title: Identification of a functional genetic variant driving racially dimorphic platelet gene expression of the thrombin receptor regulator, PCTP.
abstract: Platelet activation in response to stimulation of the Protease Activated Receptor 4 (PAR4) receptor differs by race. One factor that contributes to this difference is the expression level of Phosphatidylcholine Transfer Protein (PCTP), a regulator of platelet PAR4 function. We have conducted an expression Quantitative Trait Locus (eQTL) analysis that identifies single nucleotide polymorphisms (SNPs) linked to the expression level of platelet genes. This analysis revealed 26 SNPs associated with the expression level of PCTP at genome-wide significance (p < 5×10-8). Using annotation from ENCODE and other public data we prioritised one of these SNPs, rs2912553, for functional testing. The allelic frequency of rs2912553 is racially-dimorphic, in concordance with the racially differential expression of PCTP. Reporter gene assays confirmed that the single nucleotide change caused by rs2912553 altered the transcriptional potency of the surrounding genomic locus. Electromobility shift assays, luciferase assays, and overexpression studies indicated a role for the megakaryocytic transcription factor GATA1. In summary, we have integrated multi-omic data to identify and functionalise an eQTL. This, along with the previously described relationship between PCTP and PAR4 function, allows us to characterise a genotype-phenotype relationship through the mechanism of gene expression.
authors.forename: Xianguo
authors.initials: X
authors.lastname: Kong
authors.forename: Lukas M
authors.initials: LM
authors.lastname: Simon
authors.forename: Michael
authors.initials: M
authors.lastname: Holinstat
authors.forename: Chad A
authors.initials: CA
authors.lastname: Shaw
authors.forename: Paul F
authors.initials: PF
authors.lastname: Bray
authors.affiliation: Leonard C. Edelstein, Department of Medicine Sidney Kimmel Medical College, Thomas Jefferson University, 1020 Locust Street, Suite 394, Philadelphia, PA 19107, USA, Tel.: +1 215 955 1797, Fax: +1 215 955 9170, leonard.edelstein@jefferson.edu.
authors.forename: Leonard C
authors.initials: LC
authors.lastname: Edelstein
mesh_terms: D001741:Black or African American / Q000235:genetics*; D030541:Databases, Genetic; D024202:Electrophoretic Mobility Shift Assay; D050982:GATA1 Transcription Factor / Q000235:genetics / Q000378:metabolism; D005786:Gene Expression Regulation; D005787:Gene Frequency; D055106:Genome-Wide Association Study; D006801:Humans; D020014:K562 Cells; D049294:Phospholipid Transfer Proteins / Q000235:genetics* / Q000378:metabolism; D020641:Polymorphism, Single Nucleotide; D040641:Quantitative Trait Loci; D018179:Receptors, Thrombin / Q000235:genetics / Q000378:metabolism; D014158:Transcription, Genetic; D014162:Transfection; D044465:White People / Q000235:genetics*
chemical_list: D050982:GATA1 Transcription Factor; C494688:GATA1 protein, human; D049294:Phospholipid Transfer Proteins; D018179:Receptors, Thrombin; C112908:protease-activated receptor 4
keywords: PAR4; PCTP; Platelets; eQTL; genetics