Identification of a functional genetic variant driving racially dimorphic platelet gene expression of the thrombin receptor regulator, PCTP.

Authors

Xianguo Kong, Thomas Jefferson UniversityFollow
Lukas M. Simon, Baylor College of MedicineFollow
Michael Holinstat, Thomas Jefferson UniversityFollow
Chad A. Shaw, Baylor College of MedicineFollow
Paul F. Bray, Thomas Jefferson UniversityFollow
Leonard C. Edelstein, Thomas Jefferson UniversityFollow

Document Type

Article

Publication Date

5-3-2017

Comments

This article has been peer reviewed. It is the authors' final version prior to publication in Thrombosis and Haemostasis

Volume 117, Issue 5, May 2017, Pages 962-970.

The published version is available at DOI: 10.1160/TH16-09-0692. Copyright © Kong et al.

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.

Recommended Citation

Kong, Xianguo; Simon, Lukas M.; Holinstat, Michael; Shaw, Chad A.; Bray, Paul F.; and Edelstein, Leonard C., "Identification of a functional genetic variant driving racially dimorphic platelet gene expression of the thrombin receptor regulator, PCTP." (2017). Cardeza Foundation for Hematologic Research. Paper 43.
https://jdc.jefferson.edu/cardeza_foundation/43