Dataset Information

Genome-Wide Association Study Links Receptor Tyrosine Kinase Inhibitor Sprouty 2 to Thrombocytopenia after Coronary Artery Bypass Surgery.

ABSTRACT:

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 × 10⁹/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.

SUBMITTER: Karhausen JA

PROVIDER: S-EPMC6428429 | biostudies-literature | 2018 Sep

REPOSITORIES: biostudies-literature

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Publications

Genome-Wide Association Study Links Receptor Tyrosine Kinase Inhibitor Sprouty 2 to Thrombocytopenia after Coronary Artery Bypass Surgery.

Karhausen Jörn A JA Qi Wenjing W Smeltz Alan M AM Li Yi-Ju YJ Shah Svati H SH Kraus William E WE Mathew Joseph P JP Podgoreanu Mihai V MV Kertai Miklos D MD

Thrombosis and haemostasis 20180813 9

<h4>Introduction</h4> 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.<h4>Materials and methods</h4> Study subjects underwent isolated on-pump CABG surgery at Duke University Medical Center. Post-operative thrombocytopenia was defined as platelet count < 100 × 1 ...[more]

PMID: 30103242

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Project description:BackgroundThrombocytopenia, a common complication of coronary artery bypass graft (CABG) surgery, is particularly prevalent among elderly individuals. This study developed a risk prediction model utilizing preoperative and intraoperative variables to identify high-risk elderly patients prone to developing thrombocytopenia.MethodsThe patients were retrospectively recruited from Beijing Anzhen Hospital between February 2019 and December 2020. Postoperative thrombocytopenia was defined as a postoperative platelet (PLT) count <100×109/L as measured within 7 days after surgery. The entire population was randomly split into derivation and validation sets in a 7:3 ratio. The derivation set underwent variable screen by the least absolute shrinkage and selection operator (LASSO) regression method. To evaluate the predictive ability of the model for thrombocytopenia, decision curve analysis (DCA) and receiver operating characteristic (ROC) curves were generated in the derivation and validation sets.ResultsA total of 1,773 patients were recruited in this study, with random assignment to either the derivation set (1,242 cases) or the validation set (531 cases). LASSO regression was utilized the risk factors associated with thrombocytopenia, resulting in selection of preoperative baseline variables: body mass index (BMI), estimated glomerular filtration rate (eGFR), B-type natriuretic peptide (BNP), preoperative PLT, and use of beta-blocker, and intraoperative variables: red blood cell (RBC) transfusion, plasma transfusion, use of intra-aortic balloon pump (IABP) and cardiopulmonary bypass (CPB), reoperation for bleeding, washed RBC transfusion volume, and use of epinephrine. The logistic regression was employed to establish the risk prediction. The area under the ROC curve (AUC) for the derivation set was 0.900 [95% confidence interval (CI): 0.880-0.920], while for the validation cohort, it was 0.897 (95% CI: 0.866-0.928).ConclusionsThe model incorporating significant preoperative and intraoperative variables exhibited good predictive performance for thrombocytopenia in elderly patients undergoing CABG surgery.

Project description:BackgroundThe survival benefit of a strategy of coronary-artery bypass grafting (CABG) added to guideline-directed medical therapy, as compared with medical therapy alone, in patients with coronary artery disease, heart failure, and severe left ventricular systolic dysfunction remains unclear.MethodsFrom July 2002 to May 2007, a total of 1212 patients with an ejection fraction of 35% or less and coronary artery disease amenable to CABG were randomly assigned to undergo CABG plus medical therapy (CABG group, 610 patients) or medical therapy alone (medical-therapy group, 602 patients). The primary outcome was death from any cause. Major secondary outcomes included death from cardiovascular causes and death from any cause or hospitalization for cardiovascular causes. The median duration of follow-up, including the current extended-follow-up study, was 9.8 years.ResultsA primary outcome event occurred in 359 patients (58.9%) in the CABG group and in 398 patients (66.1%) in the medical-therapy group (hazard ratio with CABG vs. medical therapy, 0.84; 95% confidence interval [CI], 0.73 to 0.97; P=0.02 by log-rank test). A total of 247 patients (40.5%) in the CABG group and 297 patients (49.3%) in the medical-therapy group died from cardiovascular causes (hazard ratio, 0.79; 95% CI, 0.66 to 0.93; P=0.006 by log-rank test). Death from any cause or hospitalization for cardiovascular causes occurred in 467 patients (76.6%) in the CABG group and in 524 patients (87.0%) in the medical-therapy group (hazard ratio, 0.72; 95% CI, 0.64 to 0.82; P<0.001 by log-rank test).ConclusionsIn a cohort of patients with ischemic cardiomyopathy, the rates of death from any cause, death from cardiovascular causes, and death from any cause or hospitalization for cardiovascular causes were significantly lower over 10 years among patients who underwent CABG in addition to receiving medical therapy than among those who received medical therapy alone. (Funded by the National Institutes of Health; STICH [and STICHES] ClinicalTrials.gov number, NCT00023595.).

Dataset Information

Genome-Wide Association Study Links Receptor Tyrosine Kinase Inhibitor Sprouty 2 to Thrombocytopenia after Coronary Artery Bypass Surgery.

Introduction

Materials and methods

Results

Conclusion

Publications

Genome-Wide Association Study Links Receptor Tyrosine Kinase Inhibitor Sprouty 2 to Thrombocytopenia after Coronary Artery Bypass Surgery.

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