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Gene Expression Profiles Link Respiratory Viral Infection, Platelet Response to Aspirin, and Acute Myocardial Infarction.

Rose JJ, Voora D, Cyr DD, Lucas JE, Zaas AK, Woods CW, Newby LK, Kraus WE, Ginsburg GS - PLoS ONE (2015)

Bottom Line: A previously defined platelet GES was projected into blood RNA data from 81 healthy subjects before and after exposure to four respiratory viruses: Respiratory Syncytial Virus (RSV) (n=20), Human Rhinovirus (HRV) (n=20), Influenza A virus subtype H1N1 (H1N1) (n=24), Influenza A Virus subtype H3N2 (H3N2) (n=17).A viral GES of non-specific, respiratory viral infection was associated with acute MI; 18% of the top 49 genes in the viral GES are involved with hemostasis and/or platelet aggregation.Separately, H1N1 exposure, but not exposure to other respiratory viruses, increased a platelet GES previously shown to be associated with MI.

View Article: PubMed Central - PubMed

Affiliation: Center for Applied Genomics and Precision Medicine, Duke University Medical Center, Durham, North Carolina, United States of America; Department of Medicine, Duke University Medical Center, Durham, North Carolina, United States of America; Division of Pulmonary, Allergy and Critical Care Medicine, Department of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania, United States of America.

ABSTRACT

Background: Influenza infection is associated with myocardial infarction (MI), suggesting that respiratory viral infection may induce biologic pathways that contribute to MI. We tested the hypotheses that 1) a validated blood gene expression signature of respiratory viral infection (viral GES) was associated with MI and 2) respiratory viral exposure changes levels of a validated platelet gene expression signature (platelet GES) of platelet function in response to aspirin that is associated with MI.

Methods: A previously defined viral GES was projected into blood RNA data from 594 patients undergoing elective cardiac catheterization and used to classify patients as having evidence of viral infection or not and tested for association with acute MI using logistic regression. A previously defined platelet GES was projected into blood RNA data from 81 healthy subjects before and after exposure to four respiratory viruses: Respiratory Syncytial Virus (RSV) (n=20), Human Rhinovirus (HRV) (n=20), Influenza A virus subtype H1N1 (H1N1) (n=24), Influenza A Virus subtype H3N2 (H3N2) (n=17). We tested for the change in platelet GES with viral exposure using linear mixed-effects regression and by symptom status.

Results: In the catheterization cohort, 32 patients had evidence of viral infection based upon the viral GES, of which 25% (8/32) had MI versus 12.2% (69/567) among those without evidence of viral infection (OR 2.3; CI [1.03-5.5], p=0.04). In the infection cohorts, only H1N1 exposure increased platelet GES over time (time course p-value = 1e-04).

Conclusions: A viral GES of non-specific, respiratory viral infection was associated with acute MI; 18% of the top 49 genes in the viral GES are involved with hemostasis and/or platelet aggregation. Separately, H1N1 exposure, but not exposure to other respiratory viruses, increased a platelet GES previously shown to be associated with MI. Together, these results highlight specific genes and pathways that link viral infection, platelet activation, and MI especially in the case of H1N1 influenza infection.

No MeSH data available.


Related in: MedlinePlus

Association of selected viral gene expression signature genes with myocardial infarction.Genes from the viral gene expression signature (viral GES) were selected based on their role in platelet activation, thrombosis, and hemostasis (Table 4 and Discussion). The association between gene expression and myocardial infarction (MI) is plotted as the standardized odds ratio (y-axis) for each gene (x-axis). Higher odds ratio imply that higher gene expression is associated with higher risk of MI. * indicate genes that are significantly (p-value < 0.05) associated with MI.
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pone.0132259.g004: Association of selected viral gene expression signature genes with myocardial infarction.Genes from the viral gene expression signature (viral GES) were selected based on their role in platelet activation, thrombosis, and hemostasis (Table 4 and Discussion). The association between gene expression and myocardial infarction (MI) is plotted as the standardized odds ratio (y-axis) for each gene (x-axis). Higher odds ratio imply that higher gene expression is associated with higher risk of MI. * indicate genes that are significantly (p-value < 0.05) associated with MI.

Mentions: The viral GES contains a large number of genes from biologically plausible gene networks involved in host viral response [30]. Of the top 49 genes, 9 (18%) are related to platelets or hemostasis (Table 4). Of particular interest is growth arrest-specific 6 (GAS6), which appears to link viral infection and MI. GAS6 plays a key role in platelet aggregation and vascular homeostasis [31][32] by amplifying endothelial cell activation in response to inflammatory stimuli [33]. In our study, we observed that H1N1 viral infection increases GAS6 expression and higher GAS6 expression is associated with a higher risk of MI (Fig 4) which is consistent prior work demonstrating that GAS6 deficient mice are protected from thrombosis [31]. Infection then theoretically increases GAS6 which may increase thrombosis risk versus lower levels of GAS6; this could potentially be a target pathway for future study [34]. Inflammation has long been postulated to be associated with atherosclerosis, and the host inflammatory response to influenza infection may represent an alternative biological pathway by which influenza leads to MI [35]. In a case control series, patients with influenza antibodies indicative of prior influenza infection had a higher risk of MI in addition to increased levels of multiple inflammatory cytokines [36]. Therefore, the viral GES represents multiple inflammatory, coagulation, and platelet pathways that together may contribute to contribute to the development of MI after viral infection.


Gene Expression Profiles Link Respiratory Viral Infection, Platelet Response to Aspirin, and Acute Myocardial Infarction.

Rose JJ, Voora D, Cyr DD, Lucas JE, Zaas AK, Woods CW, Newby LK, Kraus WE, Ginsburg GS - PLoS ONE (2015)

Association of selected viral gene expression signature genes with myocardial infarction.Genes from the viral gene expression signature (viral GES) were selected based on their role in platelet activation, thrombosis, and hemostasis (Table 4 and Discussion). The association between gene expression and myocardial infarction (MI) is plotted as the standardized odds ratio (y-axis) for each gene (x-axis). Higher odds ratio imply that higher gene expression is associated with higher risk of MI. * indicate genes that are significantly (p-value < 0.05) associated with MI.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4507878&req=5

pone.0132259.g004: Association of selected viral gene expression signature genes with myocardial infarction.Genes from the viral gene expression signature (viral GES) were selected based on their role in platelet activation, thrombosis, and hemostasis (Table 4 and Discussion). The association between gene expression and myocardial infarction (MI) is plotted as the standardized odds ratio (y-axis) for each gene (x-axis). Higher odds ratio imply that higher gene expression is associated with higher risk of MI. * indicate genes that are significantly (p-value < 0.05) associated with MI.
Mentions: The viral GES contains a large number of genes from biologically plausible gene networks involved in host viral response [30]. Of the top 49 genes, 9 (18%) are related to platelets or hemostasis (Table 4). Of particular interest is growth arrest-specific 6 (GAS6), which appears to link viral infection and MI. GAS6 plays a key role in platelet aggregation and vascular homeostasis [31][32] by amplifying endothelial cell activation in response to inflammatory stimuli [33]. In our study, we observed that H1N1 viral infection increases GAS6 expression and higher GAS6 expression is associated with a higher risk of MI (Fig 4) which is consistent prior work demonstrating that GAS6 deficient mice are protected from thrombosis [31]. Infection then theoretically increases GAS6 which may increase thrombosis risk versus lower levels of GAS6; this could potentially be a target pathway for future study [34]. Inflammation has long been postulated to be associated with atherosclerosis, and the host inflammatory response to influenza infection may represent an alternative biological pathway by which influenza leads to MI [35]. In a case control series, patients with influenza antibodies indicative of prior influenza infection had a higher risk of MI in addition to increased levels of multiple inflammatory cytokines [36]. Therefore, the viral GES represents multiple inflammatory, coagulation, and platelet pathways that together may contribute to contribute to the development of MI after viral infection.

Bottom Line: A previously defined platelet GES was projected into blood RNA data from 81 healthy subjects before and after exposure to four respiratory viruses: Respiratory Syncytial Virus (RSV) (n=20), Human Rhinovirus (HRV) (n=20), Influenza A virus subtype H1N1 (H1N1) (n=24), Influenza A Virus subtype H3N2 (H3N2) (n=17).A viral GES of non-specific, respiratory viral infection was associated with acute MI; 18% of the top 49 genes in the viral GES are involved with hemostasis and/or platelet aggregation.Separately, H1N1 exposure, but not exposure to other respiratory viruses, increased a platelet GES previously shown to be associated with MI.

View Article: PubMed Central - PubMed

Affiliation: Center for Applied Genomics and Precision Medicine, Duke University Medical Center, Durham, North Carolina, United States of America; Department of Medicine, Duke University Medical Center, Durham, North Carolina, United States of America; Division of Pulmonary, Allergy and Critical Care Medicine, Department of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania, United States of America.

ABSTRACT

Background: Influenza infection is associated with myocardial infarction (MI), suggesting that respiratory viral infection may induce biologic pathways that contribute to MI. We tested the hypotheses that 1) a validated blood gene expression signature of respiratory viral infection (viral GES) was associated with MI and 2) respiratory viral exposure changes levels of a validated platelet gene expression signature (platelet GES) of platelet function in response to aspirin that is associated with MI.

Methods: A previously defined viral GES was projected into blood RNA data from 594 patients undergoing elective cardiac catheterization and used to classify patients as having evidence of viral infection or not and tested for association with acute MI using logistic regression. A previously defined platelet GES was projected into blood RNA data from 81 healthy subjects before and after exposure to four respiratory viruses: Respiratory Syncytial Virus (RSV) (n=20), Human Rhinovirus (HRV) (n=20), Influenza A virus subtype H1N1 (H1N1) (n=24), Influenza A Virus subtype H3N2 (H3N2) (n=17). We tested for the change in platelet GES with viral exposure using linear mixed-effects regression and by symptom status.

Results: In the catheterization cohort, 32 patients had evidence of viral infection based upon the viral GES, of which 25% (8/32) had MI versus 12.2% (69/567) among those without evidence of viral infection (OR 2.3; CI [1.03-5.5], p=0.04). In the infection cohorts, only H1N1 exposure increased platelet GES over time (time course p-value = 1e-04).

Conclusions: A viral GES of non-specific, respiratory viral infection was associated with acute MI; 18% of the top 49 genes in the viral GES are involved with hemostasis and/or platelet aggregation. Separately, H1N1 exposure, but not exposure to other respiratory viruses, increased a platelet GES previously shown to be associated with MI. Together, these results highlight specific genes and pathways that link viral infection, platelet activation, and MI especially in the case of H1N1 influenza infection.

No MeSH data available.


Related in: MedlinePlus