Genetic variation in the platelet endothelial aggregation receptor 1 gene results in endothelial dysfunction

Adam S. Fisch, Laura M. Yerges-Armstrong, Joshua D. Backman, Hong Wang, Patrick Donnelly, Kathleen A. Ryan, Ankita Parihar, Mary A. Pavlovich, Braxton D. Mitchell, Jeffrey R. O'Connell, William Raymond Herzog, Christopher R. Harman, Jonathan D. Wren, Joshua P. Lewis

Research output: Contribution to journalArticle

Abstract

Platelet Endothelial Aggregation Receptor 1 (PEAR1) is a newly identified membrane protein reported to be involved in multiple vascular and thrombotic processes. While most studies to date have focused on the effects of this receptor in platelets, PEAR1 is located in multiple tissues including the endothelium, where it is most highly expressed. Our first objective was to evaluate the role of PEAR1 in endothelial function by examining flow-mediated dilation of the brachial artery in 641 participants from the Heredity and Phenotype Intervention Heart Study. Our second objective was to further define the impact of PEAR1 on cardiovascular disease computationally through meta-analysis of 75,000 microarrays, yielding insights regarding PEAR1 function, and predictions of phenotypes and diseases affected by PEAR1 dysregulation. Based on the results of this meta-analysis we examined whether genetic variation in PEAR1 influences endothelial function using an ex vivo assay of endothelial cell migration. We observed a significant association between rs12041331 and flow-mediated dilation in participants of the Heredity and Phenotype Intervention Heart Study (P = 0.02). Meta-analysis results revealed that PEAR1 expression is highly correlated with several genes (e.g. ANG2, ACVRL1, ENG) and phenotypes (e.g. endothelial cell migration, angiogenesis) that are integral to endothelial function. Functional validation of these results revealed that PEAR1 rs12041331 is significantly associated with endothelial migration (P = 0.04). Our results suggest for the first time that genetic variation of PEAR1 is a significant determinant of endothelial function through pathways implicated in cardiovascular disease.

Original languageEnglish (US)
Article numbere0138795
JournalPLoS One
Volume10
Issue number9
DOIs
StatePublished - Sep 25 2015

Fingerprint

Platelets
Platelet Aggregation
Agglomeration
Genes
genetic variation
receptors
genes
meta-analysis
Phenotype
Meta-Analysis
Heredity
phenotype
Endothelial cells
cell movement
Dilatation
cardiovascular diseases
endothelial cells
Cardiovascular Diseases
Endothelial Cells
inheritance (genetics)

ASJC Scopus subject areas

  • Agricultural and Biological Sciences(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Medicine(all)

Cite this

Fisch, A. S., Yerges-Armstrong, L. M., Backman, J. D., Wang, H., Donnelly, P., Ryan, K. A., ... Lewis, J. P. (2015). Genetic variation in the platelet endothelial aggregation receptor 1 gene results in endothelial dysfunction. PLoS One, 10(9), [e0138795]. https://doi.org/10.1371/journal.pone.0138795

Genetic variation in the platelet endothelial aggregation receptor 1 gene results in endothelial dysfunction. / Fisch, Adam S.; Yerges-Armstrong, Laura M.; Backman, Joshua D.; Wang, Hong; Donnelly, Patrick; Ryan, Kathleen A.; Parihar, Ankita; Pavlovich, Mary A.; Mitchell, Braxton D.; O'Connell, Jeffrey R.; Herzog, William Raymond; Harman, Christopher R.; Wren, Jonathan D.; Lewis, Joshua P.

In: PLoS One, Vol. 10, No. 9, e0138795, 25.09.2015.

Research output: Contribution to journalArticle

Fisch, AS, Yerges-Armstrong, LM, Backman, JD, Wang, H, Donnelly, P, Ryan, KA, Parihar, A, Pavlovich, MA, Mitchell, BD, O'Connell, JR, Herzog, WR, Harman, CR, Wren, JD & Lewis, JP 2015, 'Genetic variation in the platelet endothelial aggregation receptor 1 gene results in endothelial dysfunction', PLoS One, vol. 10, no. 9, e0138795. https://doi.org/10.1371/journal.pone.0138795
Fisch AS, Yerges-Armstrong LM, Backman JD, Wang H, Donnelly P, Ryan KA et al. Genetic variation in the platelet endothelial aggregation receptor 1 gene results in endothelial dysfunction. PLoS One. 2015 Sep 25;10(9). e0138795. https://doi.org/10.1371/journal.pone.0138795
Fisch, Adam S. ; Yerges-Armstrong, Laura M. ; Backman, Joshua D. ; Wang, Hong ; Donnelly, Patrick ; Ryan, Kathleen A. ; Parihar, Ankita ; Pavlovich, Mary A. ; Mitchell, Braxton D. ; O'Connell, Jeffrey R. ; Herzog, William Raymond ; Harman, Christopher R. ; Wren, Jonathan D. ; Lewis, Joshua P. / Genetic variation in the platelet endothelial aggregation receptor 1 gene results in endothelial dysfunction. In: PLoS One. 2015 ; Vol. 10, No. 9.
@article{78eadbd0a0ff46f09b10313a3f3d92f0,
title = "Genetic variation in the platelet endothelial aggregation receptor 1 gene results in endothelial dysfunction",
abstract = "Platelet Endothelial Aggregation Receptor 1 (PEAR1) is a newly identified membrane protein reported to be involved in multiple vascular and thrombotic processes. While most studies to date have focused on the effects of this receptor in platelets, PEAR1 is located in multiple tissues including the endothelium, where it is most highly expressed. Our first objective was to evaluate the role of PEAR1 in endothelial function by examining flow-mediated dilation of the brachial artery in 641 participants from the Heredity and Phenotype Intervention Heart Study. Our second objective was to further define the impact of PEAR1 on cardiovascular disease computationally through meta-analysis of 75,000 microarrays, yielding insights regarding PEAR1 function, and predictions of phenotypes and diseases affected by PEAR1 dysregulation. Based on the results of this meta-analysis we examined whether genetic variation in PEAR1 influences endothelial function using an ex vivo assay of endothelial cell migration. We observed a significant association between rs12041331 and flow-mediated dilation in participants of the Heredity and Phenotype Intervention Heart Study (P = 0.02). Meta-analysis results revealed that PEAR1 expression is highly correlated with several genes (e.g. ANG2, ACVRL1, ENG) and phenotypes (e.g. endothelial cell migration, angiogenesis) that are integral to endothelial function. Functional validation of these results revealed that PEAR1 rs12041331 is significantly associated with endothelial migration (P = 0.04). Our results suggest for the first time that genetic variation of PEAR1 is a significant determinant of endothelial function through pathways implicated in cardiovascular disease.",
author = "Fisch, {Adam S.} and Yerges-Armstrong, {Laura M.} and Backman, {Joshua D.} and Hong Wang and Patrick Donnelly and Ryan, {Kathleen A.} and Ankita Parihar and Pavlovich, {Mary A.} and Mitchell, {Braxton D.} and O'Connell, {Jeffrey R.} and Herzog, {William Raymond} and Harman, {Christopher R.} and Wren, {Jonathan D.} and Lewis, {Joshua P.}",
year = "2015",
month = "9",
day = "25",
doi = "10.1371/journal.pone.0138795",
language = "English (US)",
volume = "10",
journal = "PLoS One",
issn = "1932-6203",
publisher = "Public Library of Science",
number = "9",

}

TY - JOUR

T1 - Genetic variation in the platelet endothelial aggregation receptor 1 gene results in endothelial dysfunction

AU - Fisch, Adam S.

AU - Yerges-Armstrong, Laura M.

AU - Backman, Joshua D.

AU - Wang, Hong

AU - Donnelly, Patrick

AU - Ryan, Kathleen A.

AU - Parihar, Ankita

AU - Pavlovich, Mary A.

AU - Mitchell, Braxton D.

AU - O'Connell, Jeffrey R.

AU - Herzog, William Raymond

AU - Harman, Christopher R.

AU - Wren, Jonathan D.

AU - Lewis, Joshua P.

PY - 2015/9/25

Y1 - 2015/9/25

N2 - Platelet Endothelial Aggregation Receptor 1 (PEAR1) is a newly identified membrane protein reported to be involved in multiple vascular and thrombotic processes. While most studies to date have focused on the effects of this receptor in platelets, PEAR1 is located in multiple tissues including the endothelium, where it is most highly expressed. Our first objective was to evaluate the role of PEAR1 in endothelial function by examining flow-mediated dilation of the brachial artery in 641 participants from the Heredity and Phenotype Intervention Heart Study. Our second objective was to further define the impact of PEAR1 on cardiovascular disease computationally through meta-analysis of 75,000 microarrays, yielding insights regarding PEAR1 function, and predictions of phenotypes and diseases affected by PEAR1 dysregulation. Based on the results of this meta-analysis we examined whether genetic variation in PEAR1 influences endothelial function using an ex vivo assay of endothelial cell migration. We observed a significant association between rs12041331 and flow-mediated dilation in participants of the Heredity and Phenotype Intervention Heart Study (P = 0.02). Meta-analysis results revealed that PEAR1 expression is highly correlated with several genes (e.g. ANG2, ACVRL1, ENG) and phenotypes (e.g. endothelial cell migration, angiogenesis) that are integral to endothelial function. Functional validation of these results revealed that PEAR1 rs12041331 is significantly associated with endothelial migration (P = 0.04). Our results suggest for the first time that genetic variation of PEAR1 is a significant determinant of endothelial function through pathways implicated in cardiovascular disease.

AB - Platelet Endothelial Aggregation Receptor 1 (PEAR1) is a newly identified membrane protein reported to be involved in multiple vascular and thrombotic processes. While most studies to date have focused on the effects of this receptor in platelets, PEAR1 is located in multiple tissues including the endothelium, where it is most highly expressed. Our first objective was to evaluate the role of PEAR1 in endothelial function by examining flow-mediated dilation of the brachial artery in 641 participants from the Heredity and Phenotype Intervention Heart Study. Our second objective was to further define the impact of PEAR1 on cardiovascular disease computationally through meta-analysis of 75,000 microarrays, yielding insights regarding PEAR1 function, and predictions of phenotypes and diseases affected by PEAR1 dysregulation. Based on the results of this meta-analysis we examined whether genetic variation in PEAR1 influences endothelial function using an ex vivo assay of endothelial cell migration. We observed a significant association between rs12041331 and flow-mediated dilation in participants of the Heredity and Phenotype Intervention Heart Study (P = 0.02). Meta-analysis results revealed that PEAR1 expression is highly correlated with several genes (e.g. ANG2, ACVRL1, ENG) and phenotypes (e.g. endothelial cell migration, angiogenesis) that are integral to endothelial function. Functional validation of these results revealed that PEAR1 rs12041331 is significantly associated with endothelial migration (P = 0.04). Our results suggest for the first time that genetic variation of PEAR1 is a significant determinant of endothelial function through pathways implicated in cardiovascular disease.

UR - http://www.scopus.com/inward/record.url?scp=84947234936&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84947234936&partnerID=8YFLogxK

U2 - 10.1371/journal.pone.0138795

DO - 10.1371/journal.pone.0138795

M3 - Article

C2 - 26406321

AN - SCOPUS:84947234936

VL - 10

JO - PLoS One

JF - PLoS One

SN - 1932-6203

IS - 9

M1 - e0138795

ER -