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.
authors.affiliation: Division of Endocrinology, Diabetes, and Nutrition, and Program for Personalized and Genomic Medicine, University of Maryland School of Medicine, Baltimore, Maryland, United States of America.
authors.forename: Adam S
authors.initials: AS
authors.lastname: Fisch
authors.affiliation: Division of Endocrinology, Diabetes, and Nutrition, and Program for Personalized and Genomic Medicine, University of Maryland School of Medicine, Baltimore, Maryland, United States of America.
authors.forename: Laura M
authors.initials: LM
authors.lastname: Yerges-Armstrong
authors.affiliation: Division of Endocrinology, Diabetes, and Nutrition, and Program for Personalized and Genomic Medicine, University of Maryland School of Medicine, Baltimore, Maryland, United States of America.
authors.forename: Joshua D
authors.initials: JD
authors.lastname: Backman
authors.affiliation: Division of Endocrinology, Diabetes, and Nutrition, and Program for Personalized and Genomic Medicine, University of Maryland School of Medicine, Baltimore, Maryland, United States of America.
authors.forename: Hong
authors.initials: H
authors.lastname: Wang
authors.affiliation: Division of Endocrinology, Diabetes, and Nutrition, and Program for Personalized and Genomic Medicine, University of Maryland School of Medicine, Baltimore, Maryland, United States of America.
authors.forename: Patrick
authors.initials: P
authors.lastname: Donnelly
authors.affiliation: Division of Endocrinology, Diabetes, and Nutrition, and Program for Personalized and Genomic Medicine, University of Maryland School of Medicine, Baltimore, Maryland, United States of America.
authors.forename: Kathleen A
authors.initials: KA
authors.lastname: Ryan
authors.affiliation: Division of Endocrinology, Diabetes, and Nutrition, and Program for Personalized and Genomic Medicine, University of Maryland School of Medicine, Baltimore, Maryland, United States of America.
authors.forename: Ankita
authors.initials: A
authors.lastname: Parihar
authors.affiliation: Division of Endocrinology, Diabetes, and Nutrition, and Program for Personalized and Genomic Medicine, University of Maryland School of Medicine, Baltimore, Maryland, United States of America.
authors.forename: Mary A
authors.initials: MA
authors.lastname: Pavlovich
authors.affiliation: Division of Endocrinology, Diabetes, and Nutrition, and Program for Personalized and Genomic Medicine, University of Maryland School of Medicine, Baltimore, Maryland, United States of America.
authors.forename: Braxton D
authors.initials: BD
authors.lastname: Mitchell
authors.affiliation: Division of Endocrinology, Diabetes, and Nutrition, and Program for Personalized and Genomic Medicine, University of Maryland School of Medicine, Baltimore, Maryland, United States of America.
authors.forename: Jeffrey R
authors.initials: JR
authors.lastname: O'Connell
authors.affiliation: Division of Cardiology, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland, United States of America.
authors.forename: William
authors.initials: W
authors.lastname: Herzog
authors.affiliation: Department of Obstetrics, Gynecology, and Reproductive Sciences, University of Maryland School of Medicine, Baltimore, Maryland, United States of America.
authors.forename: Christopher R
authors.initials: CR
authors.lastname: Harman
authors.affiliation: Department of Biochemistry and Molecular Biology, University of Oklahoma Health Science Center, Oklahoma City, Oklahoma, United States of America; Program in Arthritis & Clinical Immunology Research, Oklahoma Medical Research Foundation, Oklahoma City, Oklahoma, United States of America.
authors.forename: Jonathan D
authors.initials: JD
authors.lastname: Wren
authors.affiliation: Division of Endocrinology, Diabetes, and Nutrition, and Program for Personalized and Genomic Medicine, University of Maryland School of Medicine, Baltimore, Maryland, United States of America.
authors.forename: Joshua P
authors.initials: JP
authors.lastname: Lewis
mesh_terms: D000328:Adult; D001916:Brachial Artery / Q000503:physiopathology*; D002318:Cardiovascular Diseases / Q000235:genetics* / Q000503:physiopathology; D002465:Cell Movement; D042783:Endothelial Cells / Q000166:cytology*; D005260:Female; D005786:Gene Expression Regulation; D020022:Genetic Predisposition to Disease; D014644:Genetic Variation; D061307:Human Umbilical Vein Endothelial Cells; D006801:Humans; D008297:Male; D008875:Middle Aged; D011956:Receptors, Cell Surface / Q000235:genetics*
chemical_list: C502809:PEAR1 protein, human; D011956:Receptors, Cell Surface