Blood Pressure

Genetic markers which identify individuals who decrease their blood pressure through exercise

Blood Pressure Abstract
Methods of reducing blood pressure levels in hypertensive subjects through the identification of subjects with an allele and/or genotype at a gene locus that positively correlates with improved success in reducing blood pressure levels, as compared to other alleles and/or genotypes at the same gene locus, and through the engagement of these subjects in exercise training for a period of time sufficient for the reduction of the subjects' blood pressure levels.

Blood Pressure Claims
We claim:

1. A method of reducing blood pressure levels in a hypertensive subject, the method comprising:

identifying a hypertensive subject having an allele and/or genotype at the LPL gene PvuII and HindIII restriction sites, the ACE gene insertion site, and/or the angiotensinogen M235T site which positively correlate to a higher reduction of blood pressure levels as a result of exercise, as compared with other alleles and/or genotypes at the same gene locus; and

engaging the subject in exercise training for a period of time sufficient to reduce blood pressure levels in the subject.

2. A method of reducing blood pressure levels in a subject in need of such reduction, the method comprising:

identifying a subject having a "+/+" genotype for a PvuII restriction site in a lipoprotein lipase gene, wherein the subject is in need of reduced blood pressure levels; and

engaging the subject in extensive exercise training for a period of time sufficient to reduce the blood pressure levels in the subject.

3. A method of reducing blood pressure levels in a subject in need of such reduction, the method comprising:

identifying a subject having at least one "-" allele or a "+/-" or "-/-" genotype for a PvuII restriction site in a lipoprotein lipase gene, wherein the subject is in need of reduced blood pressure levels; and

engaging the subject in limited exercise training for a period of time sufficient to reduce the blood pressure levels in the subject.

4. A method of reducing blood pressure levels in a subject in need of such reduction, the method comprising:

identifying a subject having at least one "+" allele or a "+/+" or "+/-" genotype for a HindIII restriction site in a lipoprotein lipase gene, wherein the subject is in need of reduced blood pressure levels; and

engaging the subject in extensive exercise training for a period of time sufficient to reduce the blood pressure levels in the subject.

5. A method of reducing blood pressure levels in a subject in need of such reduction, the method comprising:

identifying a subject having a "+/-" genotype for a HindIII restriction site in a lipoprotein lipase gene, wherein the subject is in need of reduced blood pressure levels; and

engaging the subject in limited exercise training for a period of time sufficient to reduce the blood pressure levels in the subject.

6. A method of reducing blood pressure levels in a subject in need of such reduction, the method comprising:

identifying a subject having at least one "I" allele or an "I/I" or "I/D" genotype for an angiotensin converting enzyme gene, wherein the subject is in need of reduced blood pressure levels; and

engaging the subject in extensive exercise training for a period of time sufficient to reduce the blood pressure levels in the subject.

7. A method of reducing blood pressure levels in a subject in need of such reduction, the method comprising:

identifying a subject having a "I/I" or "D/D" genotype for an angiotensin converting enzyme gene, wherein the subject is in need of reduced blood pressure levels; and

engaging the subject in limited exercise training for a period of time sufficient to reduce the blood pressure levels in the subject.

8. A method of reducing blood pressure levels in a subject in need of such reduction, the method comprising:

identifying a subject having a "I/I" genotype for an angiotensin converting enzyme gene, wherein the subject is in need of reduced blood pressure levels; and

engaging the subject in moderate exercise training for a period of time sufficient to reduce the blood pressure levels in the subject.

9. A method of reducing blood pressure levels in a subject in need of such reduction, the method comprising:

identifying a subject having a "T/T" or "M/M" genotype for an angiotensinogen gene, wherein the subject is in need of reduced blood pressure levels; and

engaging the subject in extensive exercise training for a period of time sufficient to reduce the blood pressure levels in the subject.

10. A method of reducing systolic blood pressure levels in a subject in need of such reduction, the method comprising:

identifying a subject having a "T/T" genotype for an angiotensinogen gene, wherein the subject is in need of reduced systolic blood pressure levels; and

engaging the subject in extensive exercise training for a period of time sufficient to reduce the systolic blood pressure levels in the subject.

11. A method of reducing diastolic blood pressure levels in a subject in need of such reduction, the method comprising:

identifying a subject having a "M/M" genotype for an angiotensinogen gene, wherein the subject is in need of reduced diastolic blood pressure levels; and

engaging the subject in extensive exercise training for a period of time sufficient to reduce the diastolic blood pressure levels in the subject.

12. A method of reducing blood pressure levels in a subject in need of such reduction, the method comprising:

identifying a subject having a "T/T" genotype for an angiotensinogen gene, wherein the subject is in need of reduced blood pressure levels; and

engaging the subject in limited exercise training for a period of time sufficient to reduce the blood pressure levels in the subject.

Blood Pressure Description
FIELD OF THE INVENTION

The present invention relates to identifying one or more genetic markers which correlate with improved success in reducing blood pressure levels in hypertensive individuals.

BACKGROUND OF THE INVENTION

Studies have shown that individuals suffering from hypertension can alleviate symptoms or otherwise improve their conditions through exercise. 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. The present inventors hypothesized that upon identifying the genetic makeup of a hypertensive population and observing that some individuals of the population lower their blood pressure from a change of behavior to a much greater or lesser extent than expected, a correlation could be made between the presence or absence of certain genetic markers and success in reducing blood pressure levels.

An object of the present invention is to identify one or more genetic markers which positively correlate with improved success in reducing blood pressure levels in hypertensive individuals.

SUMMARY OF THE INVENTION

The present inventors have discovered a number of genetic markers which positively correlate with improved success in reducing blood pressure levels in hypertensive individuals, as compared with other genetic makeup at the same gene loci. Therefore, the present invention is directed to a method of reducing blood pressure levels in a subject in need of such reduction, the method comprising:

identifying a subject having an allele and/or genotype at a particular gene locus which positively correlates with improved success in reducing blood pressure levels in hypertensive individuals, as compared with other alleles and/or genotypes at the same gene locus, wherein the subject is in need of reduced blood pressure levels, and

engaging the subject in exercise training for a period of time sufficient to reduce blood pressure levels in the subject.

DETAILED DESCRIPTION OF THE INVENTION

The inventors have found that a number of genetic markers positively correlate with improved success in reducing blood pressure levels in hypertensive individuals, as compared with other genetic makeup at the same gene loci. Markers which the inventors have investigated include the lipoprotein lipase (LPL) gene PvuII and HindIII restriction sites, the angiotensin converting enzyme (ACE) gene insertion site, and the angiotensinogen M235T site.

The term "blood pressure" includes systolic blood pressure, diastolic blood pressure and mean blood pressure. A "reduction in blood pressure" may mean a reduction in systolic blood pressure and/or diastolic blood pressure and/or mean blood pressure. Such a reduction may include daytime blood pressure and/or nighttime blood pressure, or the reduction may be unrelated to time of day.

The term "single course of exercise", as used throughout this application, means a cardiovascular exercise session of any type which is conducted during one day. An exercise session may comprise an aerobics class, treadmill training, step machine, or any other suitable cardiovascular exercise regimen. For most cases, exercise may be completed in, for example, 30 minutes to 3 hours, with optional brief rest periods of 3-15 minutes, however this amount would vary depending on the health and endurance of the subject.

The term "extensive exercise" means about 10 single courses of exercise or more, preferably at least 15, at least 20, or at least 25 single courses of exercise, over a defined period of time ("the exercise period"). The exercise period in the case of an extensive exercise protocol may be from about 30-400 days, preferably from about 50-350 days or 70-300 days.

The term "limited exercise" means about 5 single courses of exercise or less, preferably at most 3, or 1 single course of exercise, over the exercise period. The exercise period in the case of a limited exercise protocol may be about 12 days or less, preferably at most 10, at most 7, or at most 5 days. It is most preferred that the limited exercise period be at most 3 days.

The term "moderate exercise" means about 5-9 single courses of exercise, preferably about 6-8, or 7 single courses of exercise, over the exercise period. The exercise period in the case of a limited exercise protocol may be from about 5-50 days, preferably from about 5-30 days, 5-20 days, or 5-15 days.

The time between exercise periods depends on whether the exercise period is an extensive, limited or moderate exercise period. In the case of extensive exercise periods, the time between exercise periods may be from about 10-120 days or more. In the case of limited exercise periods, the time between exercise periods may be from 4-60 days or more. In the case of moderate exercise periods, the time between exercise periods may be from 6-90 days or more. The term "between exercise periods" means that time during which the subject is not in an extensive, limited or moderate exercise program.

Lipoprotein lipase (LPL) is an enzyme that catalyzes the breakdown of triglycerides in the plasma to release free fatty acids. This hydrolysis also influences the metabolism of circulating lipoproteins. LPL has also been shown to enhance the triglyceride-rich chylomicron binding to low-density lipoprotein receptor-related proteins. Thus, LPL may also be an important regulator of chylomicron metabolism. The LPL gene is located on human chromosome 8p22. It is approximately 35 kilobases long and has 10 functionally differentiated exons. Two primary polymorphic variations occur at the LPL gene locus in frequencies that are important on a population basis. These two variations are detected by PvuII and HindIII restriction sites. There are three genotypes at each site, with the alleles for both PvuII and HindIII restriction sites denoted as "+" or "-", based on the presence or absence of a restriction site on that allele at the LPL locus with PvuII or HindIII. Thus, for both PvuII and HindIII there are three genotypes: +/+, +/- and -/-.

The present inventors have discovered that hypertensive individuals with different PvuII genotypes exhibit different degrees of success in reducing their blood pressure levels through exercise. These results could not have been predicted from initial patient screening.

The inventors have surprisingly discovered that each PvuII genotype potentially can benefit from exercise, however, the amount of exercise which produces the most benefits varies according to genotype. Specifically, the inventors have found that subjects having a "+/+" genotype for a PvuII restriction site exhibit more reduction in blood pressure levels than those with "+/-" or "-/-" genotypes, after extensive exercise. However, those subjects having "+/-" or "-/-" genotypes exhibit more reduction in blood pressure levels than those with "+/+" genotypes, after limited exercise.

Therefore, one method of reducing blood pressure levels in a subject in need of such reduction according to the invention comprises identifying a subject having a "+/+" genotype for a PvuII restriction site in a lipoprotein lipase gene, wherein the subject is in need of reduced blood pressure levels; and engaging the subject in extensive exercise training for a period of time sufficient to reduce the blood pressure levels in the subject.

Another method of reducing blood pressure levels in a subject in need of such reduction according to the invention comprises identifying a subject having at least one "-" allele or a "+/-" or "-/-" genotype for a PvuII restriction site in a lipoprotein lipase gene, wherein the subject is in need of reduced blood pressure levels; and engaging the subject in limited exercise training for a period of time sufficient to reduce the blood pressure levels in the subject.

The present inventors have also discovered that hypertensive individuals with different HindIII genotypes exhibit different degrees of success in reducing their blood pressure levels through exercise. These results could not have been predicted from initial patient screening.

The inventors have found that those individuals having "+/+" or "+/-" genotype for a HindIII restriction site exhibit more reduction in blood pressure levels than those with "-/-" genotypes, after extensive exercise. In addition, those subjects having "+/-" genotypes exhibit more reduction in blood pressure levels than those with "+/+" genotypes, after limited exercise.

Therefore, an additional method of reducing blood pressure levels in a subject in need of such reduction according to the invention comprises identifying a subject having at least one "+" allele or a "+/+" or "+/-" genotype for a HindIII restriction site in a lipoprotein lipase gene, wherein the subject is in need of reduced blood pressure levels; and engaging the subject in extensive exercise training for a period of time sufficient to reduce the blood pressure levels in the subject.

Another method of reducing blood pressure levels in a subject in need of such reduction according to the invention comprises identifying a subject having a "+/-" genotype for a HindIII restriction site in a lipoprotein lipase gene, wherein the subject is in need of reduced blood pressure levels; and engaging the subject in limited exercise training for a period of time sufficient to reduce the blood pressure levels in the subject.

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: "I/I", "I/D" and "D/D". 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 will clearly contribute 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.

The present inventors have discovered that hypertensive individuals with different ACE genotypes exhibit different degrees of success in reducing their blood pressure levels through exercise. These results could not have been predicted from initial patient screening.

The inventors have found that those individuals having "I/I" or "I/D" genotype for an ACE gene exhibit more reduction in blood pressure levels than those with "D/D" genotypes, after extensive exercise. However, those subjects having "I/I" or "D/D" genotypes exhibit more reduction in blood pressure levels than those with "I/D" genotypes, after limited exercise. In addition, those subjects having "I/I" genotypes exhibit more reduction in blood pressure levels than those with "I/D" or "D/D" genotypes, after moderate exercise.

Therefore, an additional method of reducing blood pressure levels in a subject in need of such reduction according to the invention comprises identifying a subject having at least one "I" allele or an "I/I" or "I/D" genotype for an ACE gene, wherein the subject is in need of reduced blood pressure levels; and engaging the subject in extensive exercise training for a period of time sufficient to reduce the blood pressure levels in the subject.

Another method of reducing blood pressure levels in a subject in need of such reduction according to the invention comprises identifying a subject having a "I/I" or "D/D" genotype for an ACE gene, wherein the subject is in need of reduced blood pressure levels; and engaging the subject in limited exercise training for a period of time sufficient to reduce the blood pressure levels in the subject.

Yet another method of reducing blood pressure levels in a subject in need of such reduction according to the invention comprises identifying a subject having a "I/I" genotype for an ACE gene, wherein the subject is in need of reduced blood pressure levels; and engaging the subject in moderate exercise training for a period of time sufficient to reduce the blood pressure levels in the subject.

Angiotensinogen (AGT) is the circulating protein substrate from which renin cleaves angiotensin I. AGT in the circulation originates in the liver. Human AGT is a glycoprotein with a molecular weight of approximately 57,000.

The method of the invention uses genetic variations at the M235T site (amino acid at position 235 changed from methionine (AUG) to threonine (ACG)) at the AGT gene locus to identify hypertensive persons who will reduce their blood pressure with exercise training. The inventors have found that hypertensives homozygous for either the "T" or the "M" allele decrease blood pressure more with extensive exercise training than those heterozygous at this loci. Hypertensives with the AGT "T/T" genotype decrease their systolic blood pressure more than those with the "M/M" or "M/T" genotype, while hypertensives with "M/M" genotype decrease their diastolic blood pressure more than those with the "T/T" or "M/T" genotype, with extensive exercise. In addition, those subjects having "T/T" genotype exhibit more reduction in blood pressure levels than those with "M/T" genotype, after limited exercise.

Therefore, a method of reducing blood pressure levels in a subject in need of such reduction according to the invention comprises identifying a subject having a "T/T" or "M/M" genotype for an AGT gene, wherein the subject is in need of reduced blood pressure levels; and engaging the subject in extensive exercise training for a period of time sufficient to reduce the blood pressure levels in the subject.

A method of reducing systolic blood pressure levels in a subject in need of such reduction according to the invention comprises identifying a subject having a "T/T" genotype for an AGT gene, wherein the subject is in need of reduced systolic blood pressure levels; and engaging the subject in extensive exercise training for a period of time sufficient to reduce the systolic blood pressure levels in the subject.

A method of reducing diastolic blood pressure levels in a subject in need of such reduction according to the invention comprises identifying a subject having a "M/M" genotype for an AGT gene, wherein the subject is in need of reduced diastolic blood pressure levels; and engaging the subject in extensive exercise training for a period of time sufficient to reduce the diastolic blood pressure levels in the subject.

Another method of reducing blood pressure levels in a subject in need of such reduction according to the invention comprises identifying a subject having a "T/T" genotype for an AGT gene, wherein the subject is in need of reduced blood pressure levels; and engaging the subject in limited exercise training for a period of time sufficient to reduce the blood pressure levels in the subject.