Dataset Information

Aspirin exposure reveals novel genes associated with platelet function and cardiovascular events.

ABSTRACT: The aim of this study was to develop ribonucleic acid (RNA) profiles that could serve as novel biomarkers for the response to aspirin.Aspirin reduces death and myocardial infarction (MI), suggesting that aspirin interacts with biological pathways that may underlie these events.Aspirin was administered, followed by whole-blood RNA microarray profiling, in a discovery cohort of healthy volunteers (HV1) (n = 50) and 2 validation cohorts of healthy volunteers (HV2) (n = 53) and outpatient cardiology patients (OPC) (n = 25). Platelet function was assessed using the platelet function score (PFS) in HV1 and HV2 and the VerifyNow Aspirin Test (Accumetrics, Inc., San Diego, California) in OPC. Bayesian sparse factor analysis identified sets of coexpressed transcripts, which were examined for associations with PFS in HV1 and validated in HV2 and OPC. Proteomic analysis confirmed the association of validated transcripts in platelet proteins. Validated gene sets were tested for association with death or MI in 2 patient cohorts (n = 587 total) from RNA samples collected at cardiac catheterization.A set of 60 coexpressed genes named the "aspirin response signature" (ARS) was associated with PFS in HV1 (r = -0.31, p = 0.03), HV2 (r = -0.34, Bonferroni p = 0.03), and OPC (p = 0.046). Corresponding proteins for the 17 ARS genes were identified in the platelet proteome, of which 6 were associated with PFS. The ARS was associated with death or MI in both patient cohorts (odds ratio: 1.2 [p = 0.01]; hazard ratio: 1.5 [p = 0.001]), independent of cardiovascular risk factors. Compared with traditional risk factors, reclassification (net reclassification index = 31% to 37%, p ? 0.0002) was improved by including the ARS or 1 of its genes, ITGA2B.RNA profiles of platelet-specific genes are novel biomarkers for identifying patients who do not respond adequately to aspirin and who are at risk for death or MI.

SUBMITTER: Voora D

PROVIDER: S-EPMC3786046 | biostudies-literature | 2013 Oct

REPOSITORIES: biostudies-literature

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Aspirin exposure reveals novel genes associated with platelet function and cardiovascular events.

Voora Deepak D Cyr Derek D Lucas Joseph J Chi Jen-Tsan JT Dungan Jennifer J McCaffrey Timothy A TA Katz Richard R Newby L Kristin LK Kraus William E WE Becker Richard C RC Ortel Thomas L TL Ginsburg Geoffrey S GS

Journal of the American College of Cardiology 20130703 14

<h4>Objectives</h4>The aim of this study was to develop ribonucleic acid (RNA) profiles that could serve as novel biomarkers for the response to aspirin.<h4>Background</h4>Aspirin reduces death and myocardial infarction (MI), suggesting that aspirin interacts with biological pathways that may underlie these events.<h4>Methods</h4>Aspirin was administered, followed by whole-blood RNA microarray profiling, in a discovery cohort of healthy volunteers (HV1) (n = 50) and 2 validation cohorts of healt ...[more]

PMID: 23831034

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Project description:Background: Identifying individuals at heightened cardiovascular risk is a priority for reducing the global burden of cardiovascular disease. Aspirin is widely used to prevent cardiovascular events, though with variable results. Therefore, we hypothesized that aspirin exposure would reveal novel biological pathways relevant to the development of cardiovascular events. Methods: We administered aspirin, followed by peripheral blood RNA microarray profiling, in a discovery cohort of healthy volunteers (n = 50, HV1), followed by two validation cohorts of healthy volunteers (n = 53, HV2) or outpatient cardiology (OPC, n = 25) patients, in conjunction with platelet function testing with the platelet functions score (PFS, HV1 and HV2) or the VerifyNow Asprin (VN, OPC) test. Sets of coexpressed genes, or “Factors” were identified via Bayesian sparse factor analysis and associated with platelet function in HV1 and validated in HV2 and OPC. Validated factors were associated with death/MI in observational (n = 191) and case:control (n = 447) patient cohorts with available RNA data collected at the time of cardiac catheterization. Results: Factor analysis yielded 20 Factors, of which one, Factor 14, contained 60 genes and was associated with PFS in HV1 (r = -0.31, p-value = 0.03). Factor 14 was associated with platelet function with the same strength and direction in HV2 (r = -0.34, p-value = 0.02) and OPC (one-sided p-value for aspirin resistant vs. aspirin sensitive = 0.046), thus validating the association. Factor 14 was associated with death/MI in the two patient cohorts, odds ratio (OR) = 1.2, 95% CI [1.02-1.4], p-value = 0.01 and hazard ratio = 1.5, [1.2-1.9], p = 0.001, respectively, independent of known cardiovascular risk factors (combined OR = 1.2, CI = [1.02, 1.4], p = 0.03). Factor 14 and the expression of the Factor 14 transcript most highly correlative of PFS, ITGA2B, improved reclassification compared to traditional risk factors (category-free net reclassification index = 31% and 37%, p ≤ 0.0002 for both). Conclusions: By challenging humans subjects with aspirin, a medication used for cardiovascular risk reduction, we elucidated genes and pathways that may underlie platelet function and mechanisms responsible for cardiovascular death/MI. This accession represents the OPC cohort microarray data 26 subjects selected for microarray analysis were divided into three groups: aspirin resistant (AR, n=8, >550 ARU), high normal (HN, n=9, ARU 500-549) and aspirin sensitive (AS, n=9, ARU<500)

Project description:The relationship between ionizing radiation (IR) and carcinogenesis is long established, but recently the association between IR and other diseases is starting to be recognized. Currently, there is limited information on the genetic mechanisms governing the role of IR in non-cancer related adverse health effects and in regards to an early developmental exposure. In this study, zebrafish embryos were exposed to a range of IR doses (0, 1, 2, 5, 10 Gy) at 26 h post fertilization (hpf). No significant increase in mortality or hatching rate was observed, but a significant decrease in total larval length, head length, and eye diameter was observed in the 10 Gy dose. Transcriptomic analysis was conducted at 120 hpf to compare gene expression profiles between the control and highest IR dose at which no significant differences were observed in morphological measurements (5 Gy). 253 genes with well-established function or orthology to human genes were significantly altered. Gene ontology and molecular network analysis revealed enrichment of genes associated with cardiovascular and neurological development, function, and disease. Expression of a subset of genetic targets with an emphasis on those associated with the cardiovascular system was assessed using Quantitative PCR (qPCR) to confirm altered expression at 5 Gy and then to investigate alterations at lower doses (1 and 2 Gy). Strong correlation between microarray and qPCR expression values was observed, but zebrafish exposed to 1 or 2 Gy resulted in a significant expression alteration in only one of these genes (LIN7B). Moreover, heart rate was analyzed through 120 hpf following IR dosing at 26 hpf. A significant decrease in heart rate was observed at 10 Gy, while a significant increase in heart rate was observed at 1, 2, and 5 Gy. Overall these findings indicate IR exposure at doses below those that induce gross morphological changes alters heart rate and expression of genes associated with cardiovascular and neurological functions.

Project description:The relationship between ionizing radiation (IR) and carcinogenesis is long established, but recently the association between IR and other diseases is starting to be recognized. Currently, there is limited information on the genetic mechanisms governing the role of IR in non-cancer related adverse health effects and in regards to an early developmental exposure. In this study, zebrafish embryos were exposed to a range of IR doses (0, 1, 2, 5, 10 Gy) at 26 hours post fertilization (hpf). No significant increase in mortality or hatching rate was observed, but a significant decrease in total larval length, head length, and eye diameter was observed in the 10 Gy dose. Transcriptomic analysis was conducted at 120 hpf to compare gene expression profiles between the control and highest IR dose at which no significant differences were observed in morphological measurements (5 Gy). 253 genes with well-established function or orthology to human genes were significantly altered. Gene ontology and molecular network analysis revealed enrichment of genes associated with cardiovascular and neurological development, function, and disease. Expression of a subset of genetic targets with an emphasis on those associated with the cardiovascular system was assessed using qPCR to confirm altered expression at 5 Gy and then to investigate alterations at lower doses (1 and 2 Gy). Strong correlation between microarray and qPCR expression values was observed, but zebrafish exposed to 1 or 2 Gy resulted in a significant expression alteration in only one of these genes (LIN7B). Moreover, heart rate was analyzed through 120 hpf following IR dosing at 26 hpf. A significant decrease in heart rate was observed at 10 Gy, while a significant increase in heart rate was observed at 1, 2, and 5 Gy. Overall these findings indicate IR exposure at doses below those that induce gross morphological changes alters heart rate and expression of genes associated with cardiovascular and neurological functions.

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Aspirin exposure reveals novel genes associated with platelet function and cardiovascular events.

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Aspirin exposure reveals novel genes associated with platelet function and cardiovascular events.

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