Genome-Wide Association Study Links Receptor Tyrosine Kinase Inhibitor Sprouty 2 to Thrombocytopenia after Coronary Artery Bypass Surgery.
| Autor: | Karhausen JA; Department of Anesthesiology, Duke Perioperative Genomics Program, Duke University Medical Center, Duke University, Durham, North Carolina, United States., Qi W; Department of Biostatistics and Bioinformatics, Duke University Medical Center, Duke University, Durham, North Carolina, United States., Smeltz AM; Department of Anesthesiology, Duke Perioperative Genomics Program, Duke University Medical Center, Duke University, Durham, North Carolina, United States., Li YJ; Department of Biostatistics and Bioinformatics, Duke University Medical Center, Duke University, Durham, North Carolina, United States.; Molecular Physiology Institute, Duke University Medical Center, Duke University, Durham, North Carolina, United States., Shah SH; Molecular Physiology Institute, Duke University Medical Center, Duke University, Durham, North Carolina, United States.; Division of Cardiology, Department of Medicine, Duke University Medical Center, Duke University, Durham, North Carolina, United States., Kraus WE; Molecular Physiology Institute, Duke University Medical Center, Duke University, Durham, North Carolina, United States.; Division of Cardiology, Department of Medicine, Duke University Medical Center, Duke University, Durham, North Carolina, United States., Mathew JP; Department of Anesthesiology, Duke Perioperative Genomics Program, Duke University Medical Center, Duke University, Durham, North Carolina, United States., Podgoreanu MV; Department of Anesthesiology, Duke Perioperative Genomics Program, Duke University Medical Center, Duke University, Durham, North Carolina, United States., Kertai MD; Department of Anesthesiology, Duke Perioperative Genomics Program, Duke University Medical Center, Duke University, Durham, North Carolina, United States.; Department of Anesthesiology, Vanderbilt University Medical Center, Vanderbilt University, Nashville, Tennessee, United States. |
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| Jazyk: | angličtina |
| Zdroj: | Thrombosis and haemostasis [Thromb Haemost] 2018 Sep; Vol. 118 (9), pp. 1572-1585. Date of Electronic Publication: 2018 Aug 13. |
| DOI: | 10.1055/s-0038-1667199 |
| Abstrakt: | Introduction: Thrombocytopenia after cardiac surgery independently predicts stroke, acute kidney injury and death. To understand the underlying risks and mechanisms, we analysed genetic variations associated with thrombocytopenia in patients undergoing coronary artery bypass grafting (CABG) surgery. Materials and Methods: Study subjects underwent isolated on-pump CABG surgery at Duke University Medical Center. Post-operative thrombocytopenia was defined as platelet count < 100 × 10 9 /L. Using a logistic regression model adjusted for clinical risk factors, we performed a genome-wide association study in a discovery cohort ( n = 860) and validated significant findings in a replication cohort ( n = 296). Protein expression was assessed in isolated platelets by immunoblot. Results: A total of 63 single-nucleotide polymorphisms met a priori discovery thresholds for replication, but only 1 (rs9574547) in the intergenic region upstream of sprouty 2 ( SPRY2 ) met nominal significance in the replication cohort. The minor allele of rs9574547 was associated with a lower risk for thrombocytopenia (discovery cohort, odds ratio, 0.45, 95% confidence interval, 0.30-0.67, p = 9.76 × 10 -5 ) with the overall association confirmed by meta-analysis (meta- p = 7.88 × 10 -6 ). Immunoblotting demonstrated expression of SPRY2 and its dynamic regulation during platelet activation. Treatment with a functional SPRY2 peptide blunted platelet extracellular signal-regulated kinase (ERK) phosphorylation after agonist stimulation. Conclusion: We identified the association of a genetic polymorphism in the intergenic region of SPRY2 with a decreased incidence of thrombocytopenia after CABG surgery. Because SPRY2 -an endogenous receptor tyrosine kinase inhibitor-is present in platelets and modulates essential signalling pathways, these findings support a role for SPRY2 as a novel modulator of platelet responses after cardiac surgery. Competing Interests: None. (Georg Thieme Verlag KG Stuttgart · New York.) |
| Databáze: | MEDLINE |
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