Chemistry: molecular biology and microbiology – Measuring or testing process involving enzymes or... – Involving nucleic acid
Reexamination Certificate
1998-03-27
2001-03-06
Carlson, Karen Cochrane (Department: 1653)
Chemistry: molecular biology and microbiology
Measuring or testing process involving enzymes or...
Involving nucleic acid
C435S183000, C536S023100, C536S024310, C530S316000
Reexamination Certificate
active
06197505
ABSTRACT:
FIELD OF THE INVENTION
The present invention relates to genetic polymorphisms useful for assessing cardiovascular status in humans.
BACKGROUND OF THE INVENTION
The renin-angiotensin-aldosterone system (RAAS) plays an important role in cardiovascular physiology in mammals. Specifically, RAAS regulates salt-water homeostasis and the maintenance of vascular tone. Stimulation or inhibition of this system raises or lowers blood pressure, respectively, and disturbances in this system may be involved in the etiology of, for example, hypertension, stroke, and myocardial infarction. The RAAS system may also have other functions such as, e.g., control of cell growth. The renin-angiotensin system includes at least renin, angiotensin converting enzyme (ACE), angiotensinogen (AGT), type 1 angiotensin II receptor (AT1), and type 2 angiotensin II receptor (AT2).
AGT is the specific substrate of renin, an aspartyl protease. The human AGT gene contains five exons and four introns which span 13Kb (Gaillard et al.,
DNA
8:87-99, 1989; Fukamizu et al.,
J. Biol. Chem.
265:7576-7582, 1990). The first exon (37 bp) codes for the 5′ untranslated region of the mRNA. The second exon codes for the signal peptide and the first 252 amino acids of the mature protein. Exons 3 and 4 are shorter and code for 90 and 48 amino acids, respectively. Exon 5 contains a short coding sequence (62 amino acids) and the 3′-untranslated region.
Plasma AGT is synthesized primarily in the liver and its expression is positively regulated by estrogens, glucocorticoids, thyroid hormones, and angiotensin II (Ang II) (Clauser et al.,
Am. J. Hypertension
2:403-410, 1989). Cleavage of the amino-terminal segment of AGT by renin releases a decapeptide prohormone, angiotensin-I, which is firther processed to the active octapeptide angiotensin II by the dipeptidyl carboxypeptidase designated angiotensin-converting enzyme (ACE). Cleavage of AGT by renin is the rate-limiting step in the activation of the renin-angiotensin system.
Several epidemiological observations indicate a possible role of AGT in blood pressure regulation. A highly significant correlation between plasma AGT concentration and blood pressure has been observed in epidemiological studies (Walker et al.,
J. Hypertension
1:287-291, 1979). Interestingly, a number of allelic dimorphisms have been identified in the AGT gene. The frequency of at least two of them (174M and 235T) have been partially characterized and in certain populations shown to be significantly elevated in hypertensive subjects (Jeunemaitre et al.,
Cell
71:169-180, 1992). In addition, a specific polymorphism, 235T, has been suggested to be directly involved in coronary atherosclerosis (Ishigami et al.,
Circulation
91:951-4, 1995). Futhermore, the presence of A or G at position 1218 in the AGT regulatory region has been correlated with differences in in vitro transcriptional capacity for this gene (Inuoe et. al.,
J. Clin. Invest.
99:1786, 1997.
The human ACE gene is also a candidate as a marker for hypertension and myocardial infarction. ACE inhibitors constitute an important and effective therapeutic approach in the control of human hypertension (Sassaho et al.
Am. J. Med.
83:227-235, 1987). In plasma and on the surface of endothelial cells, ACE converts the inactive angiotensin I molecule (Ang I) into active angiotensin II (Ang II) (Bottari et al.,
Front. Neuroendocrinology
14:123-171, 1993). Another ACE substrate is bradykinin, a potent vasodilator and inhibitor of smooth muscle cell proliferation, which is inactivated by ACE (Ehlers et al.,
Biochemistry
28:5311-5318, 1989; Erdos, E. G.,
Hypertension
16:363-370, 1990; Johnston, C. I.
Drugs
(suppl. 1) 39:21-31, 1990).
Levels of ACE are very stable within individuals, but differ greatly between individuals. Plasma ACE levels have been suggested to be genetically determined as a consequence of diallelic polymorphisms, situated within or close to the ACE gene. Prior to the present invention, no definitive association was demonstrated between polymorphisms and hypertension or blood pressure. However, a greater risk of myocardial infarction has been identified in a group of subjects with an ACE polymorphism designated ACE-DD (Cambien et al.,
Nature
359:641-644, 1992), and a 12-fold greater risk of myocardial infarction has been identified in a subgroup of patients having a combination of the ACE polymorphism ACE-DD and one of the AGT polymorphisms (235T) described above (Kamitani et al.,
Hypertension
24:381, 1994). Recently, six ACE polymorphisms were identified and characterized (Villard et al.,
Am. J. Human Genet.
58:1268-1278, 1996).
The vasoconstrictive, cell growth-promoting and salt conserving actions of Ang II are mediated through binding to and activation of angiotensin receptors, of which at least two types have been cloned (AT1 and AT2). The type 1 Ang II receptor (AT1), a G-protein-coupled seven transmembrane domain protein, is widely distributed in the body and mediates almost all known Ang II effects (Fyhrquist et al.,
J. Hum. Hypertension
5:519-524, 1995).
Several polymorphisms have been identified in the AT1 receptor gene. Initial studies suggest that at least one of them is more frequent in hypertensive subjects (AT
1166
C)(Bonnardeaux et al.,
Hypertension
24:63-69, 1994). This polymorphism, combined with the ACE-DD polymorphism, has been shown to correlate strongly with the risk of myocardial infarction (Tiret et al.,
Lancet
344:910-913, 1994).
The high morbidity and mortality associated with cardiovascular disease demonstrate a need in the art for methods and compositions that allow the determination and/or prediction of the therapeutic regimen that will result in the most positive treatment outcome in a patient suffering from cardiovascular disease. This includes identification of individuals who are more or less susceptible to particular therapeutic regimens, including, e.g., particular drugs that are conventionally used to treat cardiovascular disease. There is also a need in the art for methods and compositions that allow the identification of individuals having a predisposition to cardiovascular disease, such as, e.g., myocardial infarction, hypertension, atherosclerosis, and stroke to facilitate early intervention and disease prevention.
SUMMARY OF THE INVENTION
The present invention provides methods for assessing cardiovascular status in a human individual. Cardiovascular status is the physiological status of the cardiovascular system as reflected in one or more status markers. Status markers include without limitation clinical parameters such as, e.g., blood pressure or electrocardiographic profile, as well as diagnoses of cardiovascular status made by skilled medical practitioners, such as, e.g., acute myocardial infarction, silent myocardial infarction, stroke, and atherosclerosis. Also included in the evaluation of cardiovascular status are changes in status markers with time. The methods of the invention are carried out by the steps of:
(i) determining the sequence of one or more polymorphic positions within one or more of the genes encoding angiotensin converting enzyme (ACE), angiotensinogen (AGT), and type 1 angiotensin II receptor (AT1) in the individual to establish a polymorphic pattern for the individual; and
(ii) comparing the polymorphic pattern established in (i) with the polymorphic patterns of individuals exhibiting predetermined markers of cardiovascular status. The polymorphic pattern of the individual is, preferably, highly similar and, most preferably, identical to the polymorphic pattern of individuals who exhibit particular status markers, cardiovascular syndromes, and/or particular patterns of response to therapeutic interventions.
For example, a comparison of the polymorphic pattern of an individual with the polymorphic patterns of individuals exhibiting differing responses to a particular therapeutic intervention can be used to predict the degree of responsivity of the individual to such intervention. In a similar manner, the methods of the invention can be used t
Andersson Maria Kristina
Lindström Per Harry Rutger
Norberg Leif Torbjörn
Carlson Karen Cochrane
Darby & Darby
Pyrosequencing AB
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