M9.5 Association of single nucleotide polymorphism in the vascular endothelial growth factor gene with small for gestational age birth

Abstract

Introduction: Impaired placental angiogenesis is implicated in the pathophysiology of small for gestational age (SGA) infants. Placental expression of vascular endothelial growth factor (VEGF), a potent angiogenic factor which regulates placental angiogenesis, is reduced in SGA pregnancies. We evaluated the association of two functional single nucleotide polymorphisms in the VEGF gene (VEGF+2578C/A and VEGF+936C/T) in SGA pregnancies. Methods: 3196 nulliparous pregnant women, their partners and babies were recruited in Adelaide and Auckland to a prospective multicenter cohort study (SCOPE Study). Amongst 2597 Caucasian women, 269 (10.4%) delivered a SGA infant defined as <10th customised centile (adjusted for gestational age at delivery, infant sex, maternal ethnicity, weight, height and parity). Uncomplicated Caucasian pregnancies served as controls (n=1463). Uterine and umbilical artery Doppler velocimetry was performed at 20 weeks gestation. DNA was extracted from peripheral blood from couples and cord blood from babies. Genotyping was performed using the Sequenom MassARRAY system. Genotype frequency of SGA was compared with controls using dominant and recessive genotype models by logistic regression analysis. ANCOVA was used to compare genotypes with birthweight and placental weight (adjusted for gestational age) in the Caucasian cohort. Results: Neonatal VEGF+936 CT+TT genotypes [dominant model] were increased in SGA (OR: 1.63, 95%CI: 1.1-2.3). Neonatal VEGF+936 CT+TT genotypes were associated with lower birthweight (p=0.005), customised birthweight centile (p=0.03) and placental weight (p=0.04) than CC. Maternal VEGF+936 CT+TT genotypes were associated with increased umbilical artery resistance index (OR: 1.5, 95%CI: 1.1-2.1) and the presence of bilateral uterine artery waveform notching (OR: 1.4, 95%CI: 1.0-1.8) compared to CC. Neonatal VEGF+936 CT+TT genotypes were associated with increased uterine artery resistance index (p=0.004). All associations remained significant after adjusting for confounding factors. Conclusion: The low VEGF producing VEGF+936 CT and TT genotypes associate with increased resistance in the placental circulation. These genotypes confer an increased risk for SGA and may be implicated in impaired placental function.