Identification of a specific intronic PEAR1 gene variant associated with greater platelet aggregability and protein expression

Nauder Faraday, Lisa R. Yanek, Xiao Ping Yang, Rasika Mathias, J. Enrique Herrera-Galeano, Bhoom Suktitipat, Rehan Qayyum, Andrew D. Johnson, Ming Huei Chen, Geoffrey H. Tofler, Ingo Ruczinski, Alan D. Friedman, Arnaldur Gylfason, Unnur Thorsteinsdottir, Paul F. Bray, Christopher J. O'Donnell, Diane M. Becker, Lewis C. Becker

Research output: Contribution to journalArticlepeer-review

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 Gallele 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.

Original languageEnglish (US)
Pages (from-to)3367-3375
Number of pages9
JournalBlood
Volume118
Issue number12
DOIs
StatePublished - Sep 22 2011

ASJC Scopus subject areas

  • Biochemistry
  • Immunology
  • Hematology
  • Cell Biology

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