Annotated PGx Gene Information for ADRB2

Citation: Very important pharmacogene summary ADRB2. Litonjua AA, Gong L, Duan QL, Shin J, Moore MJ, Weiss ST, Johnson JA, Klein TE, Altman RB.
Pharmacogenet Genomics. 20(1):64-69, January 2010. PMID: 19927042.

PharmGKB VIP Submitted by: Gus Litonjua, Li Gong, Qing Ling Duan, Jaekyu Shin, Mariellen J. Moore, Scott T. Weiss, Julie A. Johnson (PHAT, PharmGKB and PEAR)
PharmGKB VIP Reviewed by: Reviewed
PharmGKB VIP Submission date: March 22, 2006
PharmGKB VIP Updated: Dec 2, 2009

Gene HGNC Name:	ADRB2
Gene Common Name:	Beta-2-AR
Introductory Information:	The beta-2-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 [PMID: 3025863,7666875]. 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 (cAMP). This, in turn, activates protein kinase A, leading to the phosphorylation and downregulation of proteins including beta2-AR itself (please refer to PharmGKB Beta-agonist and Beta-blocker Pathway for further details. 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. such as carvedilol and propranolol) are among the mostly commonly prescribed medications in the treatment of asthma and cardiovascular disease, respectively. While 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 that 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 has been identified, of which 45 single nucleotide polymorphisms (SNPs) and 2 insertion/deletion polymorphisms have been validated in more than one study [PMID: 16931635]. Two of these non-synonomous 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 [PMID: 8383511]. In vitro studies demonstrated that the Gly16 isoform enhanced the agonist-stimulated downregulation of beta2-AR, while the Glu27 variant did not regulate the expression of this receptor [PMID: 7915137,7598936]. In addition to these common polymorphisms, other less common, non-synonymous 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 wildtype Thr164 [PMID: 7901205,19422376]. Another rare, nonsynonymous variant resulting in a Valine to Methionine change at amino acid position 34 (Val34Met) in beta2-AR has a MAF <1% [PMID: 16142389]. 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 non-synonymous SNPs in ADRB2 have concluded that these polymorphisms are not associated with the diagnosis of asthma [PMID: 15153795,15867853,15987731]. However, homozygotes of Arg16 treated with regular short acting beta-agonist (SABA) therapy tend to experience more adverse effects [PMID: 18303970]. 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%) [PMID: 16189366]. Congestive heart failure 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 while others did not observe this finding [PMID: 9788966,18068431]. Common ADRB2 haplotypes were not associated with adverse clinical outcome (all cause mortality, non-fatal MI and non-fatal stroke) in patients with coronary artery diseases who were treated with either beta-blocker-based or calcium channel blocker-based strategy [PMID: 18615004].None of the major ADRB2 genotypes or haplotypes was associated with the increased risk of MI or ischemic stroke in patients with pharmacologically treated hypertension. In addition, none of the genetic variants interacted with beta blocker use [PMID: 18219297]. None of the major ADRB2 genotypes (Arg16Gly and Glu27Gln) or haplotypes (Gly16Glu27, Arg16Gln27 and Gly16Gln27) was associated with the increased risk of sudden cardiac death and ventricular arrhythmias in patients with coronary artery disease [PMID: 18534365]. After receiving percutaneous coronary intervention, patients carrying Ile164 variant were 3.7 times more like to have cardiac death and 4.1 times more likely to have a major cardiac adverse event (cardiac death, acute MI, new PCI, CABG, and CHF) than those homozygous for Thr164 [PMID: 18940527]. Studies have produced conflicting results as to the association of the Arg16Gln27 haplotype with the risk of death or cardiac transplantation in heart failure patients. While one study reported patients carrying two copies of the haplotype had a 91% increased risk of the adverse outcomes compared with those who did not carry the haplotype, others did not observe the association [PMID: 17223428, 18702968]. The differences may be explained in part by the percent of patients treated with beta-blockers. 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 due to small sample sizes and less than 2% of the associations were replicated by two or more groups [PMID: 17001289]. 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 gender effects. Cagliani et al described ethnicity-specific and sex-based haplotype distributions of the ADRB2 variants [PMID: 19576569]. Similar finding were reported in a meta-analysis by Jalba et al, which resulted in differences in association across populations [PMID: 19186333]. 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 (eg. Fluorescence resonance energy transfer (FRET)) will also help clarify the discrepancies with respect to the role of these polymorphisms in disease susceptibilities and therapeutic responses [PMID: 19272658].
Key PubMed IDs:	3025863, 15867853, 15987731, 15153795, 16189366, 9788966, 18068431, 18615004, 18219297, 18534365, 18940527, 17223428, 18702968
Key Pathways:	Beta-agonist and Beta-blocker Pathway
Drugs/Substrates:	Albuterol [PMID: 15500895]; beta blockers [PMID: 16189366]
Phenotypes/Diseases:	Asthma [PMID:15867853, 15987731, 15153795]; Acute coronary syndrome [PMID: 16189366]; Heart failure [PMID: 9788966, 18068431, 17223428, 18702968]; Coronary artery disease [PMID: 18615004, 18534365, 18940527]; Hypertension [PMID: 18219297]; Ocular pressure [PMID: 18625943]
Important Variants:	ADRB2:16Arg>Gly , ADRB2:27Glu>Gln , ADRB2:164 Thr>Ile

PharmGKB® is a registered trademark of HHS and is financially supported by NIH/NIGMS. It is managed at Stanford University (GM61374).
©2001-2010 PharmGKB.