title: Identification of a specific intronic PEAR1 gene variant associated with greater platelet aggregability and protein expression.
abstract: Genetic variation is thought to contribute to variability in platelet function; however, the specific variants and mechanisms that contribute to altered platelet function are poorly defined. With the use of a combination of fine mapping and sequencing of the platelet endothelial aggregation receptor 1 (PEAR1) gene we identified a common variant (rs12041331) in intron 1 that accounts for ≤ 15% of total phenotypic variation in platelet function. Association findings were robust in 1241 persons of European ancestry (P = 2.22 × 10⁻⁸) and were replicated down to the variant and nucleotide level in 835 persons of African ancestry (P = 2.31 × 10⁻²⁷) and in an independent sample of 2755 persons of European descent (P = 1.64 × 10⁻⁵). Sequencing confirmed that variation at rs12041331 accounted most strongly (P = 2.07 × 10⁻⁶) for the relation between the PEAR1 gene and platelet function phenotype. A dose-response relation between the number of G alleles at rs12041331 and expression of PEAR1 protein in human platelets was confirmed by Western blotting and ELISA. Similarly, the G allele was associated with greater protein expression in a luciferase reporter assay. These experiments identify the precise genetic variant in PEAR1 associated with altered platelet function and provide a plausible biologic mechanism to explain the association between variation in the PEAR1 gene and platelet function phenotype.
authors.affiliation: Department of Anesthesiology and Critical Care Medicine,J ohns Hopkins University School of Medicine, Baltimore, MD, USA. nfaraday@jhmi.edu
authors.forename: Nauder
authors.initials: N
authors.lastname: Faraday
authors.forename: Lisa R
authors.initials: LR
authors.lastname: Yanek
authors.forename: Xiao Ping
authors.initials: XP
authors.lastname: Yang
authors.forename: Rasika
authors.initials: R
authors.lastname: Mathias
authors.forename: J Enrique
authors.initials: JE
authors.lastname: Herrera-Galeano
authors.forename: Bhoom
authors.initials: B
authors.lastname: Suktitipat
authors.forename: Rehan
authors.initials: R
authors.lastname: Qayyum
authors.forename: Andrew D
authors.initials: AD
authors.lastname: Johnson
authors.forename: Ming-Huei
authors.initials: MH
authors.lastname: Chen
authors.forename: Geoffrey H
authors.initials: GH
authors.lastname: Tofler
authors.forename: Ingo
authors.initials: I
authors.lastname: Ruczinski
authors.forename: Alan D
authors.initials: AD
authors.lastname: Friedman
authors.forename: Arnaldur
authors.initials: A
authors.lastname: Gylfason
authors.forename: Unnur
authors.initials: U
authors.lastname: Thorsteinsdottir
authors.forename: Paul F
authors.initials: PF
authors.lastname: Bray
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: O'Donnell
authors.forename: Diane M
authors.initials: DM
authors.lastname: Becker
authors.forename: Lewis C
authors.initials: LC
authors.lastname: Becker
mesh_terms: D000483:Alleles; D001241:Aspirin / Q000008:administration & dosage; D044383:Black People / Q000235:genetics*; D001792:Blood Platelets / Q000166:cytology / Q000378:metabolism*; D002460:Cell Line; D003324:Coronary Artery Disease / Q000188:drug therapy / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D015870:Gene Expression; D017930:Genes, Reporter; D056726:Genetic Association Studies; D014644:Genetic Variation; D005838:Genotype; D006801:Humans; D007438:Introns; D008156:Luciferases / Q000032:analysis; D010641:Phenotype; D010974:Platelet Aggregation / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide; D011956:Receptors, Cell Surface / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D017422:Sequence Analysis, DNA; D014162:Transfection; D044465:White People / Q000235:genetics*
chemical_list: C502809:PEAR1 protein, human; D011956:Receptors, Cell Surface; D008156:Luciferases; D001241:Aspirin