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Clinical Trial
. 2018 Jan 12;11(1):1.
doi: 10.1186/s12920-017-0318-6.

Peripheral Blood Gene Expression Signatures Which Reflect Smoking and Aspirin Exposure Are Associated With Cardiovascular Events

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Free PMC article
Clinical Trial

Peripheral Blood Gene Expression Signatures Which Reflect Smoking and Aspirin Exposure Are Associated With Cardiovascular Events

James A Wingrove et al. BMC Med Genomics. .
Free PMC article

Abstract

Background: Cardiovascular disease and its sequelae are major causes of global mortality, and better methods are needed to identify patients at risk for future cardiovascular events. Gene expression analysis can inform on the molecular underpinnings of risk factors for cardiovascular events. Smoking and aspirin have known opposing effects on platelet reactivity and MACE, however their effects on each other and on MACE are not well described.

Methods: We measured peripheral blood gene expression levels of ITGA2B, which is upregulated by aspirin and correlates with platelet reactivity on aspirin, and a 5 gene validated smoking gene expression score (sGES) where higher expression correlates with smoking status, in participants from the previously reported PREDICT trial (NCT 00500617). The primary outcome was a composite of death, myocardial infarction, and stroke/TIA (MACE). We tested whether selected genes were associated with MACE risk using logistic regression.

Results: Gene expression levels were determined in 1581 subjects (50.5% female, mean age 60.66 +/-11.46, 18% self-reported smokers); 3.5% of subjects experienced MACE over 12 months follow-up. Elevated sGES and ITGA2B expression were each associated with MACE (odds ratios [OR] =1.16 [95% CI 1.10-1.31] and 1.42 [95% CI 1.00-1.97], respectively; p < 0.05). ITGA2B expression was inversely associated with self-reported smoking status and the sGES (p < 0.001). A logistic regression model combining sGES and ITGA2B showed better performance (AIC = 474.9) in classifying MACE subjects than either alone (AIC = 479.1, 478.2 respectively).

Conclusion: Gene expression levels associated with smoking and aspirin are independently predictive of an increased risk of cardiovascular events.

Keywords: Aspirin exposure; Cardiovascular events; Gene expression; Smoking.

Conflict of interest statement

Ethics approval and consent to participate

Subjects in this study were part of PREDICT, a multi-center US study of patients referred for coronary angiography (http://www.clinicaltrials.gov, NCT00500617). The institutional review boards at all centers approved the study (Duke University School of Medicine, Durham, North Carolina; Minneapolis Heart Institute and Foundation, Minneapolis, Minnesota; Piedmont Heart Institute, Atlanta, Georgia; Cleveland Clinic Foundation, Cleveland, Ohio; Oklahoma Cardiovascular Research Group, Oklahoma City, Oklahoma; Cardiovascular Research Institute, Medstar Research Institute, Washington, DC; Vanderbilt Heart and Vascular Institute, Nashville, Tennessee; Cardiovascular Research Foundation, New York, New York; and Scripps Translational Science Institute, La Jolla, California), and all patients gave written informed consent. Specific IRB protocol numbers can be found in Additional file 3: Table S3.

Consent for publication

Not applicable.

Competing interests

JAW, BR, and KF are/were full-time employees of and hold stock in CardioDx. SR reported serving as a consultant and advisory board member for CardioDx and holding stock and stock options in CardioDx.

Publisher’s Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Figures

Fig. 1
Fig. 1
Distribution of ITGA2B gene expression in Females and Males. Median is represented by solid red lines, 25/75th percentile by small dashed green lines and 5th and 95th percentile by large dashed blued lines respectively. Expression values have been transformed from Cp values, so that higher values on the x-axis represent higher expression levels
Fig. 2
Fig. 2
AUC of GES for prediction of self-reported smoking status in full cohort (a; AUC = 0.877, 95% CI 0.860 to 0.893) and novel cohort (b;: AUC = 0.864,95% CI 0.860 to 0.893)
Fig. 3
Fig. 3
Scatterplot of expression levels of ITGA2B (x axis) versus the sGES (y axis) across the 1581 subjects in the study. A weak but significant negative correlation (r = −0.126; p < 0.001) existed between ITGA2B levels and the sGES (red line in graph)
Fig. 4
Fig. 4
Primary and secondary effects of aspirin, smoking, and ITGA2B gene expression on platelet function and MACE. Aspirin (1) and smoking (2) have primary, anti- and pro- thrombotic effects on platelet function, respectively. Secondary, compensatory effects of aspirin (3) and smoking (4) on ITGA2B expression are opposite their primary effects on platelet function and act to restore platelet function in a homeostatic manner (5, 6). ITGA2B expression represents a component of overall platelet function; higher levels (regardless of their cause) are associated with higher MACE risk. The overall effect of aspirin on MACE is the combination of its primary and compensatory effects (1, 3, and 5), and is protective. The effect of smoking on MACE is the combination of its primary and compensatory effects (2, 4, and 6), and overall increases risk

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