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A vascular endothelial growth factor A genetic variant is associated with improved ventricular function and transplant-free survival after surgery for non-syndromic CHD

Published online by Cambridge University Press:  20 September 2017

Constantine D. Mavroudis
Affiliation:
Department of Cardiothoracic Surgery, The Children’s Hospital of Philadelphia, Philadelphia, Pennsylvania, United States of America
Daniel Seung Kim
Affiliation:
Department of Medicine, Division of Medical Genetics, The University of Washington School of Medicine, Seattle, Washington, United States of America Department of Biostatistics, School of Public Health, The University of Washington School of Medicine, Seattle, Washington, United States of America Department of Genome Sciences, The University of Washington School of Medicine, Seattle, Washington, United States of America
Nancy Burnham
Affiliation:
Department of Cardiothoracic Surgery, The Children’s Hospital of Philadelphia, Philadelphia, Pennsylvania, United States of America
Alexandra H. Morss
Affiliation:
Department of Cardiothoracic Surgery, The Children’s Hospital of Philadelphia, Philadelphia, Pennsylvania, United States of America
Jerry H. Kim
Affiliation:
Department of Anesthesia and Pain Medicine, The University of Washington School of Medicine, Seattle, Washington, United States of America
Amber A. Burt
Affiliation:
Department of Medicine, Division of Medical Genetics, The University of Washington School of Medicine, Seattle, Washington, United States of America
David R. Crosslin
Affiliation:
Department of Genome Sciences, The University of Washington School of Medicine, Seattle, Washington, United States of America
Donna M. McDonald-McGinn
Affiliation:
Department of Clinical Genetics, The Children’s Hospital of Philadelphia, Philadelphia, Pennsylvania, United States of America
Elaine H. Zackai
Affiliation:
Department of Clinical Genetics, The Children’s Hospital of Philadelphia, Philadelphia, Pennsylvania, United States of America
Meryl S. Cohen
Affiliation:
Department of Cardiology, The Children’s Hospital of Philadelphia, Philadelphia, Pennsylvania, United States of America
Susan C. Nicolson
Affiliation:
Department of Anesthesiology and Critical Care, The Children’s Hospital of Philadelphia, Philadelphia, Pennsylvania, United States of America
Thomas L. Spray
Affiliation:
Department of Cardiothoracic Surgery, The Children’s Hospital of Philadelphia, Philadelphia, Pennsylvania, United States of America
Ian B. Stanaway
Affiliation:
Department of Genome Sciences, The University of Washington School of Medicine, Seattle, Washington, United States of America Department of Environmental and Occupational Health Services, The University of Washington School of Medicine, Seattle, Washington, United States of America
Deborah A. Nickerson
Affiliation:
Department of Genome Sciences, The University of Washington School of Medicine, Seattle, Washington, United States of America
Mark W. Russell
Affiliation:
Department of Cardiology, CS Mott Children’s Hospital, Ann Arbor, Michigan, United States of America
Hakon Hakonarson
Affiliation:
The Center for Applied Genomics, The Children’s Hospital of Philadelphia, Philadelphia, Pennsylvania, United States of America
Gail P. Jarvik
Affiliation:
Department of Medicine, Division of Medical Genetics, The University of Washington School of Medicine, Seattle, Washington, United States of America
J. William Gaynor*
Affiliation:
Department of Cardiothoracic Surgery, The Children’s Hospital of Philadelphia, Philadelphia, Pennsylvania, United States of America
*
Correspondence to: J. W. Gaynor, MD, Department of Cardiothoracic Surgery, Children’s Hospital of Philadelphia, 34th Street and Civic Center Boulevard, Philadelphia, PA 19104-4399, United States of America. Tel: 215 590 2708; Fax: 215 590 2715; E-mail: Gaynor@email.chop.edu

Abstract

Background

We have previously shown that the minor alleles of vascular endothelial growth factor A (VEGFA) single-nucleotide polymorphism rs833069 and superoxide dismutase 2 (SOD2) single-nucleotide polymorphism rs2758331 are both associated with improved transplant-free survival after surgery for CHD in infants, but the underlying mechanisms are unknown. We hypothesised that one or both of these minor alleles are associated with better systemic ventricular function, resulting in improved survival.

Methods

This study is a follow-up analysis of 422 non-syndromic CHD patients who underwent neonatal cardiac surgery with cardiopulmonary bypass. Echocardiographic reports were reviewed. Systemic ventricular function was subjectively categorised as normal, or as mildly, moderately, or severely depressed. The change in function was calculated as the change from the preoperative study to the last available study. Stepwise linear regression, adjusting for covariates, was performed for the outcome of change in ventricular function. Model comparison was performed using Akaike’s information criterion. Only variables that improved the model prediction of change in systemic ventricular function were retained in the final model.

Results

Genetic and echocardiographic data were available for 335/422 subjects (79%). Of them, 33 (9.9%) developed worse systemic ventricular function during a mean follow-up period of 13.5 years. After covariate adjustment, the presence of the VEGFA minor allele was associated with preserved ventricular function (p=0.011).

Conclusions

These data support the hypothesis that the mechanism by which the VEGFA single-nucleotide polymorphism rs833069 minor allele improves survival may be the preservation of ventricular function. Further studies are needed to validate this genotype–phenotype association and to determine whether this mechanism is related to increased vascular endothelial growth factor production.

Type
Original Articles
Copyright
© Cambridge University Press 2017 

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