Chemistry: molecular biology and microbiology – Measuring or testing process involving enzymes or... – Involving nucleic acid
Reexamination Certificate
2001-03-16
2003-07-01
Eyler, Yvonne (Department: 1609)
Chemistry: molecular biology and microbiology
Measuring or testing process involving enzymes or...
Involving nucleic acid
C435S091100, C435S091200, C536S023500
Reexamination Certificate
active
06586183
ABSTRACT:
FIELD OF THE INVENTION
This invention relates to the fields of genomics and pharmacogenetics. More specifically, the present invention relates to polymorphisms and haplotypes of the &bgr;
2
-adrenergic receptor gene and their use as predictors of disease susceptibility and response to &bgr;-agonists.
BACKGROUND OF THE INVENTION
The &bgr;
2
-adrenergic receptor (&bgr;
2
AR) is a G protein coupled receptor that mediates the actions of catecholamines in multiple tissues and thus plays important roles in regulating cardiac, vascular, pulmonary, and metabolic functions. An abnormal level of expression of &bgr;
2
AR is believed to be a risk factor for or to modify the severity of a number of diseases and conditions, including congestive heart failure, arrhythmia, ischemic heart disease, hypertension, migraine, asthma, chronic obstructive pulmonary disease (COPD), anaphylaxis, obesity, diabetes, myasthenia gravis, and premature labor.
The &bgr;
2
AR is encoded by an intronless gene on chromosome 5q31-32 Kobilka, B. K. et al.,
Proc. Natl. Acad. Sci., USA
84:46-50, 1987). Several single nucleotide polymorphisms (SNPs) in the coding block of the &bgr;
2
AR gene that lead to significant genetic variability in the structure of the &bgr;
2
AR protein in the human population have been reported (Reihsaus, E. et al.,
Am J Resp Cell Mol Biol
8:334-339, 1993; Liggett, S. B.,
News in Physiologic Sciences
10:265-273, 1995; and GenBank accession numbers AF022953.1 GI:2570526; AF022954.1 GI:2570528; and AF022956.1 GI:2570532). These SNPs are located at nucleotides 46 (A or G), 79 (C or G), and 491 (C or T) of the &bgr;
2
AR coding sequence, and result in variation that occurs in the amino-terminus of the receptor at amino acids 16 (Arg or Gly) and 27 (Gln or Glu) and in the fourth transmembrane spanning domain at amino acid 164 (Thr or Ile), respectively. These amino acid variants have clear phenotypic differences as demonstrated by recombinant cell studies (Green, S. A. et al.,
Biochem
33:9414-9419, 1994; Green, S. A., et al.,
J Biol Chem
268:23116-23121, 1993), primary cultures of cells endogenously expressing these variants (Green, S. A., et al.,
Am J Resp Cell Mol Biol
13:25-33, 1995), and transgenic mice overexpressing the Thr164 or Ile164 receptors in the heart (Turki et al.,
Proc. Nat. Acad. Sci., USA
93:10483-10488, 1996). In addition, a synonymous polymorphism of C or A at nucleotide 523 in the coding sequence has been reported to be associated with altered responsiveness to salbutamol in Japanese families (Ohe, M. et al.,
Thorax
50:353-359, 1995).
In addition to the above polymorphisms in the coding block, several SNPs in the 5′ promoter region have recently been identified and are located at nucleotides −1023 (A or G), −654 G or A), −468 (C or G), −367 (T or C), −47 (C or T) and −20 (T or C) (Scott, M. G. H. et al.,
Br J Pharmacol
126:841-844, 1999). Thus, eleven polymorphic sites have previously been identified in the region of the &bgr;
2
AR gene located between nucleotides 565 and 2110 of GenBank Accession No. M15169.1 (see
FIG. 1
(SEQ ID NO:1)).
Messenger RNA transcripts of the &bgr;
2
AR gene have a 5′ leader region harboring a short open reading frame (ORF), termed the &bgr;
2
AR 5′-leader cistron (5′LC), that encodes a 19 amino acid peptide (Kobilka, B. K. et al.,
J. Biol. Chem.:
262:7321-7327, 1996). This &bgr;
2
AR upstream peptide (BUP) modulates translation of &bgr;
2
AR mRNA, and thereby regulates cellular expression of the receptor (Parola, A. L. et al.,
J Biol Chem
269:4497-4505, 1994). The polymorphic site located at −47, described above, is in this 5′LC and results in either Arg or Cys being encoded at the terminal amino acid position 19) of the BUP. It was recently reported that the Cys19 variant of the BUP is associated with greater &bgr;
2
AR expression than the Arg19 BUP variant (McGraw et al.,
J. Clin. Invest.
102:1927-1932, 1998).
Several groups have suggested associations between some of the above &bgr;
2
AR amino acid variants and increased susceptibility to various conditions, including: high blood pressure (Gly16 variant, Hoit et al.,
Am Heart J
139:537-542, 2000; Gratze et al.,
Hypertension
33:1425-1430, 1999 and Kotanko, P. et al.,
Hypertension
30:773-776, 1997; cf. Arg16 variant, Busjahn et al.,
Hypertension
35:555-560, 2000); atopy (Gly16 variant, Dewar et al.,
Clin. Exp. Allergy
28:442-448, 1998); nocturnal asthma (Gly16 variant, Turki et al.,
J. Clin. Invest.
95:1635-1641, 1995); response to treatment for obesity (Gly16 variant, Sakane et al.,
Lancet
353:1976, 1999); myasthenia gravis (Arg16 variant, Xu, B. -Y. et al.,
Clin. & Exp. Immunol.
119:156-160, 2000); childhood asthma (Gln27 variant, Dewar et al.,
J. Allergy Clin. Immun.
100:261-265, 1997); obesity (Glu27 variant, Large et al.,
J. Clin. Invest.
100:3005-3013, 1997); and mortality from congestive heart failure (Ile164 variant, Liggett et al.,
J. Clin. Invest.
102:1534-1539, 1998).
Several of the polymorphic sites (PS) in the &bgr;
2
AR gene have been reported to be in linkage disequilibrium with each other, including between the +46 and +79 PS (Martinez et al.,
J. Clin. Invest.
100:261-265, 1997; Dewar et al., supra), between the −47, +46 and +79 PS (McGraw et al., supra), between the −47, −20, +46, and +79 PS (Yamada et al., J. Clin. Endocrinol. Metab. 84:1754-1757, 1999), and between the +79 and +523 PS (Dewar et al., Clin. and Exp. Allergy 28:442-448, 1998). In addition, associations between various in vivo phenotypes and haplotypes for various combinations of these polymorphic sites have been suggested: obesity and a −47 C/−20 C haplotype (Yamada et al., supra), asthma severity and a +46G/+79G haplotype (which encodes the Gly16/Gln27 variant) (Weir et al.,
Am J. Resp. Crit Care Med.
158:787-791, 1998); bronchial hyperresponsiveness (BHR) and a +46 G/+79 G haplotype (D'amato et al.,
Am. J. Resp. Crit. Care Med.
158:1968-1973, 1998); hypertension and a −47 T/+46 A/+79 C haplotype, and the following expanded version thereof: −1023 G/−654 A/−47 T/−20 C/+46 A/+79 C (Timmerman et al.
Kidney Int.
53:1455-1460, 1998; WO 99/37761). An association between reduced &bgr;
2
AR promoter activity in vitro and a haplotype of −468 G/−367 C/−47 C/−20 C has also been reported (Scott et al.,
Br. J. Pharmacol.
126:841-844, 1999). However, no haplotypes covering more than six of the above 11 sites have been reported.
It has also been suggested that some of the &bgr;
2
AR gene polymorphisms discussed above may act as disease modifiers in asthma or may be the basis for the known interindividual variation in the bronchodilating response to &bgr;-agonists (Liggett, S. B. “The genetics of &bgr;
2
-adrenergic receptor polymorphisms: relevance to receptor function and asthmatic phenotypes.” in: Liggett, S. B. & Meyers, D. A.,
The Genetics of Asthma (
1996) pp. 455-478). Indeed, two groups have reported that individuals homozygous or heterozygous for the Arg16 variant are more likely to respond to albuterol than individuals homozygous for the Gly16 variant. (Martinez, F. D. et al.,
J Clin Invest
100:3184-3188, 1997 and Lima, J. J., et al.,
Clin Pharmacol Ther
65:519-525, 1999). It has also been reported that asthmatic individuals who are homozygous for the Arg16 variant are more likely to exhibit decreased response to repeated use of albuterol (Drazen et al., WO 98/39477). Interestingly, another group reported bronchodilator desensitization in asthmatics homozygous for the Gly16 variant following continuous therapy with the &bgr;-agonist formoterol (Tan et al.,
Lancet
350:995-999, 1997). Other studies failed to demonstrate any correlations between adverse drug response and regular treatment with &bgr;-agonists (Hancox, R. J. et al.,
Eur Respir J
11:589-593, 1998; Lipworth, B. J. et al.,
Clinical Science
96:253-259, 199
Drysdale Connie M.
Judson Richard S.
Liggett Stephen B.
Nandabalan Krishnan
Stack Catherine B.
Carlson Gisela F.
Eyler Yvonne
Genaissance Pharmaceuticals, Inc.
Henderson Melodie W.
Murphy Joseph F.
LandOfFree
Association of &bgr;2-adrenergic receptor haplotypes with... does not yet have a rating. At this time, there are no reviews or comments for this patent.
If you have personal experience with Association of &bgr;2-adrenergic receptor haplotypes with..., we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and Association of &bgr;2-adrenergic receptor haplotypes with... will most certainly appreciate the feedback.
Profile ID: LFUS-PAI-O-3099578