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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.