title: VEGF polymorphisms are associated with endocardial cushion defects: a family-based case-control study.
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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authors.affiliation: Departments of Obstetrics and Gynecology, University Medical Center, Rotterdam 3015 GD, The Netherlands.
authors.forename: Huberdina P M
authors.initials: HP
authors.lastname: Smedts
authors.forename: Aaron
authors.initials: A
authors.lastname: Isaacs
authors.forename: Dominique
authors.initials: D
authors.lastname: de Costa
authors.forename: André G
authors.initials: AG
authors.lastname: Uitterlinden
authors.forename: Cornelia M
authors.initials: CM
authors.lastname: van Duijn
authors.forename: Adriana C
authors.initials: AC
authors.lastname: Gittenberger-de Groot
authors.forename: Willem A
authors.initials: WA
authors.lastname: Helbing
authors.forename: Eric A P
authors.initials: EA
authors.lastname: Steegers
authors.forename: Régine P M
authors.initials: RP
authors.lastname: Steegers-Theunissen
mesh_terms: D016022:Case-Control Studies; D004699:Endocardium / Q000473:pathology*; D005260:Female; D005787:Gene Frequency; D006801:Humans; D007223:Infant; D008297:Male; D020641:Polymorphism, Single Nucleotide; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics*
chemical_list: D042461:Vascular Endothelial Growth Factor A