Genetic association studies of angiogenesis- and vasoconstriction-related genes in women with recurrent pregnancy loss: a systematic review and meta-analysis

BACKGROUND: Angiogenesis and an adequate blood supply are critical for several steps in human early pregnancy. Some studies have reported angiogenesis- and vasoconstriction-related genes are associated with recurrent pregnancy loss (RPL), but their sample size was limited. This study was conducted to investigate the genetic association between these angiogenesis- and vasoconstriction-related genes and idiopathic RPL, using meta-analyses. METHODS: A systematic review of the published literature from MEDLINE and EMBASE databases was conducted and investigations of an angiogenesis- and vasoconstriction-related gene polymorphism in RPL reported more than three times were selected. Aggregating data from eligible studies were integrated into meta-analyses by means of random effects models. RESULTS: Of 185 potentially relevant studies, 18 case-control studies comprising a total of 2397 RPL patients and 1760 controls were included into the meta-analyses. Among these genetic association studies were 4 reports of vascular endothelial growth factor (VEGF) (-1154G>A) polymorphisms, 4 reports of p53 (codon72) and 10 reports of endothelial nitric oxide synthase (eNOS) (B/A, Glu298Asp) with RPL. The integrated results showed that VEGF (-1154G>A), p53 (codon 72) and eNOS (Glu298Asp) polymorphisms were significantly associated with RPL, and their summary odd ratios [95% confidence interval (CI)] were 1.51 (1.13-2.03), 1.84(1.07-3.16) and 1.37 (1.11-1.69), respectively. The summary odd ratio of the eNOS (B/A) polymorphism in RPL was 1.15 (0.94-1.41), and failed to show significance at meta-analysis. CONCLUSIONS: Meta-analyses of available data showed significant associations between the VEGF (-1154G>A), p53 (codon72) and eNOS (Glu298Asp) polymorphisms and idiopathic RPL. These angiogenesis- and vasoconstriction-related genes jointly confer higher susceptibility to idiopathic RPL.