Chemistry: molecular biology and microbiology – Measuring or testing process involving enzymes or... – Involving nucleic acid
Reexamination Certificate
2001-11-13
2004-06-01
Johannsen, Diana B. (Department: 1634)
Chemistry: molecular biology and microbiology
Measuring or testing process involving enzymes or...
Involving nucleic acid
C435S091200, C536S023200, C536S023500
Reexamination Certificate
active
06743587
ABSTRACT:
FIELD OF THE INVENTION
The present invention relates to identifying an ACE genotype which correlate with improved success in sodium excretion in hypertensive individuals engaged in exercise training.
BACKGROUND OF THE INVENTION
Regular endurance exercise has been shown to lower blood pressure in hypertensive patients (see, e.g., Hagberg et al.,
J. Cardiov. Risk
, vol. 2, pp. 296 et seq., 1995) and is widely recommended as an initial non-pharmacological treatment. One of the potential mechanisms underlying this effect of exercise training is an increase in sodium excretion. Unfortunately, some individuals, no matter how rigorously they exercise, are unable to improve their conditions, while others benefit to a much greater extent than predicted. These results underscore the fact that many factors contribute to an individual's well-being. Such factors include, for example, behaviors such as diet and exercise, genetic makeup, and environment. While behavior and environment can be controlled, altered or regulated, an individual's genetic makeup is essentially predetermined and set at birth.
Angiotensin converting enzyme (ACE) is the enzyme responsible for catalyzing the conversion of angiotensin I, a relatively inactive tissue and plasma vasopressor hormone, into the potent and highly active vasopressor hormone angiotensin II. This cascade of reactions is part of the renin-angiotensin-aldosterone system that has long been known to be an important regulator of arteriolar relaxation and vasoconstriction, and hence blood pressure, in humans and animals. The ACE gene is polymorphic with two common alleles designated “I” and “D”, resulting in three genotypes: “II”, “ID” and “DD”. The “D” allele has a 287-base pair marker in intron 16 of the ACE gene deleted, whereas the “I” allele has the 287-base pair marker inserted. The “D” allele is associated with increased levels of ACE in both plasma and ventricular tissues. Increased levels of ACE contributes to increased myocardial and vascular smooth muscle growth and increased arteriolar vasoconstriction. Thus, the presence of the “D” allele is hypothesized to have deleterious effects on the cardiovascular system, and, in fact, the “D” allele has been associated with increased risk of left ventricular hypertrophy, cardiovascular disease, and sudden cardiovascular death. Prior studies have sought to determine if an association exists between ACE “DD” genotype and blood pressure regulation. Results from human studies have been mixed, with most studies unable to identify an association between ACE gene variants and blood pressure in Caucasian and African Americans. (Schunkert et al.,
Hypertension
, vol.29, pp. 628 et seq., 1997; Rotimi et al.,
Hypertension
, vol. 24, pp. 591 et seq., 1994.) However, one study found an association between hypertension and the “D” allele in African Americans. (Duru et al.
Am. J. Hypertension
, vol. 7, pp. 759 et seq., 1994.)
Published PCT application WO 99/45383 (Hagberg et al.) discloses that hypertensive individuals with different ACE genotypes exhibited different degrees of success in reducing their blood pressure levels through exercise. The results were dependent on the duration of the exercise protocol. The inventors found that those individuals having an “II” or “ID” genotype exhibited more reduction in blood pressure levels than those with a “DD” genotype, after the long-term exercise protocol. However, after the most short-term exercise protocol, those subjects having “II” or “DD” genotypes exhibited more reduction in blood pressure levels than those with “ID” genotypes. After a limited exercise protocol that was more extensive than the short-term exercise protocol, those subjects having an “II” genotype exhibit more reduction in blood pressure levels than those with “ID” or “DD” genotypes.
In a separate study, it was reported that sodium excretion rate in African American hypertensive women increased 37% after 7 days of exercise. (Brown et al.,
Hypertension
, vol. 30, pp. 1549 et seq., 1997.) However, no genotyping was reported in this study, and thus there was no identification with respect to whether those individuals with a certain genotype derived more benefit from the exercise. An object of the present invention is to identify those hypertensive individuals who are more likely to benefit from exercise in increasing sodium excretion, based on their genotype.
SUMMARY OF THE INVENTION
The present inventors have discovered that the angiotensin converting enzyme (ACE) gene serves as a genetic marker which positively correlates with improved success in increasing sodium excretion levels in hypertensive individuals. Specifically, the inventors have found that those individuals possessing the “II” ACE genotype increased their sodium excretion levels significantly more than those individuals possessing either the “ID” or “DD” ACE genotype. The present invention is directed to a method of increasing sodium excretion levels in a hypertensive subject, comprising:
identifying a hypertensive subject having an II genotype for an angiotensin converting enzyme gene; and
engaging the subject in limited exercise training for a period of time sufficient to increase the subject's sodium excretion levels.
REFERENCES:
patent: 6399306 (2002-06-01), Hagberg et al.
patent: WO 99/45383 (1999-09-01), None
Donoghue, M. et al. A novel angiotensin-converting enzyme-related carboxypeptidase (ACE2) converts angiotensin I to angiotensin 1-9. Circulation Research 87(5):e1-e9 (Sep. 2000).*
Kingwell, B.A. et al. Effects of walking and other exercise programs upon blood pressure in normal subjects. Medical Journal of Australia 158(4):234-238 (Feb. 1993).*
Hagberg, J.M. et al. Effect of exercise training in 60- to 69-year-old persons with essential hypertension. American Journal of Cardiology 64(5):348-353 (Aug. 1989).*
Urata, H. et al. Antihypertensive and volume-depleting effects of mild exercise on essential hypertension. Hypertension 9(3):245-252 (Mar. 1987).*
Brown, et al., “Improvement of Insuline Sensitivity by Short-term Exercise Training in Hypertensive African American Women”, Hypertension, vol. 30, No. 6, pp. 1549-1553 Dec. 1997.
Brown Michael
Ferrell Robert
Hagberg James
Arent & Fox PLLC
Johannsen Diana B.
University of Maryland
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