【作者】 李晨阳；

【导师】 严薇荣；

【作者基本信息】 华中科技大学 ， 流行病与卫生统计学， 2018， 硕士

【摘要】 目的:探讨中国汉族人群中母亲、子代血管紧张素转化酶(ACE)基因、血管紧张素原(AGT)基因和血管紧张素Ⅱ受体1(AT1R)基因遗传变异及ACE、AGT和AT1R基因-基因/环境交互作用与子痫前期发病风险之间的关联性,从而为子痫前期的病因学机制提供新的理论依据。方法:本研究采用病例-父母/对照-母亲混合设计,于2008年1月至2015年10月在湖北省宜昌市和河南省安阳市两家妇幼保健院收集研究对象,共纳入子痫前期孕产妇及其配偶胎儿(病例组)和正常孕产妇及其胎儿(对照组)共256组和360组。采用统一的调查问卷收集孕产妇的一般人口学特征、疾病家族史、怀孕分娩情况、生活行为习惯和精神状况等信息,在此基础上采用多因素logistic回归法筛选子痫前期发病风险相关的环境因素。采集病例组孕妇及其配偶和对照组孕妇的外周静脉血样及所有孕产妇分娩时的胎儿的脐静脉血样各5ml。选取ACE、AGT和AT1R基因的6个单核苷酸多态性(SNP)位点,采用Taq Man探针法对上述位点进行基因分型。采用非条件logistic回归模型结合对数线性模型对混合设计的数据进行分析,讨论母亲和子代的SNP位点对子痫前期的遗传学效应;采用多因素降维法(MDR)分别分析母亲和子代ACE、AGT和AT1R的基因-基因交互作用和母亲基因-环境交互作用,并探讨其与子痫前期发病风险的关联性。结果:本研究共纳入了ACE:rs4343;AGT:rs2478545,rs4762,rs699;AT1R:rs5182,rs5186共6个多态位点进行分析。logistic回归分析显示,在超显性遗传模型下子代rs5182位点的CC+TT vs CT基因型会增加子痫前期的发病风险(OR=1.70,95%CI:1.09-2.66);利用对数线性模型对混合设计的数据分析后得出:对于rs5182,与其子代基因型为TT相比较,子代基因型为CT时其母亲患有子痫前期的风险会有所降低(OR=0.49,95%CI:0.33-0.74),余未发现母子rs4343、rs2478545、rs4762、rs699、rs5186及母亲rs5182基因多态性与子痫前期的发生存在关联(P>0.05);MDR法发现母亲和子代ACE、AGT和AT1R基因各位点之间存在基因-基因交互作用并不存在;Logistic回归筛选出孕妇职业、孕前身高体重指数(BMI)及孕期被动吸烟为子痫前期的环境危险因素,但MDR分析未发现母亲基因-环境交互作用。结论:孕妇职业、孕前身高体重指数(BMI)及孕期被动吸烟为子痫前期的环境危险因素;在中国汉族人群中,子代AT1R基因rs5182位点可能会对子痫前期的发病风险产生影响,其中CT基因型可能会降低其母亲的发病风险。更多还原

【Abstract】 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.更多还原