Abstract
Endocardial cushion defects (ECDs) of the cardiac outflow tract are among the most common congenital heart disease phenotypes. VEGF is essential for endocardial cushion formation and derangements in VEGF synthesis lead to ECD. Three functional single nucleotide polymorphisms (SNPs) in the VEGF gene −2578 C>A, −1154 G>A, and −634 G>C play a role in cardiogenesis. In a Dutch case-control family study of triads, 190 case and 317 control children with both parents, we investigated linkage and association between these VEGF SNPs and ECD. Allele frequencies for the three VEGF SNPs were comparable between ECD children and controls. However, VEGF alleles −2578 C and −1154 G were transmitted more frequently to children with ECD (p = 0.003 and p = 0.002), in particular perimembranous ventricular septal defects (p = 0.012 and p = 0.006). The −2578A/−1154A/−634G haplotype was associated with a reduced risk of ECD (OR 0.7; 95% CI, 0.6–1.0) and was significantly less transmitted to children with ECD (p = 0.002). In a Dutch population, we show that the VEGF 2578 C, −1154 G alleles, and the AAG haplotype are associated with ECD. Possible VEGF gene-environment interactions exposures are discussed.
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Abbreviations
- ECD:
-
endocardial cushion defect
- FBAT:
-
family-based association test
- HBAT:
-
haplotype-based association test
- PS:
-
pulmonary valve stenosis
- pVSD:
-
perimembranous ventricular septal defect
- SNP:
-
single nucleotide polymorphism
- TOF:
-
Tetralogy of Fallot
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Acknowledgements
We thank all participating children and their parents. We thank Professor J. Ottenkamp and Dr. F.M.H. Siebel for their contributions in the recruitment of the case and control families. We are also indebted to Dr. A.C. Verkleij-Hagoort, Ms. L.M.J.W. van Driel, and Ms. S. Borst for data collection, to Mr. B. van Zelst and Mr. P. Arp for technical support, and to Dr. M. Wildhagen for his contribution to data management.
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Supported by the Corporate Development International (grant 2005) and Netherlands Heart Foundation (grant 2002.B027).
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Smedts, H., Isaacs, A., de Costa, D. et al. VEGF Polymorphisms Are Associated With Endocardial Cushion Defects: A Family-Based Case-Control Study. Pediatr Res 67, 23–28 (2010). https://doi.org/10.1203/PDR.0b013e3181c1b144
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DOI: https://doi.org/10.1203/PDR.0b013e3181c1b144
