&bgr;-adrenergic receptor polymorphisms

Details &bgr;-adrenergic receptor polymorphisms &bgr;-adrenergic receptor polymorphisms

1997-10-10

2002-12-24

Arthur, Lisa B. (Department: 1634)

Chemistry: molecular biology and microbiology

Measuring or testing process involving enzymes or...

Involving nucleic acid

C435S091200, C536S023500, C536S024300, C536S024310, C536S024330

Reexamination Certificate

active

06498009

ABSTRACT:

FIELD OF THE INVENTION
The invention relates to gene mutations that predispose an individual to cardiac disease, obesity, and diabetes. More specifically, the present invention relates to specific polymorphisms in the &bgr;
1
- and the &bgr;
2
-adrenergic receptor genes. The invention further relates to methods and molecules for identifying one or more polymorphisms in the &bgr;
1
- or the &bgr;
2
-adrenergic receptor genes.
BACKGROUND OF THE INVENTION
Beta adrenergic receptors (&bgr;AR) are the receptors for the endogenous catecholamines, epinephrine (adrenaline) and norepinephrine (noradrenaline). There are at least nine sub-types of adrenergic receptors (H. G. Dohlman et al.,
Annu. Rev. Biochem
. 60:653-688 (1991); S. B. Liggett et al., In:
Catecholamines, Bouloux
, ed. W. B. Sounders, London (1993)), of which at least three sub-types are &bgr;-adrenergic receptors.
The &bgr;
1
- and &bgr;
2
-adrenergic receptors (&bgr;
1
AR, &bgr;
2
AR) are expressed in many organs in the body, including heart, lung, vascular tissue, and pancreas (S. B. Ligget In:
The Lung: Scientific Foundations
, R. G. Crystal et al. (ed.) Lippincott-Raven Publishers, Philadelphia (1996); J. R. Carstairs et al.,
Am. Rev. Respir. Dis
. 132:541-547 (1985); Q. A. Hamid et al.,
Eur. J. Pharmacol
. 206:133-138 (1991)). In the heart, one or both of these receptors regulate heart rate and pumping function; in the lung the &bgr;AR regulate airway tone; in the vasculature they regulate vascular tone; in adipose tissue they regulate lipolysis; and in the pancreas they contribute to insulin release. These receptors mediate not only the actions of adrenaline and noradrenaline, but a host of synthetic agonists as well.
The &bgr;
1
adrenergic receptor has been cloned and sequenced (T. Frielle et al.,
Proc. Natl. Acad. Sci
. (
USA
) 84:7920-7924 (1987)). The gene has been localized to chromosome q24-q26 of chromosome 10 (T. L. Yang-Feng et al.,
Proc. Natl. Acad. Sci
. (
USA
) 87:1516-1520 (1990). The human &bgr;
1
AR has a deduced amino acid sequence of 477 amino acids and is structurally similar to the &bgr;
2
AR in many respects. Only a single polymorphism (identified by restriction fragment length polymorphism analysis (RFLP)) has been reported in the human &bgr;
1
AR (W. H. Berrettini, et al.,
Nucl. Acids Res
. 16:7754 (1988). To date, polymorphisms resulting in amino acid changes in the &bgr;
1
AR protein have not been reported.
The gene encoding the human &bgr;
2
AR has also been cloned and sequenced (B. K. Kobilka et al.,
Proc. Natl. Acad. Sci
. (
USA
) 84:46-50 (1987)). It is an intronless gene that has been localized to q31-q32 of chromosome 5. The deduced amino acid sequence consists of 413 amino acids, with seven clusters of hydrophobic residues thought to represent transmembrane spanning domains. The N-terminus is extracellular, containing two sites for asparagine-linked glycosylation. The transmembrane spanning domains are connected by three extracellular and three intracellular loops. The C-terminus is intracellular. Several polymorphisms in the &bgr;
2
AR gene sequence have been reported (E. Reihsaus et al.,
Am. J. Resp. Cell. Mol. Biol
. 8:334-339 (1993); K.-U. Lentes et al.,
Nucleic Acids Res
. 16:2359 (1988); and C. K. McQuitty et al.,
Hum. Genet
. 93:225 (1994)).
Polymorphisms in the &bgr;
2
AR have been studied in the context of asthma (E. Reihsaus et al.,
Am. J. Resp. Cell. Mol. Biol
. 8:334-339 (1993), herein incorporated by reference; K. J. Holroyd et al.,
Am. J. Respir. Crit. Care Med
. (Abstract) 151:A673 (1995); D. M. Cooper et al.,
Am. J. Respir. Crit. Care Med
. (Abstract) 153:A254 (1996); K. S. Tan et al.,
Am. J. Respir. Crit. Care Med
. (Abstract) 155:A208 (1997)). There appears to be no difference in the distribution of &bgr;
2
AR polymorphisms between individuals suffering from asthma and normal individuals. There is evidence, however, of an association between one polymorphism and more severe asthma (Reihsaus et al.). More recently, these polymorphisms have been shown to be associated with the nocturnal asthmatic phenotype (J. Turki et al.,
J. Clin. Invest
. 95:1635-1641 (1995)), bronchial hyper-reactivity (I. P. Hall et al.,
The Lancet
345:1213-1214 (1995)), and IgE levels (J. C. Dewar et al.,
J. Allergy Clin. Imm
. (In Press)). Using site directed mutagenesis and recombinant expression in fibroblasts, the pharmacologic properties of these variants have been assessed in vitro (S. A. Green et al.,
J. Biol. Chem
. 268:23116-23121 (1993); S. A. Green et al.,
Biochemistry
33:9414-9419 (1994))and in transgenic mice (J. Turki et al.,
Proc. Natl. Acad. Sci
. (
USA
) 93:10483-10488 (1996)).
Given the importance of the &bgr;
1
- and the &bgr;
2
-adrenergic receptors in modulating a variety of physiological functions, there is a need in the art for improved methods to identify these polymorphisms and to correlate the identity of these polymorphisms with the other functions of &bgr;-adrenergic receptors. The present invention addresses these needs and more by providing polymorphisms, molecules, and methods useful for the diagnosis and prognosis of cardiovascular diseases, obesity, and diabetes.


REFERENCES:
patent: 4965188 (1990-10-01), Mullis et al.
patent: 5679524 (1997-10-01), Nikiforov et al.
patent: 5766851 (1998-06-01), Shuldiner et al.
Stratagene pp. 83-90, 1993.*
Reihsaus et al., Am. J. Respir. Cell Mol. Biol. 8:334-339, Mar. 1993.*
Green et al., Am. J. Respir. Cell Mol. Biol. 13:25-33, Jul. 1995.*
Frielle et al., P.N.A.S, USA 84:7920-7924, Nov. 1987.*
Thon. Mutation Research 285:125-144, Jan. 1993.*
Berrettini et al Nucl. Acids Res. 16:7754, Aug. 1988.*
Turki et al. P.N.A.S., USA 93:10483-10488, Sep. 1996.*
Goodman and Gilman'sThe Pharmacological Basis of Therapuetics,Pergamon Press, 1990, New York, pp. 89-90.
Bristow et al.,Circulation Research59:297-309, 1986.
Liggett, S.B., L.E. Wagoner, L.L. Craft, R.W. Hornung, B.D. Hoit, T.C. McIntosh, R.A., Walsh. The Ile164 &bgr;2-adrenergic receptor polymorphism adversely affects the outcome of congetive heart failure. J. Clin Invest 102:1534-1539, 1998.
Timmermann, B., R. Mo, F.C. Luft, E. Gerdts, A. Busjahn, P. Omvik, G.-H. Li, H. Schuster, T.F. Wienker, M.R. Hoehe, and P. Lund-Johansen. 1998. &bgr;-2 Adrenoceptor genetic variation is asociated with genetic predisposition to essential hypertension: The Bergen Blood Pressure Study,Kidney International53:1455-1460.
Gratze, G., J. Fortin, R. Labugger, A. Binder, P. Kotanko, B. Timmermann, F.C. Luft, M.R. Hoehe, and F. Skrabal. 1999 &bgr;-2 Adrenergic Receptor Variants Affect Resting Blood Pressure and Agonist-Induced Vasodilation in Young Adult Caucasions.Hypertension33:1425-1430.
Ishiyama-Shigemoto, S., K. Yamada, X. Yuan, F. Ichikawa, and K. Nonaka. 1999, Association of polymorphisms in the &bgr;2-adrenergic receptor gene with obesity, hypertriglyceridaemia, and diabetes mellitus.Diabetologia42:98-101.
Large, V., L. Hellströam, S. Reynisdottir, F. Lönnqvist, P. Eriksson, L. Lannfelt, and P. Arner. 1997. Human Beta-2 Adrenoceptor Gene Polymorphisms are Highly Frequent in Obesity and Associate with Altered Adipocyte Beta-2 Adrenoceptor function.J. Clin Invest100:3005-3013.
Arner, P. and J. Hoffstedt. 1999. Adrenoceptor genes in human obesity.Journal of Internal Medicine245:667-672.
Sakane, N., T. Yoshida, T. Umekawa, A. Kogure, and M. Kondo. 1999. &bgr;2-adrenoceptor gene polymorphism and obesity.Lancet353:1976.
Meirhaeghe, A., N. Helbecque, D. Cottel, and P. Amouyel. 1999. &bgr;2-adrenoceptor gene polymorphism, body weight, and physical activity.Lancet353:896.
Hellström, L., V. Large, S. Reynisdottir, H. Wahrenberg, and P. Arner. 1999. The different effects of a Gln27 Glu &bgr;2-adrenoceptor gene polymorphism on obesity in males and in females.Journal of Internal Medicine245:253-259.
Mason, D.A., J.D. Moore, S.A. Green, and S.B. Liggett. 1999. A gain-of-function polymorphism in a G-protein coupling domain of the human &bgr;1-adrenergic receptor.J Biol Chem274:12670-12674.
Moore, J.D., D.A. Mason. S.A. Green, J.Hsu, and S.B. Liggett. 1999. Racial differences in the

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