title: Gene-gene interactions and gene polymorphisms of VEGFA and EG-VEGF gene systems in recurrent pregnancy loss.
abstract: OBJECTIVE
  Both vascular endothelial growth factor A (VEGFA) and endocrine gland-derived vascular endothelial growth factor (EG-VEGF) systems play major roles in angiogenesis. A body of evidence suggests VEGFs regulate critical processes during pregnancy and have been associated with recurrent pregnancy loss (RPL). However, little information is available regarding the interaction of these two major major angiogenesis-related systems in early human pregnancy. This study was conducted to investigate the association of gene polymorphisms and gene-gene interaction among genes in VEGFA and EG-VEGF systems and idiopathic RPL.
  
  
  METHODS
  A total of 98 women with history of idiopathic RPL and 142 controls were included, and 5 functional SNPs selected from VEGFA, KDR, EG-VEGF (PROK1), PROKR1 and PROKR2 were genotyped. We used multifactor dimensionality reduction (MDR) analysis to choose a best model and evaluate gene-gene interactions. Ingenuity pathways analysis (IPA) was introduced to explore possible complex interactions.
  
  
  RESULTS
  Two receptor gene polymorphisms [KDR (Q472H) and PROKR2 (V331M)] were significantly associated with idiopathic RPL (P<0.01). The MDR test revealed that the KDR (Q472H) polymorphism was the best loci to be associated with RPL (P=0.02). IPA revealed EG-VEGF and VEGFA systems shared several canonical signaling pathways that may contribute to gene-gene interactions, including the Akt, IL-8, EGFR, MAPK, SRC, VHL, HIF-1A and STAT3 signaling pathways.
  
  
  CONCLUSIONS
  Two receptor gene polymorphisms [KDR (Q472H) and PROKR2 (V331M)] were significantly associated with idiopathic RPL. EG-VEGF and VEGFA systems shared several canonical signaling pathways that may contribute to gene-gene interactions, including the Akt, IL-8, EGFR, MAPK, SRC, VHL, HIF-1A and STAT3.
authors.affiliation: Division of Genetics, Department of Obstetrics and Gynecology, National Cheng Kung University Hospital, 138 Sheng-Li Road, Tainan, 704, Taiwan.
authors.forename: Mei-Tsz
authors.initials: MT
authors.lastname: Su
authors.forename: Sheng-Hsiang
authors.initials: SH
authors.lastname: Lin
authors.forename: Yi-Chi
authors.initials: YC
authors.lastname: Chen
authors.forename: Pao-Lin
authors.initials: PL
authors.lastname: Kuo
mesh_terms: D000026:Abortion, Habitual / Q000235:genetics* / Q000473:pathology; D016022:Case-Control Studies; D004843:Epistasis, Genetic; D005260:Female; D056726:Genetic Association Studies; D006801:Humans; D011247:Pregnancy; D015398:Signal Transduction / Q000235:genetics; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics*; D042662:Vascular Endothelial Growth Factor, Endocrine-Gland-Derived / Q000235:genetics*
chemical_list: C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A; D042662:Vascular Endothelial Growth Factor, Endocrine-Gland-Derived