Thromb Haemost 2018; 118(09): 1572-1585
DOI: 10.1055/s-0038-1667199
Blood Cells, Inflammation and Infection
Georg Thieme Verlag KG Stuttgart · New York

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

Jörn A. Karhausen*
1  Department of Anesthesiology, Duke Perioperative Genomics Program, Duke University Medical Center, Duke University, Durham, North Carolina, United States
,
Wenjing Qi*
2  Department of Biostatistics and Bioinformatics, Duke University Medical Center, Duke University, Durham, North Carolina, United States
,
Alan M. Smeltz
1  Department of Anesthesiology, Duke Perioperative Genomics Program, Duke University Medical Center, Duke University, Durham, North Carolina, United States
,
Yi-Ju Li
2  Department of Biostatistics and Bioinformatics, Duke University Medical Center, Duke University, Durham, North Carolina, United States
3  Molecular Physiology Institute, Duke University Medical Center, Duke University, Durham, North Carolina, United States
,
Svati H. Shah
3  Molecular Physiology Institute, Duke University Medical Center, Duke University, Durham, North Carolina, United States
4  Division of Cardiology, Department of Medicine, Duke University Medical Center, Duke University, Durham, North Carolina, United States
,
William E. Kraus
3  Molecular Physiology Institute, Duke University Medical Center, Duke University, Durham, North Carolina, United States
4  Division of Cardiology, Department of Medicine, Duke University Medical Center, Duke University, Durham, North Carolina, United States
,
Joseph P. Mathew
1  Department of Anesthesiology, Duke Perioperative Genomics Program, Duke University Medical Center, Duke University, Durham, North Carolina, United States
,
Mihai V. Podgoreanu*
1  Department of Anesthesiology, Duke Perioperative Genomics Program, Duke University Medical Center, Duke University, Durham, North Carolina, United States
,
Miklos D. Kertai*
1  Department of Anesthesiology, Duke Perioperative Genomics Program, Duke University Medical Center, Duke University, Durham, North Carolina, United States
5  Department of Anesthesiology, Vanderbilt University Medical Center, Vanderbilt University, Nashville, Tennessee, United States
,
for the Duke Perioperative Genetics Safety Outcomes (PEGASUS) Investigative Team› Author Affiliations
Funding Funding for this study was provided by: the Duke Anesthesiology Developing Research Excellence in Anesthesia Management (DREAM) Award (to Dr. Kertai); the National Institutes of Health grants 1R56HL126891–01 (to Dr. Karhausen), HL075273 and HL092071 (to Dr. Podgoreanu), HL096978, HL108280 and HL109971 (to Dr. Mathew), HL095987 (to Dr. Shah) and HL101621 (to Dr. Kraus); the American Heart Association grants 15SDG25080046 (to Dr. Karhausen), 9951185U (to Dr. Mathew) and 0120492U (to Dr. Podgoreanu); and a Duke School of Medicine Health Scholar award (to Dr. Karhausen). Logistics support was provided by CATHGEN. The authors are solely responsible for the design and conduct of this study, all study analyses and drafting and editing of the manuscript and its final contents.
Further Information

Publication History

16 December 2017

08 June 2018

Publication Date:
13 August 2018 (eFirst)

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.

* The first two and last two authors contributed equally to this work.


** Members of the Duke Perioperative Genetics and Safety Outcomes (PEGASUS) Investigative Team are acknowledged in the Acknowledgment section.


Supplementary Material