1. Project Title: Heart Disease Outcomes: Impact of Genetics and Pharmacogenetics

Principal Investigator:
Carl J. Pepine, M.D., Professor and Chairman,
Division of Cardiovascular Medicine

Julie A. Johnson, Pharm.D., Associate Professor,
Department of Pharmacy Practice

 Co-Investigators:
 Rhonda Cooper-DeHoff, Pharm D.
 Eileen Handberg, PhD
 Bob Kolb, RN

3. Abstract:

In the United States, approximately 60 million people have cardiovascular disease, which accounts for 2,600 deaths each day. Genetic polymorphisms have been identified among many of the factors involved in the pathophysiology of cardiovascular disease and its safe and effective treatment. The purpose of this study is to develop a genetics database of patients with cardiovascular disease.  By collecting genetic samples and pairing them with clinical information already collected in the INVEST, specific hypotheses can be tested on the relationship between genetics and specific clinical outcomes.

The first hypotheses we will test are the relationships between genetic polymorphisms to be related to cardiovascular disease and drug response (such as polymorphisms of the various proteins involved in the signal transduction systems of the b-adrenergic receptors, and the renin angiotensin system) and survival, morbidity, and treatment response in patients enrolled in INVEST.  Future studies using the genetics database may include studies of the role of other genetic polymorphisms (e.g. Gp IIb/IIIa, proteins regulating lipid levels, a-adrenergic system, endothelin, and methylenetetrahydrofolate reductase) in the development and outcome of various cardiovascular diseases.

4. Specific Aims:

The goals of this study are to identify genetic polymorphisms in INVEST patients which may play an important role in cardiovascular disease progression and outcomes and responsiveness to drug therapy.

5. Background and Significance:

Cardiovascular disease is the number one cause of death in this country.  Numerous mediators are involved in the pathogenesis of heart disease. The b-adrenergic receptor system and renin-angiotensin system play important roles in the progression of cardiovascular disease.  Among the mediators involved in the development and promotion of CHD are lipoproteins, platelet receptor activators, and homocysteine.  Genetic polymorphisms have been identified for many of the receptors or enzymes in these systems. The purpose of this study is to collect a genetics database so that we can test hypotheses of the contribution of genetic polymorphisms to the response to various antihypertensive medications, and progression, and outcome of heart disease.

The first hypothesis we will specifically test will be that genetic polymorphisms of the proteins of the b-adrenergic receptor system affect survival, morbidity, and treatment response in INVEST patients, particularly those randomized to the b-blocker strategy.  The second hypothesis will test the same outcomes relative to genetic polymorphisms in the protein of the renin angiotensin system  since blockade of the renin angiotensin system has clear clinical benefit in hypertension and other cardiovascular diseases.  We will also evaluate the relationship between response to antihypertensive medications and the above mentioned genetic polymorphisms.

The above named genetic polymorphisms will be studied, but are presented merely as representative examples of the types of questions that might be addressed through this genetics database.  Other possible candidates include studying genes of the calcium channels, Gp IIb/IIIa receptor, proteins involved in regulation of lipids, endothelin, the a-adrenergic receptors, and methylenetetrahydrofolate reductase, among others.  The studies proposed herein will generate strictly associative data as any true cause-and-effect cannot be established with this observational design.  We do, however, expect the data to provide insight into the effects of various genetic polymorphisms on the pathogenesis of heart disease.  The data collected, may provide preliminary evidence about the utility of testing for genetic polymorphisms in patients, in order to predict prognosis and response to drug therapy.  This study may also stimulate research in genetic therapies, to prevent the development or slow the progression of cardiovascular diseases.

6. Research Plan:

Patient Eligibility

A. Inclusion Criteria
1. Age > 50 years, currently enrolled in the INVEST protocol..
2. History of coronary artery disease as defined in the INVEST protocol inclusion criteria
3. Written informed consent for genetic testing obtained from patient.

B. Exclusion Criteria
1. Not participating in the INVEST

Study Design

This study will determine if various genetic polymorphisms influence the risk and progression of heart disease and the response to treatment of CV diseases.  Clinical data is already collect on all patients enrolled in INVEST and maintained in the INVEST database.  We will obtain a buccal cell sample from each eligible patient in the database.  From the buccal cells, genomic DNA will be isolated, and used to analyze the relationships between genetic polymorphisms, response to antihypertensive therapy and patient outcomes.

Methods

All participating INVEST sites will be provided with the necessary materials to participate in this substudy if they choose to. Written informed consent will be obtained from each patient. The patient will be instructed to swish 10ml of Cool Mint Scope^® in their mouth for 1 minute, and then to spit the solution back into a container. They will be asked to do this up to a total of three times, or as many times as they can tolerate it, if they can’t tolerate all three washes.  The sample will then be shipped back to the UF with appropriate patient identifiers.  Genomic DNA will be isolated from the buccal cell sample, and it will be stored frozen at –20o C. Following Polymerase Chain Reaction of the region of interest, genotype will be determined by primer extension, restriction fragment length polymorphism, or other applicable methods.

Patients will continue to be followed clinically according to the INVEST protocol.

Data Analysis

The data will be analyzed as deemed appropriate by a genetics statistician.

7. Potential Health Risks:

Risk to the patient from participation in this study are minimal.  The patient may experience some discomfort from swishing the Scope^® in their mouth.  If they are unable to keep the Scope^® in their mouth for 1 minute, or do not want to do the swish 3 times,  they may spit it into the container prior to 1 minute passing and not continue.

Genetic testing results will not be provided back to any of the sites or patients, and thus will not be included in the subject’s medical record and will be stored in locked file cabinets that are accessible only to the investigators.

8. Potential Health Benefits:

Patients will not receive any direct benefits from participation in this study.  However, the results of this study may help to identify new genetic influences of CV disease development, prognosis, and treatment response.  Various genetic polymorphisms could serve as important variables in evaluating the need for heart revascularization, determining appropriate drug therapy or other treatments.  The results of this study could also lead to the development of gene therapy to target various polymorphisms and improve outcomes in patients with CV diseases.  The potential information gained from this study therefore outweighs the minimal risk associated with study participation.

9. Potential Financial Risks:

There are no financial risks to the patients as a result of their participation in this study.

10. Potential Financial Benefits:

There are no financial benefits to patients participating in this study.

11. Conflict of Interest:

These is no conflict on interest involved with this study beyond the professional benefit from academic publication or presentation of the results.

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