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Low expression VEGF haplotype increases the risk for tetralogy of Fallot: a family based association study
  1. D Lambrechts1,
  2. K Devriendt3,
  3. D A Driscoll4,
  4. E Goldmuntz5,
  5. M Gewillig3,
  6. R Vlietinck2,
  7. D Collen1,
  8. P Carmeliet1
  1. 1The Center for Transgene Technology and Gene Therapy, Flanders Interuniversity Institute for Biotechnology, Leuven, Belgium
  2. 2Division of Population Genetics and Bioinformatics, University of Maastricht, The Netherlands
  3. 3The Center for Human Genetics and Department of Pediatrics, Katholieke Universiteit Leuven, Leuven, Belgium
  4. 4Division of Human Genetics and Molecular Biology, University of Pennsylvania School of Medicine, Philadelphia, PA, USA
  5. 5Division of Pediatric Cardiology, Department of Pediatrics, University of Pennsylvania School of Medicine, Philadelphia, PA, USA
  1. Correspondence to:
 Professor Peter Carmeliet
 The Center for Transgene Technology and Gene Therapy, Flanders Interuniversity Institute for Biotechnology, KULeuven, Herestraat 49, Leuven, B-3000, Belgium;

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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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  • DL is a post doctoral fellow supported by the Fund for Scientific Research-Flanders (FWO, Belgium). PC is supported in part by the European Union (Biomed BMH4 CT98 3380), by grant #G0125.00 from the FWO, Belgium, by an unrestricted Bristol-Myers-Squibb grant, by grant #GOA2001/09 from the Concerted Research Activities, Belgium, and by grant #IAP-P5/02 from the Belgian Science Policy. KD is a senior clinical investigator of the FWO and is supported by grants from the Interuniversity Attraction Poles and the Belgian Foundation for Research in Paediatric Cardiology. This study was further supported by the National Institute of Health grant P50 HL62177 to DAD and EG, and by the Nutrition and Toxicology and Growth and Development Research Institutes in Maastricht to RV.

  • Competing interests: none declared

  • Ethics approval: The study was approved by the Institutional Review Board for the Protection of Human Subjects and the Research Ethics Board in Philadelphia and Leuven, respectively, and written informed consent to participate in the study was obtained from all subjects or their legal representatives.