The Maternal/Fetal RAS Gene-gene/environment Interactions In Preeclampsia:A Hybrid Study

Objectives: To provide a new theoretical basis for the etiological mechanism of preeclampsia(PE),we investigate the genetic effects of maternal/fetal single nucleotide polymorphisms(SNPs)and the gene-gene/environment interactions of angiotensin-converting enzyme(ACE),angiotensinogen(AGT)and angiotensin Ⅱ receptor 1(AT1R)gene on the risk of PE among pregnant Han Chinese women.Methods: In our case-parents/control-mother hybrid study,256 patients experiencing PE,along with their fetuses and partners,and 360 normotensive controls with their fetuses were recruited from January 2008 to October 2015 in two Maternal and Child Care hospitals in Anyang City,Henan Province and Yichang City,Hubei Province.A well-designed questionnaire was used to collect the information of socio-demographic characteristics,family history of diseases,pregnancy-related characteristics,daily life behaviors and psychosocial characteristics during pregnancy.Then by using the multi-factor logistic regression,the possible risky environmental factors of PE were picked out.Venous and cord vein blood samples were collected from all the pregnant women,venous blood samples were also collected from partners of women who have preeclampsia.Six SNPs of ACE,AGT and AT1 R gene were selected and were genotyped by using Taq Man? SNP Genotyping Assays.A logistic regression approach and a log-linear modeling approach in hybrid study were employed to investigate the genetic effects of maternal/fetal SNPs on PE;Multifactor dimensionality reduction(MDR)was applied to study the maternal/fetal ACE,AGT and AT1 R gene-gene interaction and the maternal gene-environment interactions,their effects on PE risk were also analyzed.Results: Six SNPs(ACE:rs4343;AGT:rs2478545,rs4762,rs699;AT1R:rs5182,rs5186)were selected in our study.The fetal rs5182 polymorphism in the overdominant genetic model(CC+TT vs CT)was found to be associated with a increased PE risk(OR=1.70,95% CI: 1.09-2.66).In hybrid study,the log-linear modeling approach shows that,when compared with the controls,Mothers of offspring carrying the rs5182 CT genotype had a reduced PE risk(OR=0.49,95%CI:0.33-0.74);no significant associations were detected between the maternal/fetal rs4343,rs2478545,rs4762,rs699,rs5186,maternal rs5182 and PE risk(P>0.05);Gene-gene interaction of maternal/fetal ACE,AGT and AT1 R genes was not found by using MDR;By using multivariate logistic regression model,we found that maternal occupation,passive smoking during pregnancy and pre-pregnancy Body Mass Index(BMI)were risk factors of PE;However there was no maternal gene-environment interactions.Conclusions: The maternal occupation,passive smoking during pregnancy and pre-pregnancy(BMI)were risk factors of PE;Moreover our findings demonstrate that fetal AT1 R rs5182 polymorphisms may play a significant role in PE development among pregnant Han Chinese women,and the CT genotype might have a protective effect on it.