Gene Marker IDs Aspirin Response, Predicts Heart Attacks

Gene Marker IDs Aspirin Response, Predicts MI

Published: Jul 3, 2013 | Updated: Jul 3, 2013

By  Todd Neale , Senior Staff Writer, MedPage Today
Reviewed by Robert Jasmer, MD; Associate Clinical Professor of Medicine, University of California, San Francisco and Dorothy Caputo, MA, BSN, RN, Nurse Planner

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.

The study was funded by institutional funds provided by the Duke Institute for Genome Sciences & Policy, an NIH T32 Training grant, a grant from the National Center for Research Resources (NCRR) and NIH Roadmap for Medical Research, a grant from the National Institute of General Medical Sciences, a grant from the CDC, and the David H. Murdock Research Institute.

Voora and five of the study authors have filed a provisional patent application regarding the ARS. The study authors reported relationships with United States Diagnostic Standards, CardioDx, Pappas Ventures, Universal Medicine, CellGenex, Amylin, Bristol-Myers Squibb, Daiichi Sankyo, Genentech, GlaxoSmithKline, Merck, the MURDOCK study, the National Heart, Lung, and Blood Institute, Novartis, Roche Diagnostics, Janssen Pharmaceuticals, Navigant, and Daiichi Sankyo-Lilly.

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