death in 3 years (3-year mortality rate 20%) compared to the other diplotypes (3-year mortality rate 6–11%) [15]. Although these findings have not been replicated, the Arg16Gln27 diplotype is associated with higher mortality in patients who receive a β-blocker after acute coronary syndrome.

Association studies of the Gln27Glu variant and type-2 diabetes mellitus have yielded neutral [3537], positive [43,51], and contradictory [52,53] results in various populations. In a case-control study of 7808 unrelated, middle-aged Whites, no association was found with obesity, hypertension and type-2 diabetes [36]. However, in another case–control study of 400 nonobese individuals (BMI<27 kg/m2) and 108 obese individuals (BMI ≥ 27 kg/m2), the frequency of the Glu27 variant was higher in type-2 diabetics than nondiabetic participants (0.14 vs. 0.07, P=0.001, odds ratio (OR): 2.13, 95% confidence interval 1.34–3.41) [43]. Conversely, in 342 type-2 diabetic patients and 305 unrelated nondiabetic controls, Glu27 homozygotes had a lower frequency of diabetes when compared to Gln27 carriers (OR: 0.56, 95% confidence interval 0.36–0.91) [52]. A study in 1054 Swedish participants with varying degrees of glucose tolerance had different findings. In 219 type-2 diabetic patients, the Gln27 variant was seen more frequently than in 237 matched nondiabetic participants (59.8 vs. 52.3%; OR=1.72, P=0.02). Glu27 homozygous individuals had the lowest prevalence of diabetes [53]. In a case-control genetic association study of 161 healthy Whites and 74 African–Americans, Gln27 homozygotes compared to Glu27 carriers tended toward higher insulin levels and greater insulin resistance as determined by homeostasis model assessment of insulin resistance [54]. Similarly, a cohort of 102 black South African women found that the Glu27 isoform was associated with higher insulin resistance among obese individuals [55].

Homozygotes of the Gln27 variant in the presence of Arg16 had increased risk of obesity [41], whereas the Glu27 was also associated with increased BMI in African– Americans and Hispanic Americans [56]. Another study reported that the Glu27 receptor was a risk factor for abdominal obesity among males, particularly among those with low HDL cholesterol [57]. A meta-analysis of 23 populations reported variable association results across the different populations, with a summary of OD showing no association between this polymorphism and obesity [44]. However, the prevalence of Glu27 ranged from 6.71 to 78.29% across the populations, so that the polymorphism encoding this isoform is significantly associated with obesity in race groups with low frequency of this allele such as Asians, Pacific Islanders, and American– Indians, but not European populations, in which this allele is highly prevalent.

A cohort of 1050 Whites were evaluated to determine if ADRB2 polymorphisms would predict the occurrence of metabolic abnormalities in hypertensive patients given a β-blocker (atenolol 50–100 mg or metoprolol 100–200 mg daily) for 6 months. They found the Glu27 variant was associated with a higher incidence of dyslipidemia [58], which has been found by other groups as well [59] where heterozygous Gln27Glu hypertensive patients had an increase in triglyceride levels following use of 100 mg metoprolol daily for 2 months and also after use of propranolol in healthy individuals [60]. These data are similar to others, with others [61,62] who observed the same association of the Glu27 variant and hypertriglyceridemia.

ADRB2: Thr164Ile; 730C > T (rs1800888)

As mentioned in an earlier section, the Thr164Ile variant is less common than the Arg16Gly and Gln27Glu amino acid changes. The estimated frequency of the allele encoding the Ile164 isoform is 1% in Whites, less than 2% in Africans, and nonpolymorphic in Chinese [10]. Receptors containing the Ile164 variant showed a substantial decrease in basal and epinephrine-stimulated adenylyl cyclase activities because of defective coupling of the receptor to the stimulatory G protein, Gs, and impaired agonist-promoted sequestration. Ile164 also displayed a lower binding affinity for epinephrine as compared with the wild-type beta2-AR [8]. Consequently, this amino acid change has been associated with reduced response to the long-acting beta2-agonist salmeterol [8,63].

In-vivo studies found that an increase in heart rate and contractibility mediated by beta2-AR in response to terbutaline is blunted in individuals heterozygous for Ile164 compared with those homozygous for Thr164 [64]. A potential association between the Ile164 variant and hypertension was found only in women in a large cross-sectional study with 9185 participants [65]. The impact of the Thr to Ile change at codon 164 on death or heart transplantation in heart failure is not clear at this time because of conflicting results. A prospective cohort study of 257 patients found that those with the Ile164 variant were at higher risk for death or heart transplantation in 1 year (event rate 76%) compared to patients homozygous for Thr164 [16]. However, the Ile164 variant was not associated with these outcomes, but may interact with β-blocker treatment in a recent prospective cohort study with 443 heart failure patients [17]. The low frequency of the Ile164 isoform and unmeasured confounders may have contributed to the conflicting results. Impact of the Thr164Ile substitution on the outcomes in patients who received percutaneous coronary intervention has also been studied. In a prospective cohort study with 330 patients, those carrying the Ile164 variant were 3.7 times more likely to have cardiac death and 4.1 times more likely to have a major cardiac adverse event than patients homozygous for Thr164 after percutaneous coronary intervention [66]. The higher incidences of acute MI and a major cardiac adverse event have been replicated in a separate cohort of 150 patients with peripheral arterial disease [28]. Overall, the roles of the Thr164Ile variant in cardiovascular outcomes have not been well defined. Because of the low allele frequency, studies with larger sample sizes would help define the effect of this amino acid substitution on the clinical outcomes of cardiovascular diseases.

Conclusion

Variants in the ADRB2 gene encoding beta2-AR have been correlated with variable response to drugs for asthma and cardiovascular medications as well as disease risks such as type-2 diabetes, obesity and hypertension. However, the directions of these correlations differ across studies and remain to be replicated in larger studies. A meta-analysis by Contopoulos-Ioannidis et al. reported that most associations between the two common polymorphisms in ADRB2 and asthma drug response and other asthma related phenotypes are statistically insignificant because of small sample sizes and less than 2% of the associations were replicated by two or more groups [67]. In addition, correlations between these variants and beta2-agonists may be specific to short-acting beta2-agonists, and not affect response to long-acting drugs. Pharmacogenetic correlations may also be affected by the interval of drug treatment (regular use or use as needed) and interactions with other medications. Furthermore, these associations may also be specific to certain ethnicities and subject to sex effects. Cagliani et al. described ethnicity-specific and sex-based haplotype distributions of the ADRB2 variants [68]. Similar findings were reported in a meta-analysis by Jalba et al. which resulted in differences in association across populations [44]. Moreover, the relative fitness associated with these haplotypes varies under the influence of epistasis and imprinting. Experiment techniques that can directly access the functional importance of beta-adrenoceptor polymorphisms on ligand-induced conformation changes (e.g. fluorescence resonance energy transfer) will also help clarify the discrepancies with respect to the role of these polymorphisms in disease susceptibilities and therapeutic responses [69].

References

1. Kobilka BK, Dixon RA, Frielle T, Dohlman HG, Bolanowski MA, Sigal IS, et al. cDNA for the human beta 2-adrenergic receptor: a protein with multiple membrane-spanning domains and encoded by a gene whose chromosomal location is shared with that of the receptor for platelet-derived growth factor. Proc Natl Acad Sci U S A. 1987;84:46–50. [PubMed]
2. Postma DS, Bleecker ER, Amelung PJ, Holroyd KJ, Xu J, Panhuysen CI, et al. Genetic susceptibility to asthma–bronchial hyperresponsiveness coinherited with a major gene for atopy. N Engl J Med. 1995;333:894–900. [PubMed]
3. Hawkins GA, Tantisira K, Meyers DA, Ampleford EJ, Moore WC, Klanderman B, et al. Sequence, haplotype, and association analysis of ADRbeta2 in a multiethnic asthma case-control study. Am J Respir Crit Care Med. 2006;174:1101–1109. [PMC free article] [PubMed]
4. Ortega VE, Montealegre F, Chardon D, Meyers DA, Diallo AF, Bleecker ER. Sequencing of the beta2 adrenergic receptor gene in the Puerto Ricans with asthma. Am J Respir Crit Care Med. 2007;175:665–684.
5. Reihsaus E, Innis M, MacIntyre N, Liggett SB. Mutations in the gene encoding for the beta 2-adrenergic receptor in normal and asthmatic subjects. Am J Respir Cell Mol Biol. 1993;8:334–339. [PubMed]
6. Green SA, Turki J, Innis M, Liggett SB. Amino-terminal polymorphisms of the human beta 2-adrenergic receptor impart distinct agonist-promoted regulatory properties. Biochemistry. 1994;33:9414–9419. [PubMed]
7. Green SA, Turki J, Bejarano P, Hall IP, Liggett SB. Influence of beta 2-adrenergic receptor genotypes on signal transduction in human airway smooth muscle cells. Am J Respir Cell Mol Biol. 1995;13:25–33. [PubMed]
8. Green SA, Cole G, Jacinto M, Innis M, Liggett SB. A polymorphism of the human beta 2-adrenergic receptor within the fourth transmembrane domain alters ligand binding and functional properties of the receptor. J Biol Chem. 1993;268:23116–23121. [PubMed]
9. Leineweber K, Heusch G. beta(1) and beta(2)-Adrenoceptor polymorphisms and cardiovascular diseases. Br J Pharmacol. 2009;158:61–69. [PubMed]
10. Maxwell TJ, Ameyaw MM, Pritchard S, Thornton N, Folayan G, Githang’a J, et al. Beta-2 adrenergic receptor genotypes and haplotypes in different ethnic groups. Int J Mol Med. 2005;16:573–580. [PubMed]
11. Contopoulos-Ioannidis DG, Manoli EN, Ioannidis JP. Meta-analysis of the association of beta2-adrenergic receptor polymorphisms with asthma phenotypes. J Allergy Clin Immunol. 2005;115:963–972. [PubMed]
12. Thakkinstian A, McEvoy M, Minelli C, Gibson P, Hancox B, Duffy D, et al. Systematic review and meta-analysis of the association between beta2- adrenoceptor polymorphisms and asthma: a HuGE review. Am J Epidemiol. 2005;162:201–211. [PubMed]
13. Migita O, Noguchi E, Jian Z, Shibasaki M, Migita T, Ichikawa K, et al. ADRB2 polymorphisms and asthma susceptibility: transmission disequilibrium test and meta-analysis. Int Arch Allergy Immunol. 2004;134:150–157. [PubMed]
14. Hawkins GA, Weiss ST, Bleecker ER. Clinical consequences of ADRbeta2 polymorphisms. Pharmacogenomics. 2008;9:349–358. [PubMed]
15. Lanfear DE, Jones PG, Marsh S, Cresci S, McLeod HL, Spertus JA. Beta2-adrenergic receptor genotype and survival among patients receiving beta-blocker therapy after an acute coronary syndrome. JAMA. 2005;294:1526–1533. [PubMed]
16. Liggett SB, Wagoner LE, Craft LL, Hornung RW, Hoit BD, McIntosh TC, Walsh RA. The Ile164 beta2-adrenergic receptor polymorphism adversely affects the outcome of congestive heart failure. J Clin Invest. 1998;102:1534–1539. [PMC free article] [PubMed]
17. Littlejohn MD, Palmer BR, Richards AM, Frampton CM, Pilbrow AP, Troughton RW, et al. Ile164 variant of beta2-adrenoceptor does not influence outcome in heart failure but may interact with beta blocker treatment. Eur J Heart Fail. 2008;10:55–59. [PubMed]
18. Martinez FD, Graves PE, Baldini M, Solomon S, Erickson R. Association between genetic polymorphisms of the beta2-adrenoceptor and response to albuterol in children with and without a history of wheezing. J Clin Invest. 1997;100:3184–3188. [PMC free article] [PubMed]
19. Lima JJ, Thomason DB, Mohamed MH, Eberle LV, Self TH, Johnson JA. Impact of genetic polymorphisms of the beta2-adrenergic receptor on albuterol bronchodilator pharmacodynamics. Clin Pharmacol Ther. 1999;65:519–525. [PubMed]
20. Choudhry S, Ung N, Avila PC, Ziv E, Nazario S, Casal J, et al. Pharmacogenetic differences in response to albuterol between Puerto Ricans and Mexicans with asthma. Am J Respir Crit Care Med. 2005;171:563–570. [PubMed]
21. Martin AC, Zhang G, Rueter K, Khoo SK, Bizzintino J, Hayden CM, et al. Beta2-adrenoceptor polymorphisms predict response to beta2-agonists in children with acute asthma. J Asthma. 2008;45:383–388. [PubMed]
22. Tsai HJ, Shaikh N, Kho JY, Battle N, Naqvi M, Navarro D, et al. Beta 2-adrenergic receptor polymorphisms: pharmacogenetic response to bronchodilator among African American asthmatics. Hum Genet. 2006;119:547–557. [PubMed]
23. Taylor DR, Epton MJ, Kennedy MA, Smith AD, Iles S, Miller AL, et al. Bronchodilator response in relation to beta2-adrenoceptor haplotype in patients with asthma. Am J Respir Crit Care Med. 2005;172:700–703. [PubMed]
24. Drysdale CM, McGraw DW, Stack CB, Stephens JC, Judson RS, Nandabalan K, et al. Complex promoter and coding region beta 2-adrenergic receptor haplotypes alter receptor expression and predict in vivo responsiveness. Proc Natl Acad Sci U S A. 2000;97:10483–10488. [PubMed]
25. Telleria JJ, Blanco-Quiros A, Muntion S, Antonio Garrote J, Arranz E, Armentia A, et al. Tachyphylaxis to beta2-agonists in Spanish asthmatic patients could be modulated by beta2-adrenoceptor gene polymorphisms. Respir Med. 2006;100:1072–1078. [PubMed]
26. Summerhill E, Leavitt SA, Gidley H, Parry R, Solway J, Ober C. Beta(2)-adrenergic receptor Arg16/Arg16 genotype is associated with reduced lung function, but not with asthma, in the Hutterites. Am J Respir Crit Care Med. 2000;162:599–602. [PubMed]
27. Israel E, Chinchilli VM, Ford JG, Boushey HA, Cherniack R, Craig TJ, et al. Use of regularly scheduled albuterol treatment in asthma: genotypestratified, randomised, placebo-controlled cross-over trial. Lancet. 2004;364:1505–1512. [PubMed]
28. Dishy V, Sofowora GG, Xie HG, Kim RB, Byrne DW, Stein CM, Wood AJ. The effect of common polymorphisms of the beta2-adrenergic receptor on agonist-mediated vascular desensitization. N Engl J Med. 2001;345:1030–1035. [PubMed]
29. Bruck H, Leineweber K, Park J, Weber M, Heusch G, Philipp T, Brodde OE. Human beta2-adrenergic receptor gene haplotypes and venodilation in vivo. Clin Pharmacol Ther. 2005;78:232–238. [PubMed]
30. Wagoner LE, Craft LL, Singh B, Suresh DP, Zengel PW, McGuire N, et al. Polymorphisms of the beta(2)-adrenergic receptor determine exercise capacity in patients with heart failure. Circ Res. 2000;86:834–840. [PubMed]
31. De Groote P, Helbecque N, Lamblin N, Hermant X, Mc Fadden E, Foucher-Hossein C, et al. Association between beta-1 and beta-2 adrenergic receptor gene polymorphisms and the response to beta-blockade in patients with stable congestive heart failure. Pharmacogenet Genomics. 2005;15:137–142. [PubMed]
32. Forleo C, Resta N, Sorrentino S, Guida P, Manghisi A, De Luca V, et al. Association of beta-adrenergic receptor polymorphisms and progression to heart failure in patients with idiopathic dilated cardiomyopathy. Am J Med. 2004;117:451–458. [PubMed]
33. Shin J, Lobmeyer MT, Gong Y, Zineh I, Langaee TY, Yarandi H, et al. Relation of beta(2)-adrenoceptor haplotype to risk of death and heart transplantation in patients with heart failure. Am J Cardiol. 2007;99:250–255. [PubMed]
34. Sehnert AJ, Daniels SE, Elashoff M, Wingrove JA, Burrow CR, Horne B, et al. Lack of association between adrenergic receptor genotypes and survival in heart failure patients treated with carvedilol or metoprolol. J Am Coll Cardiol. 2008;52:644–651. [PubMed]
35. Kim SH, Kim DJ, Seo IA, Min YK, Lee MS, Kim KW, Lee MK. Significance of beta2-adrenergic receptor gene polymorphism in obesity and type 2 diabetes mellitus in Korean subjects. Metabolism. 2002;51:833–837. [PubMed]
36. Gjesing AP, Andersen G, Burgdorf KS, Borch-Johnsen K, Jorgensen T, Hansen T, Pedersen O. Studies of the associations between functional beta2-adrenergic receptor variants and obesity, hypertension and type 2 diabetes in 7808 white subjects. Diabetologia. 2007;50:563–568. [PubMed]
37. Chang TJ, Tsai MH, Jiang YD, Lee B, Lee KC, Lin JY, et al. The Arg16Gly polymorphism of human beta2-adrenoreceptor is associated with type 2 diabetes in Taiwanese people. Clin Endocrinol (Oxf) 2002;57:685–690. [PubMed]
38. Ikarashi T, Hanyu O, Maruyama S, Souda S, Kobayashi C, Abe E, et al. Genotype Gly/Gly of the Arg16Gly polymorphism of the beta2-adrenergic receptor is associated with elevated fasting serum insulin concentrations, but not with acute insulin response to glucose, in type 2 diabetic patients. Diabetes Res Clin Pract. 2004;63:11–18. [PubMed]
39. Masuo K, Katsuya T, Fu Y, Rakugi H, Ogihara T, Tuck ML. Beta2- adrenoceptor polymorphisms relate to insulin resistance and sympathetic overactivity as early markers of metabolic disease in nonobese, normotensive individuals. Am J Hypertens. 2005;18:1009–1014. [PubMed]
40. Bengtsson K, Orho-Melander M, Melander O, Lindblad U, Ranstam J, Rastam L, Groop L. Beta(2)-adrenergic receptor gene variation and hypertension in subjects with type 2 diabetes. Hypertension. 2001;37:1303–1308. [PubMed]
41. Pereira AC, Floriano MS, Mota GF, Cunha RS, Herkenhoff FL, Mill JG, Krieger JE. Beta2 adrenoceptor functional gene variants, obesity, and blood pressure level interactions in the general population. Hypertension. 2003;42:685–692. [PubMed]
42. Hayakawa T, Nagai Y, Kahara T, Yamashita H, Takamura T, Abe T, et al. Gln27Glu and Arg16Gly polymorphisms of the beta2-adrenergic receptor gene are not associated with obesity in Japanese men. Metabolism. 2000;49:1215–1218. [PubMed]
43. Ishiyama-Shigemoto S, Yamada K, Yuan X, Ichikawa F, Nonaka K. Association of polymorphisms in the beta2-adrenergic receptor gene with obesity, hypertriglyceridaemia, and diabetes mellitus. Diabetologia. 1999;42:98–101. [PubMed]
44. Jalba MS, Rhoads GG, Demissie K. Association of codon 16 and codon 27 beta 2-adrenergic receptor gene polymorphisms with obesity: a metaanalysis. Obesity (Silver Spring) 2008;16:2096–2106. [PubMed]
45. Wu HM, Bai H, Fan P, Liu R, Liu Y, Liu BW. Analysis of beta2-adrenergic receptor gene (beta2AR) Arg16Gly polymorphism in patients with endogenous hypertriglyceridemia in Chinese population. Zhonghua Yi Xue Yi Chuan Xue Za Zhi. 2008;25:50–54. [PubMed]
46. Tseng ZH, Aouizerat BE, Pawlikowska L, Vittinghoff E, Lin F, Whiteman D, et al. Common beta-adrenergic receptor polymorphisms are not associated with risk of sudden cardiac death in patients with coronary artery disease. Heart Rhythm. 2008;5:814–821. [PMC free article] [PubMed]
47. Lemaitre RN, Heckbert SR, Sotoodehnia N, Bis JC, Smith NL, Marciante KD, et al. beta1- and beta2-adrenergic receptor gene variation, beta-blocker use and risk of myocardial infarction and stroke. Am J Hypertens. 2008;21:290–296. [PubMed]
48. Khalaila JM, Elami A, Caraco Y. Interaction between beta2 adrenergic receptor polymorphisms determines the extent of isoproterenol-induced vasodilatation ex vivo. Pharmacogenet Genomics. 2007;17:803–811. [PubMed]
49. Wallerstedt SM, Eriksson AL, Ohlsson C, Hedner T. Haplotype association analysis of the polymorphisms Arg16Gly and Gln27Glu of the adrenergic beta2 receptor in a Swedish hypertensive population. J Hum Hypertens. 2005;19:705–708. [PubMed]
50. Kaye DM, Smirk B, Williams C, Jennings G, Esler M, Holst D. Beta-adrenoceptor genotype influences the response to carvedilol in patients with congestive heart failure. Pharmacogenetics. 2003;13:379–382. [PubMed]
51. Yamada K, Ishiyama-Shigemoto S, Ichikawa F, Yuan X, Koyanagi A, Koyama W, Nonaka K. Polymorphism in the 5′-leader cistron of the beta2-adrenergic receptor gene associated with obesity and type 2 diabetes. J Clin Endocrinol Metab. 1999;84:1754–1757. [PubMed]
52. Pinelli M, Giacchetti M, Acquaviva F, Cocozza S, Donnarumma G, Lapice E, et al. Beta2-adrenergic receptor and UCP3 variants modulate the relationship between age and type 2 diabetes mellitus. BMC Med Genet. 2006;7:85. [PMC free article] [PubMed]
53. Carlsson M, Orho-Melander M, Hedenbro J, Groop LC. Common variants in the beta2-(Gln27Glu) and beta3-(Trp64Arg)–adrenoceptor genes are associated with elevated serum NEFA concentrations and type II diabetes. Diabetologia. 2001;44:629–636. [PubMed]
54. Lima JJ, Feng H, Duckworth L, Wang J, Sylvester JE, Kissoon N, Garg H. Association analyses of adrenergic receptor polymorphisms with obesity and metabolic alterations. Metabolism. 2007;56:757–765. [PMC free article] [PubMed]
55. Rooyen JM, Pretorius PJ, Britz M, Huisman HW, Schutte AE, Towers GW, et al. Genetic polymorphisms of beta2 and beta3-adrenergic receptor genes associated with characteristics of the metabolic syndrome in black South African women. Exp Clin Endocrinol Diabetes. 2008;116:236–240. [PubMed]
56. Lange LA, Norris JM, Langefeld CD, Nicklas BJ, Wagenknecht LE, Saad MF, Bowden DW. Association of adipose tissue deposition and beta-2 adrenergic receptor variants: the IRAS family study. Int J Obes (Lond) 2005;29:449–457. [PubMed]
57. Corbalan MS, Marti A, Forga L, Martinez-Gonzalez MA, Martinez JA. Beta(2)-adrenergic receptor mutation and abdominal obesity risk: effect modification by gender and HDL-cholesterol. Eur J Nutr. 2002;41:114–118. [PubMed]
58. Iaccarino G, Trimarco V, Lanni F, Cipolletta E, Izzo R, Arcucci O, et al. Beta-blockade and increased dyslipidemia in patients bearing Glu27 variant of beta2 adrenergic receptor gene. Pharmacogenomics J. 2005;5:292–297. [PubMed]
59. Isaza CA, Henao J, Sanchez JC, Porras GL, Cardona J, Bedoya G. Beta-2-adrenergic receptor polymorphisms and changes in lipids induced by metoprolol. Pharmacology. 2007;80:279–285. [PubMed]
60. Isaza C, Henao J, Ramirez E, Cuesta F, Cacabelos R. Polymorphic variants of the beta2-adrenergic receptor (ADRB2) gene and ADRB2-related propanolol-induced dyslipidemia in the Colombian population. Methods Find Exp Clin Pharmacol. 2005;27:237–244. [PubMed]
61. Iwamoto N, Ogawa Y, Kajihara S, Hisatomi A, Yasutake T, Yoshimura T, et al. Gln27Glu beta2-adrenergic receptor variant is associated with hypertriglyceridemia and the development of fatty liver. Clin Chim Acta. 2001;314:85–91. [PubMed]
62. Ehrenborg E, Skogsberg J, Ruotolo G, Large V, Eriksson P, Arner P, Hamsten A. The Q/E27 polymorphism in the beta2-adrenoceptor gene is associated with increased body weight and dyslipoproteinaemia involving triglyceride-rich lipoproteins. J Intern Med. 2000;247:651–656. [PubMed]
63. Green SA, Rathz DA, Schuster AJ, Liggett SB. The Ile164 beta(2)-adrenoceptor polymorphism alters salmeterol exosite binding and conventional agonist coupling to G(s) Eur J Pharmacol. 2001;421:141–147. [PubMed]
64. Brodde OE, Buscher R, Tellkamp R, Radke J, Dhein S, Insel PA. Blunted cardiac responses to receptor activation in subjects with Thr164Ile beta(2)-adrenoceptors. Circulation. 2001;103:1048–1050. [PubMed]
65. Sethi AA, Tybjaerg-Hansen A, Jensen GB, Nordestgaard BG. 164Ile allele in the beta2-adrenergic receptor gene is associated with risk of elevated blood pressure in women. The Copenhagen City Heart Study. Pharmacogenet Genomics. 2005;15:633–645. [PubMed]
66. Piscione F, Iaccarino G, Galasso G, Cipolletta E, Rao MA, Brevetti G, et al. Effects of Ile164 polymorphism of beta2-adrenergic receptor gene on coronary artery disease. J Am Coll Cardiol. 2008;52:1381–1388. [PubMed]
67. Contopoulos-Ioannidis DG, Alexiou GA, Gouvias TC, Ioannidis JP. An empirical evaluation of multifarious outcomes in pharmacogenetics: beta-2 adrenoceptor gene polymorphisms in asthma treatment. Pharmacogenet Genomics. 2006;16:705–711. [PubMed]
68. Cagliani R, Fumagalli M, Pozzoli U, Riva S, Comi GP, Torri F, et al. Diverse evolutionary histories for beta-adrenoreceptor genes in humans. Am J Hum Genet. 2009;85:64–75. [PubMed]
69. Ahles A, Engelhardt S. Polymorphisms determine beta-adrenoceptor conformation: implications for cardiovascular disease and therapy. Trends Pharmacol Sci. 2009;30:188–193. [PubMed]