GeneSTAR Research Center - Genetic Studies of Atherosclerosis Risk

PARes Study
Pharmacogenomics of Anti Platelet Responses


The PARes Study has two parts. One is based on using clopidogel plus aspirin in African American families only (PARes I), and the other is based on aspirin alone in both European Americans and African Americans (PARes II).

Our goal is to find the best antiplatelet regimen for very high risk persons from a primary prevention population, those with a family history of premature coronary disease and evidence of occult disease in two vascular beds, usually the coronary arteries and the brain. Given that the responses are highly heritable, we are seeking genes that regular responsiveness to assure targeted effective therapy to assure a pro-heath risk benefit ratio.Because so little s known about coronary disease prevention in African Americans, most of the study is focused on African American families. The PARes 2 study (aspirin only) involves African Americans and European Americns.
 
Why Do the Study


Currently there is considerable controversy about using antiplatelet agents in primary prevention, and this study represents an effort to identify those very high-risk patients with silent preclinical disease for whom antiplatelet agents would be effective and to refine possible indications based on atherogenic pathology and platelet physiology. Through a better understanding of pharmacogenomics, we may identify subsets of at-risk primary prevention populations where demonstrable benefit favors use of antiplatelet chemoprophylaxis. Very little in particular is known about how to prevent heart attack in high risk African American families.

 
Biological and Genetic Background

Platelet aggregation on disrupted atherosclerotic plaques initiates vascular thrombosis, resulting in acute myocardial infarction (MI) and stroke. Aspirin (ASA) is the mainstay of primary prevention and reduces future MI risk by 32% in men, and future stroke risk by 17% in women. Failure to protect everyone at risk has been attributed in part to suboptimal platelet suppression.
 
ASA only inhibits a single pathway; therefore, it remains possible that in the highest risk subset of a primary prevention population, inhibition of an additional pathway will be of benefit. Clopidogrel selectively and irreversibly blocks the platelet PYreceptor pathway and might be of benefit if added to ASA in a targeted population selected on the basis of risk phenotypes and genotypes.
 
Recent candidate gene work in families  in the GeneSTAR study, yielded a potent signal in a gene for increased native platelet aggregation as well as reduced inhibition by ASA in response to agonists for multiple pathways in European Americans. Sequencing of this gene yielded a common that was replicated in African American subjects, and in the Framingham Heart Study.


Main Goals and Protocols

The main goal is to explore the impact our strongest genetic finding on responsiveness to clopidogrel (Plavix) alone or to dual anti-platelet therapy using both ASA and clopidogrel.
 
We will further assess the role of other genetic variants in determining the response to single or dual anti-platelet therapy. Apparently healthy high risk subjects have been (a) identified from a proband with early-onset CAD , (b) genotyped on the Illumina 1 million platform, with imputation to 2.5 million SNPs, and (c) fully phenotyped for occult vascular disease in the brain using MRI and heart using CT angiography.
 
We plan to characterize the variance in platelet aggregation to multiple agonists after therapy with clopidogrel alone and therapy with clopidogrel and ASA in a subjects having both significant occult CAD identified by coronary CT angiography, and small or large vessel cerebrovascular disease identified by cranial MRI/MRA. We further plan to determine the extent to which variants identified modify platelet responsiveness to inhibition by clopidogrel alone and in combination with ASA in this high-risk subset. In addition, our aim is to determine the extent to which variants in other recently discovered genes, by themselves, and in combination with our known gene finding,  modify platelet responsiveness to clopidogrel alone and with ASA in this high-risk subset. Lastly, we also want to determine what changes in platelet mRNA are produced by aspirin alone and by aspirin with clopidogrel.

Pharmacogenomics and Tailored Medicine
 
Currently there is controversy about using antiplatelet agents in primary prevention, and this study represents an effort to identify high-risk seemingly healthy people with silent preclinical disease for whom antiplatelet agents would be effective. The study is also designed to refine possible medication indications based on platelet physiology.

Through a better understanding of pharmacogenomics, we may identify subsets of at-risk primary prevention populations, particularly among high risk African Americans,  where demonstrable benefit and low risk favors the use of one or more antiplatelet agents for  chemoprophylaxis, particularly in myocardial infarction and thrombotic stroke.

GeneSTAR has  longstanding history of studying the pharmacogenomics of antithrombotic therapies for primary prevention in high risk populations, and in PARes I is focusing on African American families because so little has been done to understand  the benefits of these agents in this population which has a particularly pro-aggregable platelet profile, and high risk for acute thombotic events. Funded in part by the NHLBI.

The study involves Drs. Rehan Qayuum as the Principal Investigator, Drs. Lewis Becker, Diane Becker, Jay Vaidya, Rasika MathiasNauder Faraday, and Brian Kral




Rehan Qayyum, MD, MPH
Assistant Professor, Medicine (Adjunct)
Principal Investigator

Professor, Medicine
Virginia Commonwealth University