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

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 x 10(-8)) and were replicated down to the variant and nucleotide level in 835 persons of African ancestry (P = 2.31 x 10(-27)) and in an independent sample of 2755 persons of European descent (P = 1.64 x 10(-5)). Sequencing confirmed that variation at rs12041331 accounted most strongly (P = 2.07 x 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. (Blood. 2011;118(12):3367-3375)