The Association Between Maternal And Fetal VEGF-A Gene Polymorphisms And Preeclampsia-a Hybrid Study

Objectives:1.To explore the risk factors associated with preeclampsia.2.To investigate the association between maternal and fetal vascular endothelial growth factor A(VEGF-A)single nucleotide polymorphisms(SNPs)and preeclampsia.3.To analyze the gene-environment interactions between maternal VEGF-A SNPs and risk factors of environment.4.To explore the association between maternal/fetal VEGF-A haplotype and preeclampsia.Methods:1.The research including 1353 subjects(221 preeclampsia patients with their partners and fetuses,345 normotensive controls with their fetuses)were recruited from two Maternal and Child Care Hospitals in Anyang and Yichang city(in Henan and Hubei province respectively)from January 2008 to October 2015.A well-designed questionnaire consisting of five aspects(demographic characteristics,family history,information about pregnancy,lifestyle,mental condition)was used to collect the subject's information.Venous blood of the PE/E patients with their partners and the normotensive controls,and umbilical cord blood of the all fetuses were collected.2.The targeted sequencing of VEGF-A gene was conducted in the case-control research including 50 preeclampsia patients and normotensive controls with their fetuses.The results of association analysis between VEGF-A SNP and preeclampsia were used to select the interesting SNP,which were genotyped by using TaqMan? SNP Genotyping in all subjects.3.The differences in the distributions of allelic and genotype frequency between the cases and the controls were evaluated by Pearson's ?2 test.An unconditional logistic regression was used to explore the association between maternal and fetal genotypes and preeclampsia under dominant,recessive,additive and co-dominant genetic models.In the case-parents/control-mother designed research,a log-linear modeling was used to investigate the maternal and fetal genetic effects in preeclampsia.4.A multivariate logistic stepwise regression was used to pick out the environmental risk factors associated with preeclampsia.The log-linear modeling was used to explore the gene-environment interactions based on the case-parents design.5.Phase 2.1 software was used to construct maternal and fetal VEGF-A haplotypes and unconditional logistic regression was used to analyze the association between the haplotypes and preeclampsia.Results:1.The pre-pregnancy BMI and maternal passive smoking during gestation were finally picked out as the risk factors of preeclampsia by using multivariate logistic stepwise regression,and then they were recruited in the subsequent gene-environment analysis.2.Three SNPs(rs25648,rs2010963,rs3025000)were selected in the study.For maternal and fetal rs2010963,there were significant differences in the distribution of the three genotypes in both cases and controls.In the genetic model analysis,maternal rs2010963 in the dominant model(OR:1.85,95% CI:1.25-2.75),fetal rs2010963 in the dominant model(OR:1.90,95% CI:1.28-2.83)and co-dominant model(OR:2.00,95% CI:1.37-2.91)were significantly associated with an increased risk of preeclampsia.In the log-linear model analysis,fetal GC genotype compared to GG genotype increased the risk of preeclampsia.No association was observed between other SNPs and preeclampsia.3.In the gene-environment interaction analysis,maternal rs2010963 had a significant interaction with passive smoking.But in the passive smoking group,maternal rs2010963 GC or CC genotype compared with GG genotype was not associated with the risk of preeclampsia.4.Compared with GCC haplotype(rs2010963-rs25648-rs3025000),mother carrying CCC haplotype(OR: 2.04,95% CI: 1.27-3.30)and fetus carrying GTC haplotype(OR: 1.89,95% CI: 1.07-3.35)increased the risk of preeclampsia in the haplotype analysis.Conclusions:1.Pre-pregnancy BMI and passive smoking during gestation were associated with preeclampsia.2.Maternal rs2010963 increased the risk of preeclampsia under the dominant model(GC+CC/GG).Fetal rs2010963 was associated with the increased risk of preeclampsia under the dominant(GC+CC/GG)and co-dominant model(GC/CC+GG).Fetal rs2010963 GC compared to GG genotype was associated with the increased risk of preeclampsia.3.Maternal rs2010963 had an interaction with passive smoking,but in the passive smoking group,maternal rs2010963 GC or CC genotype compared with GG genotype was not associated with the risk of preeclampsia.4.Compared to GCC(rs2010963-rs25648-rs3025000),maternal GCC haplotype and fetal GTC haplotype increased the risk of preeclampsia.