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Journal of the American College of Cardiology © 2008 by the American College of Cardiology Foundation Published by Elsevier Inc. EDITORIAL COMMENT Beta2-Adrenergic Receptor Gene Polymorphisms Will the Important One Please Step Forward?* Martin C. Michel, MD,† Rainer Büscher, MD‡ Amsterdam, the Netherlands; and Essen, Germany Beta2-adrenergic receptors (B2ARs) contribute to the regulation of many physiological functions in, for example, blood vessels, the heart, airways, and the uterus. They also are the molecular target of clinically important drugs, particularly in the treatment of obstructive airway disease. The human gene encoding the B2AR resides on chromosome 5q31-32. However, at least 12 single nucleotide polymorphisms (SNPs) in the coding and several more in the promoter region have been identified (1). Many of these are synonymous SNPs and/or have not been well characterized at the molecular level or in clinical association studies. Most reported studies relate to the nonsynonymous polymorphisms arginine at position 16 replaced by glycine (Arg16Gly) and glutamine at position 27 replaced by glutamic acid (Gln27Glu) and, more rarely, threonine at position 164 replaced by isoleucine (Thr164Ile). Even though polymorphisms in positions 16 and 27 may be associated with altered treatment responses in some cases, association studies have not consistently implicated them alone or as part of haplotypes in the pathophysiology of cardiovascular or airway disease (1–3). See page 1381 In this issue of the Journal, Piscione et al. (4) report that the Thr164Ile SNP of the B2AR gene is associated with coronary and peripheral artery disease. The Thr164Ile polymorphism is infrequent in the general population of various ethnicities, typically being present in ⬍4% in its heterozygous form, and subjects homozygous for the isoleucine at position 164 (Ile164) genotype may not exist (1). Despite its limited prevalence, this SNP may be important *Editorials published in the Journal of the American College of Cardiology reflect the views of the authors and do not necessarily represent the views of JACC or the American College of Cardiology. From the †Department of Pharmacology and Pharmacotherapy, Academic Medical Center, University of Amsterdam, Amsterdam, the Netherlands; and the ‡Department of Pediatrics II, University of Duisburg-Essen, Essen, Germany. Vol. 52, No. 17, 2008 ISSN 0735-1097/08/$34.00 doi:10.1016/j.jacc.2008.07.040 as it has consistently been shown in transfected cells (4 – 6) or in native cells from genotyped subjects (7–9) that the Ile164 variant is hypofunctional: that is, it produces smaller cellular responses upon agonist stimulation. This hyporesponsiveness is not explained by altered expression levels but rather is due to an intrinsically impaired signaling capacity of the receptor variant. Accordingly, mice transgenic for the Ile164 genotype exhibit smaller adenylyl cyclase, heart rate, and inotropic responses than those transgenic for threonine at position 164 (Thr164) (10). Taken together, these data consistently establish the Ile164 variant of the B2AR as hypofunctional. To assess the clinical relevance of the Thr164Ile polymorphism, both disease association and drug response studies have been performed. Association studies have been hampered by the low prevalence of the Thr164Ile polymorphism, which necessitates large patient groups to reach robust conclusions. With regard to arterial hypertension, Ile164 was associated with an increased risk for high blood pressure in women (but not men) of 1 large (9,185 subjects) Danish population study (11), whereas no such association between genotype at this locus and blood pressure was observed in a smaller Italian population (775 hypertensive patients) study (12), the lack of association in the latter possibly reflecting the limited statistical power of a smaller population. Piscione et al. (4) now report that Ile164 is much more prevalent in a population of coronary artery disease patients than in a control population (12% vs. 3%), and that within the patient group, Ile164 carriers exhibit a more severe pathology than those with Thr164 genotype. Similarly, a group of patients with peripheral artery disease also exhibited a high prevalence of the Ile164 genotype (7%) and a more severe clinical phenotype than those with Thr164 (4). An early report on reduced survival in patients with congestive heart failure carrying 1 Ile164 allele (13) was confirmed in 1 (14) but not 2 other studies (15,16). Thus, in line with its hypofunctional properties in vitro, the Ile164 genotype is associated with clinical phenotypes reflecting a reduced vasodilation in most studies. Although B2AR can affect cardiac function in some settings (17), this role may be insufficient to yield consistent associations of the Thr164Ile polymorphism with heart failure. However, the Thr164Ile polymorphism may not only have pathophysiological but also therapeutic relevance. Thus, inotropy and heart rate responses to infusions of the B2AR agonist terbutaline were reduced in Ile164 carriers, and such findings were obtained in both healthy volunteers (18,19) and heart failure patients (14). Similarly, studies using the dorsal hand vein model reported impaired vasodilation in healthy Ile164 carriers; this was based on a lower agonist potency, whereas maximum dilation responses to local agonist infusion were not affected (20,21). Reduced B2AR responses of Ile164 carriers were also reported for lipolysis in isolated adipocytes (7), inhibition of histamine release from mast cells (9), and airway dilation and lympho- 1390 Michel and Büscher B2AR Polymorphisms cyte cyclic adenosine monophosphate formation in cystic fibrosis patients (8). Accordingly, the B2AR were proposed to be disease-modifying genes in cystic fibrosis (22). Taken together, the available data demonstrate that the Ile164 variant of the B2AR is hypofunctional. This appears to be associated with cardiovascular disease states in which B2AR are considered to be important. Moreover, it is consistently associated with reduced functional responses to agonist stimulation in cardiovascular and other tissues. The latter finding most likely is most important therapeutically for airway disease but has only been studied to a limited extent in such patients. In a more general sense, these data demonstrate that infrequent gene polymorphisms with major effects on the function of the associated protein may be clinically more relevant, at least in the afflicted subjects, than more frequent polymorphisms that affect gene function to a more limited extent. Reprint requests and correspondence: Prof. Martin C. Michel, Department of Pharmacology and Pharmacotherapy, Academic Medical Center, Meibergdreef 15, 1105AZ Amsterdam, the Netherlands. E-mail: [email protected]. REFERENCES 1. Brodde O-E. -1 and -2 adrenoceptor polymorphisms: functional importance, impact on cardiovascular diseases and drug responses. Pharmacol Ther 2008;117:1–29. 2. Hahntow IN, Koopmans RP, Michel MC. The 2-adrenoceptor gene and hypertension: is it the promoter or the coding region or neither? J Hypertension 2006;24:1003–7. 3. Rosskopf D, Schürks M, Rimmbach C, Schäfers RF. Genetics of arterial hypertension and hypotension. Naunyn Schmiedebergs Arch Pharmacol 2007;374:429 – 69. 4. Piscione F, Iaccarino G, Galasso G, et al. Effects of Ile164 polymorphism of beta2-adrenergic receptor gene on coronary artery disease. J Am Coll Cardiol 2008;52:1381– 8. 5. Green SA, Cole G, Jacinto M, Innis M, Liggett SB. A polymorphisms of the human 2-adrenergic receptor within the fourth transmembrane domain alters ligand binding and functional properties of the receptor. J Biol Chem 1993;268:23116 –21. 6. Iaccarino G, Ciccarelli M, Sorriento D, et al. Ischemic neoangiogenesis enhanced by 2-adrenergic receptor overexpression. A novel role for the endothelial adrenergic system. Circ Res 2005;97:1182–9. 7. Hoffstedt J, Iliadou A, Pedersen NL, Schalling M, Arner P. The effect of the beta2 adrenoceptor gene Thr164Ile polymorphism on human adipose tissue lipolytic function. Br J Pharmacol 2001;133:708 –12. JACC Vol. 52, No. 17, 2008 October 21, 2008:1389–90 8. Büscher R, Eilmes KJ, Grasemann H, et al. 2 adrenoceptor gene polymorphisms in cystic fibrosis lung disease. Pharmacogenetics 2002; 12:347–53. 9. Kay LJ, Chong LK, Rostami-Hodjegan A, Peachell PT. Influence of the Thr164Ile polymorphism in the 2-adrenoceptor on the effects of -adrenoceptor agonists on human lung mast cells. Int Immunopharmacol 2003;3:91–5. 10. Turki J, Lorenz JN, Green SA, Donnelly ET, Jacinto M, Liggett SB. Myocardial signaling defects and impaired cardiac function of a human 2-adrenergic receptor polymorphism expressed in transgenic mice. Proc Natl Acad Sci U S A 1996;93:10483– 8. 11. Sethi AA, Tybjaerg-Hansen A, Jensen GB, Nordestgaard BG. 164Ile allele in the 2-adrenergic receptor gene is associated with risk of elevated blood pressure in women. The Copenhagen City Heart Study. Pharmacogenet Genomics 2005;15:633– 45. 12. Iaccarino G, Lanni F, Cipolletta E, et al. The Glu27 allele of the 2 adrenergic receptor increases the risk of cardiac hypertrophy in hypertension. J Hypertension 2004;22:2117–22. 13. Liggett SB, Wagoner LE, Craft LL, et al. The Ile164 2-adrenergic receptor polymorphism adversely affects the outcome of congestive heart failure. J Clin Invest 1998;102:1534 –9. 14. Barbato E, Penicka M, Delrue L, et al. The Ile164 polymorphism of 2-adrenergic receptor negatively modulates cardiac contractility: implications for prognosis of patients with idiopathic dilated cardiomyopathy. Heart 2007;93:856 – 61. 15. Forleo C, Resta N, Sorrentino S, et al. Association of -adrenergic receptor polymorphisms and progression to heart failure in patients with idiopathic dilated cardiomyopathy. Am J Med 2004;117:451– 8. 16. De Groote P, Lamblin N, Helbecque N, et al. The impact of beta-adrenoceptor gene polymorphisms on survival in patients with congestive heart failure. Eur J Heart Fail 2005;7:966 –73. 17. Brodde O-E, Michel MC. Adrenergic and muscarinic receptors in the human heart. Pharmacol Rev 1999;51:651– 89. 18. Brodde O-E, Büscher R, Tellkamp R, Radke J, Dhein S, Insel PA. Blunted cardiac responses to receptor activation in subjects with Thr164Ile 2-adrenoceptors. Circulation 2001;103:1048 –50. 19. Bruck H, Leineweber K, Ulrich A, et al. Thr164Ile polymorphism of the human 2-adrenoceptor exhibits blunted desensitization of cardiac functional responses in vivo. Am J Physiol 2003;285:H2034 – 8. 20. Dishy V, Landau R, Sofowora GG, et al. 2-adrenoceptor Thr164Ile polymorphism is associated with markedly decreased vasodilator and increased vasoconstrictor sensitivity in vivo. Pharmacogenetics 2004; 14:517–22. 21. Bruck H, Leineweber K, Park J, et al. Human 2-adrenergic receptor gene haplotypes and venodilation in vivo. Clin Pharmacol Ther 2005;78:232– 8. 22. Büscher R, Grasemann H. Disease modifying genes in cystic fibrosis: therapeutic option or one-way road? Naunyn Schmiedebergs Arch Pharmacol 2006;374:65–77. Key Words: beta2-adrenergic receptor y single nucleotide polymorphism y vasodilation.