Gene Marker IDs Aspirin Response, Predicts MI
A collection of 60 co-expressed genes --
called the Aspirin Response Signature (ARS)
-- predicted both response to aspirin
treatment and the risk of death or
myocardial infarction among patients
undergoing cardiac catheterization,
researchers found.
The ARS was
significantly
associated
with platelet
function in
two groups
of healthy
volunteers
taking 325
mg of aspirin
per day, and
in a group of
cardiology
patients
taking 81 mg
of aspirin per
day (P <0.05
for all),
according to
Deepak Voora, MD, of Duke University, and
colleagues.
In addition, among patients undergoing
cardiac catheterization, the ARS was
associated with a 30% increased likelihood of
death or myocardial infarction (MI), even
after adjustment for Framingham risk factors,
race, platelet count, and presence of
angiographic coronary artery disease (odds
ratio 1.3, 95% CI 1.1-1.5), the researchers
reported online in the Journal of the
American College of Cardiology.
Clinicians are limited in detecting whether
patients are having an adequate response to
aspirin, which differs from other drugs used
for cardiovascular disease like
antihypertensives and statins, Voora said in
an interview.
"The main finding of our study is that we've
developed a whole blood-based biomarker
that physicians could potentially use as a
diagnostic test to identify those who are
adequately responding to aspirin or not, and
also to identify those individuals who are at
highest risk for MI and death in patients who
are taking aspirin," he said, adding that
further validation of these proof-of-principle
findings is needed.
He and his colleagues noted in their paper
that platelet function assays are available to
assess the response to aspirin but that "their
widespread use is severely constrained by the
need for specialized equipment and trained
personnel. Point-of-care tests are available,
but require testing to be completed within
hours of phlebotomy; thus, they are out of
reach for the vast majority of outpatients on
aspirin."
In the current study, the researchers
examined the feasibility of using an RNA
profile from whole blood -- the ARS -- as a
biomarker for the response to aspirin.
After giving aspirin to 50 healthy volunteers
in a discovery cohort, 53 volunteers in two
validation cohorts, and 25 outpatient
cardiology patients, Voora and colleagues
identified sets of co-expressed genes that
were associated with platelet function.
Platelet function was assessed using the
platelet function score for the healthy
volunteers or the VerifyNow Aspirin assay for
the cardiology patients. The ARS, which
include 60 co-expressed genes, was selected
for further study.
The ARS was associated with platelet
function in all three groups of patients, even
after adjustment for mean platelet volume
and count. The relationships were seen only
after the administration of aspirin, however,
"suggesting that the latent effect of ARS
genes on platelet function is unmasked in
response to aspirin," the authors wrote.
In two cohorts of patients who were
undergoing cardiac catheterization at Duke
University -- the CATHGEN cohorts -- the
ARS, as well as one of the component genes
(ITGA2B ), predicted death or MI after
adjustment for traditional cardiovascular risk
factors.
And the ARS appeared to add some
prognostic value to the traditional risk
factors. Compared with a model using risk
factors alone, adding information from the
ARS improved net reclassification and
integrated discrimination.
The authors acknowledged that the study was
limited by the lack of platelet function or
platelet volume measurements in the
CATHGEN cohorts; the uncertainty about
whether improving certain modifiable risk
factors like diabetes, hyperlipidemia, or
hypertension can affect ARS levels; and the
fact that some of the ARS genes are also
expressed in nonplatelet cell types,
"suggesting that mechanism(s) represented
by ARS genes may involve more than just
platelets."
Also, Voora noted, it's unclear what the
treatment approach should be for patients
who are identified as having an inadequate
response to aspirin, an area of research that
is being pursued by his group.
