title: Low multiple electrode aggregometry platelet responses are not associated with non-synonymous variants in G-protein coupled receptor genes.
abstract: BACKGROUND
  Multiple electrode aggregometry (MEA) improves prediction of thrombosis and bleeding in cardiac patients. However, the causes of inter-individual variation in MEA results are incompletely understood. We explore whether low MEA results are associated with platelet G-protein coupled receptor (GPCR) gene variants.
  
  
  METHODS
  The effects of P2Y12 receptor (P2Y12), thromboxane A2 receptor (TPα) and protease-activated receptor 1 (PAR1) dysfunction on the MEA ADP-test, ASPI-test and TRAP-test were determined using receptor antagonists. Cardiac surgery patients with pre-operative MEA results suggesting GPCR dysfunction were selected for P2Y12 (P2RY12), TPα (TBXA2R) and PAR1 (F2R) sequencing.
  
  
  RESULTS
  In control blood samples, P2Y12, TPα or PAR1 antagonists markedly reduced ADP-test, ASPI-test and TRAP-test results respectively. In the 636 patients from a cohort of 2388 cardiac surgery patients who were not receiving aspirin or a P2Y12 blocker, the median ADP-test result was 75.1 U (range 4.8-153.2), ASPI-test 83.7 U (1.4-157.3) and TRAP-test 117.7 U (2.4-194.1), indicating a broad range of results unexplained by anti-platelet drugs. In 238 consenting patients with unexplained low MEA results, three P2RY12 variants occurred in 70/107 (65%) with suspected P2Y12 dysfunction and four TBXA2R variants occurred in 19/22 (86%) with suspected TPα dysfunction although the later group was too small to draw meaningful conclusions about variant frequency. All the variants were synonymous and unlikely to cause GPCR dysfunction. There were no F2R variants in the 109 cases with suspected PAR1 dysfunction.
  
  
  CONCLUSIONS
  MEA results suggesting isolated platelet GPCR dysfunction were common in cardiac surgery patients, but were not associated with non-synonymous variants in P2RY12 or F2R.
authors: School of Clinical Sciences, University of Bristol, Bristol, UK. Electronic address: jane.norman@bristol.ac.uk.
authors: Jane E
authors: JE
authors: Norman
authors: University Hospitals Bristol NHS Foundation Trust, Bristol, UK.
authors: Kurtis R
authors: KR
authors: Lee
authors: University Hospitals Bristol NHS Foundation Trust, Bristol, UK.
authors: Mary E
authors: ME
authors: Walker
authors: University Hospitals Bristol NHS Foundation Trust, Bristol, UK.
authors: Sherina L
authors: SL
authors: Murden
authors: School of Clinical Sciences, University of Bristol, Bristol, UK.
authors: Jessica
authors: J
authors: Harris
authors: School of Physiology and Pharmacology, University of Bristol, Bristol, UK.
authors: Stuart
authors: S
authors: Mundell
authors: Department of Cardiovascular Sciences, University of Leicester, Leicester, UK.
authors: Gavin
authors: G
authors: J Murphy
authors: School of Cellular and Molecular Medicine, University of Bristol, Bristol, UK.
authors: Andrew D
authors: AD
authors: Mumford
mesh_terms: D001792:Blood Platelets / Q000378:metabolism*; D005260:Female; D006801:Humans; D008297:Male; D010974:Platelet Aggregation / Q000235:genetics*; D010979:Platelet Function Tests / Q000379:methods*; D043562:Receptors, G-Protein-Coupled / Q000096:biosynthesis / Q000235:genetics*; D015398:Signal Transduction
chemical_list: D043562:Receptors, G-Protein-Coupled
keywords: G-protein coupled receptor (GPCR); Multiple electrode aggregometry (MEA); Platelet function