Pharmacogenomics of Antiplatelet Response - I

The main goal of this study is to explore the impact of the PEAR1 genetic variant
(rs12041331) on responsiveness to clopidogrel. The investigators will further assess the
role of other genetic variants in determining the response to single or dual anti-platelet
therapy. Apparently healthy subjects (N= 2108) from high-risk families are being (a)
identified from a proband with early-onset CAD and (b) genotyped on the Illumina 1 million
platform, with imputation to 2.5 million single nucleotide polymorphisms. The investigators
plan to characterize the variance in platelet aggregation to multiple agonists (ADP,
collagen, and arachidonic acid) after 1-week therapy with clopidogrel in a high-risk subset
of GeneSTAR subjects (N=100). The investigators further plan to determine the extent to
which variants identified in the PEAR1 gene modify platelet responsiveness to inhibition by
clopidogrel in this high-risk subset. In addition, the investigators aim is to determine the
extent to which variants in other recently discovered genes, by themselves, and in
combination with PEAR1, modify platelet responsiveness to clopidogrel alone and with aspirin
in this high-risk subset. Lastly, the investigators also want to determine what changes in
platelet mRNA are produced by aspirin alone and by aspirin with clopidogrel.

Inclusion Criteria:

- Participants from the GeneSTAR cohort

- Unaffected with no overt coronary artery disease or serious vascular event (stroke or
peripheral vascular disease diagnosis

- Presence of an occult coronary artery disease phenotype as defined by coronary artery
calcium scores about the MESA (Multiethnic Study of Atherosclerosis) 75th percentile
for age sex, and race or ≥ 1 stenoses in any of the major coronary arteries or main
branches of > 50%, or coronary plaque volumetric scores above our own 75th
percentile, or any combination on cardiac computed tomographic angiography (performed
recently as part of the GeneSTAR study and present for all persons being recruited)/

- Presence of occult cerebrovascular disease defined as presence of white matter
hyperintensities (WMH) thought to represent ischemic small vessel cerebrovascular
disease, and /or the presence of lacunes (old small strokes), or the presence of an
Atherosclerosis Risk in Communities Study (ARIC) silent stroke score on a visual
analogue scales of 4 or more (on a scale of 0-9).

- Women who are postmenopausal.

- Women who use a reliable contraceptive method; a reliable contraceptive method will
be defined as personal history of tubal ligation, ongoing use of intra-uterine
device, or ongoing use of oral contraceptive pills.

Exclusion Criteria:

- Presence of any CAD or stroke, transient ischemic attacks, peripheral arterial
disease

- Persons taking aspirin, NSAIDS, or any anti-coagulants who are medically unable to
stop them for a two week pre-trial

- A history of allergy to aspirin or clopidogrel

- Weight < 60kg

- Age < 45 and > 75 years of age

- A history of recent or any active bleeding

- Serious or current co-morbidity (AIDS, cancer)

- Pregnant women as determined by urine dipstick pregnancy test

- Any aneurysms on cranial magnetic resonance imaging/magnetic resonance angiography
(obtained recently in the GeneSTAR participants)

- Blood pressure above >=159/95mmHg

- History of a gastric or duodenal ulcer, or significant gastrointestinal disease, like
regional enteritis

- Mental incompetence to make a decision to participate (developmentally disabled, and
persons with diagnosed psychiatric disorders—documented in primary care records).