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- CHD, congenital heart disease
- DGS, DiGeorge syndrome
- SNP, single nucleotide polymorphism
- TDT, transmission disequilibrium test
- TGA, transposition of the great arteries
- TOF, tetralogy of Fallot
- VEGF, vascular endothelial growth factor
- VSD, ventricular septum defect
Congenital heart disease (CHD) presents a huge medical problem, as it affects between two and eight newborn children per 100 live births.1 Risk factors include alcohol and drug consumption as well as genetic defects. However, chromosomal and single gene defects cause only a relatively minor proportion of cases and, thus, most CHD is considered to be multi-factorial in origin, with various genes interacting with each other or with environmental factors to determine disease liability.2 To date, none of the CHD genetic susceptibility factors have been discovered.
Tetralogy of Fallot (TOF) is a common form of CHD, characterised by a subaortic ventricular septum defect (VSD), an overriding aorta, a right ventricular outflow tract obstruction, and right ventricular hypertrophy. TOF occurs in 4.21 of every 10 000 births and is the most common type of CHD with cyanosis after 1 year of life.1 TOF may occur as part of the DiGeorge syndrome (DGS) which is caused by deletions of chromosome 22q11 and characterised by conotruncal cardiac, craniofacial, thymic, and parathyroid anomalies. However, in most cases (in 2.65 per 10 000 children) TOF occurs as an isolated defect. Mutations in the JAGGED1 or NKX2.5 genes have been found in only a few percentages of cases with isolated, non-syndromic TOF and thus, the genetic etiology in the large majority of these cases remains entirely unknown.2 By using a multi-genetic approach, we recently discovered that VEGF is a modifier of DGS.3 We therefore assessed here whether VEGF might be a modifier of the cardiac birth defects in subjects with isolated, non-syndromic TOF.
Study design and participants
To examine whether VEGF gene variations are associated with TOF, we used the transmission disequilibrium test (TDT) to analyse linkage disequilibrium of single nucleotide polymorphisms (SNPs) in the VEGF gene in trios of parents and their proband affected …
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