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 Ϫ2578 CϾA, Ϫ1154 GϾA, and Ϫ634 GϾC 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 Ϫ2578 C and Ϫ1154 G were transmitted more frequently to children with ECD (p ϭ 0.003 and p ϭ 0.002), in particular perimembranous ventricular septal defects (p ϭ 0.012 and p ϭ 0.006). The Ϫ2578A/Ϫ1154A/Ϫ634G 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 ϭ 0.002). In a Dutch population, we show that the VEGF 2578 C, Ϫ1154 G alleles, and the AAG haplotype are associated with ECD. Possible VEGF gene-environment interactions exposures are discussed. (Pediatr Res 67: 23-28, 2010) C ongenital heart diseases are the most frequent major congenital malformations with a worldwide birth prevalence rate of over one million per year (1). Because of the high infant mortality and morbidity rates, the causes of these malformations should be identified and targeted for preventive strategies in the future (2). Most congenital heart diseases have a complex origin, in which interactions between subtle genetic variations and periconception exposures play a role (3). Vasculogenesis and heart development are dependent on the genetic constitution of the embryo derived from both parents, and the maternal genetically controlled nutritional, endocrine and metabolic environment (4). During cardiac development, the outflow tract is divided into the ascending aorta and the pulmonary trunk and aligned to the left and right ventricle, respectively. The formation of the endocardial cushions in the atrioventricular canal and outflow tract takes place by epithelial-mesenchymal transformation, which is a key process in the development of the heart septa and valves. Numerous lines of research have implicated a strict spatiotemporal expression pattern of the VEGF gene in the control of endocardial cushion development (5). In addition to its tight regulation during cardiogenesis, VEGF gene expression is also regulated by environmental exposures. A nice example is that hypoxia induces VEGF gene expression and seems to contribute as such to the generation of major malformations in the atrioventricular-canal and outflow tract in mice (6). Hyperglycemia inhibits epithelial-mesenchymal transformation by reducing VEGF gene expression (7). Furthermore, hyperhomocysteinemia, which increases the risk of human congenital heart disease, was shown to up-regulate VEGF mRNA in a human endothelial cell line (8). Intere...

Hypoplastic left heart syndrome is associated with structural and vascular placental abnormalities and leptin dysregulation

“…The recent identification of a bona vide mouse model of HLHS [50] suggests the mechanisms underlying these observations may be delineated. Previous studies have highlighted the involvement of angiogenic pathways such as VEGF in the development of CVM [51, 52], and future studies into other angiogenic pathways, including Placental Growth Factor and FLT-1, and metabolic/growth factors will aid in elucidating mechanisms involved in the altered placental vasculature and structure. While the findings of this study support the general idea that there may be a shared etiology for placenta and cardiac defects, or a placental cause for some cases of HLHS or other CVM, the generalizability of this concept is limited by disease heterogeneity.…”

Possible Common Aetiology behind Maternal Preeclampsia and Congenital Heart Defects in the Child: a Cardiovascular Diseases in Norway Project Study

“…It is especially interesting that we found the association between AVSD and early‐onset preeclampsia to be much stronger than for any other type of CHD. In mouse heart tissue models, VEGF has been found to be important for cardiac development, particularly in the atrioventricular field and the endocardial cushion tissue, and single nucleotide polymorphism of the VEGF gene has been shown to be associated with endocardial cushion defects in human . The anti‐angiogenic factor sFlt‐1, which is upregulated in early‐onset preeclampsia, acts as an endogenous inhibitor of the pro‐angiogenic factors VEGF and PlGF .…”

“…In mouse heart tissue models, VEGF has been found to be important for cardiac development, particularly in the atrioventricular field and the endocardial cushion tissue, 31 and single nucleotide polymorphism of the VEGF gene has been shown to be associated with endocardial cushion defects in human. 32,33 The antiangiogenic factor sFlt-1, which is upregulated in earlyonset preeclampsia, acts as an endogenous inhibitor of the pro-angiogenic factors VEGF and PlGF. 19,25 In the study by Llurba et al, 18 CHDs were categorised into only three groups, and the group called 'atrioventricular valve defects' showed the strongest associations with low levels of PlGF and high levels of sFlt-1 in maternal and fetal blood.…”

VEGF Polymorphisms do not contribute to the risk of congenital heart defect

“…A total of 4 articles explored a single type of CHD [13,14,21,22], whereas various types of CHD were included in the other two articles [2,23]. Among them, three studies were carried out in China [13,21,24], one in Chile [14], one in Germany [22], and one in the Netherlands [24]. The distributions of the genotypes in the control groups were consistent with Hardy-Weinberg equilibrium (p>0.05) in all six studies in which the control groups were representative (Tables 1-3).…”