title: Disruption of vascular homeostasis in patients with Kawasaki disease: involvement of vascular endothelial growth factor and angiopoietins.
abstract: OBJECTIVE
  In Kawasaki disease (KD), a pediatric vasculitis of medium-sized arteries, the coronary arteries are most commonly affected. Angiopoietins and vascular endothelial growth factor (VEGF) play an important role in maintaining vascular homeostasis. Recently, we identified ANGPT1 and VEGFA as susceptibility loci for KD. This study was undertaken to fine-map these associations and to gain further insight into their role in this vasculitis of unknown etiology to further the search for improved diagnostic and therapeutic options.
  
  
  METHODS
  A total of 292 single-nucleotide polymorphisms (SNPs) located in VEGF and ANGPT and their receptors were genotyped in 574 families, including 462 trios. For replication, 123 cases and 171 controls were genotyped.
  
  
  RESULTS
  A significant association with KD susceptibility was observed with 5 SNPs in the ANGPT1 gene (most significantly associated SNP +265037 C>T; Pcombined=2.3×10(-7) ) and 2 SNPs in VEGFA (most significantly associated SNP rs3025039; Pcombined=2.5×10(-4) ). Both ANGPT1 +265037 C>T and VEGFA rs3025039 are located in 3' regulatory regions at putative transcription factor binding sites. We observed significantly down-regulated transcript levels of angiopoietin 1 (Ang-1) in patients with acute KD compared to patients with convalescent KD. In patients with acute KD, high serum protein levels of VEGF and Ang-2 were observed compared to patients with convalescent KD and to both controls with and controls without fever. Immunohistochemistry demonstrated VEGF and angiopoietin expression in the coronary artery wall in autopsy tissue.
  
  
  CONCLUSIONS
  Our data support the hypothesis that dysregulation of VEGF and angiopoietins contributes to the disruption of vascular homeostasis in KD.
authors: Emma Children's Hospital, Academic Medical Center, and Sanquin Research and Landsteiner Laboratory, University of Amsterdam, Amsterdam, The Netherlands. w.b.breunis@amc.uva.nl
authors: Willemijn B
authors: WB
authors: Breunis
authors: Sonia
authors: S
authors: Davila
authors: Chisato
authors: C
authors: Shimizu
authors: Toshiaki
authors: T
authors: Oharaseki
authors: Kei
authors: K
authors: Takahashi
authors: Michel
authors: M
authors: van Houdt
authors: Chiea Chuen
authors: CC
authors: Khor
authors: Victoria J
authors: VJ
authors: Wright
authors: Michael
authors: M
authors: Levin
authors: Jane C
authors: JC
authors: Burns
authors: David
authors: D
authors: Burgner
authors: Martin L
authors: ML
authors: Hibberd
authors: Taco W
authors: TW
authors: Kuijpers
mesh_terms: D042683:Angiopoietin-1 / Q000235:genetics* / Q000378:metabolism; D042702:Angiopoietin-2 / Q000235:genetics / Q000378:metabolism; D002675:Child, Preschool; D003289:Convalescence; D003331:Coronary Vessels / Q000378:metabolism / Q000473:pathology; D005260:Female; D020022:Genetic Predisposition to Disease; D006706:Homeostasis; D006801:Humans; D007223:Infant; D008297:Male; D009080:Mucocutaneous Lymph Node Syndrome / Q000175:diagnosis / Q000235:genetics* / Q000378:metabolism; D020641:Polymorphism, Single Nucleotide; D042787:Receptor, TIE-2; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics* / Q000378:metabolism
chemical_list: C467630:ANGPT1 protein, human; D042683:Angiopoietin-1; D042702:Angiopoietin-2; C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A; D042787:Receptor, TIE-2