A Study Of Single Nucleotide Polymorphisms And Their Interactions In Susceptibility Of Pre-eclampsia

Background and objectiveWith an average incidence rate of about 3%-5%,pre-eclampsia(PE)is one of the major causes leading to maternal morbidity,mortality and premature delivery;the incidence rate of PE is even higher in some developing countries,and the incidence rate in China is 9.4%-10.4%;moreover,about 42%of pregnancy-related deaths are caused by PE.For a long time,its etiology and pathogenesis have not yet been clarified,and there is no effective treatment currently except termination of pregnancy.At present,PE is considered to be the result of genetic and environmental interactions.Furthermore,genetic changes of PE are mainly polygenic inheritance,manifesting as genetic susceptibility.In recent years,genes-based studies on single nucleotide polymorphisms(SNPs)have obtained important achievements in the research field of complex diseases,such as hypertension,tumor,and diabetes.However,there are few studies of polygenic interactions of PE with Chinese Han population as the study subjects.SNP is different in different races.It is expected to further deepen the understanding of the pathogenesis of PE,and provide new way of thinking for prevention,diagnosis and treatment of disease by studying the relationship between genetic susceptibility and PE in Chinese Han population,and confirming relevant high-risk SNP loci,thus investigating potential gene interactions based on relevant studies abroad,with Chinese Han population as the study subjects,and on the basis of genetic levels.Study subjects and methodsStudy subjects:A case-control study was conducted with the Han population in Shenzhen as the study subjects.A total of 442 cases of PE patients who underwent cesarean delivery as well as normal pregnant women in the Affiliated Maternal and Child Health Hospital of Shenzhen Municipality,Southern Medical University from July 2014 to May 2015 were selected.There were 156 cases in the PE group,and 286 cases in the control group,which included normal pregnant women,and women underwent cesarean delivery due to abnormal birth canal or fetal position,as well as social factors.Study methods:Blood DNAs of the subjects were extracted,and SnapShot was used to detect SNP loci of the candidate genes,including genotypes of ACE rs4646994,AGT rs699 rs4762,APOE rs429358 rs7412,ATIR rs5186,CTLA4 rs231775,F2 rs1799963,FVrs6020 rs6025,IL-10 rs1800896,LPL rs1800590 rs268,MTHFR rs1801133,NOS3 27bp-VNTR in intron 4 rs2070744 rs1799983,SERPINEl rs1799889,TLR4 Rs4986790 rs4986791,TNF-alpha rs1800629 rs1799724,VEGF rs3025039,EPHXl rs1051740,GSTPl rs1695,ERAP2 rs2549782,IGFl rs5742620.Population in the control group performed Hardy.Weinberg test,and loci that did not satisfy Hardy.Weinberg equilibrium were excluded from subsequent analyses.R language software package,and Pearson chi-square test were used to compare the 17 SNP polymorphisms and the genotype distribution between the control group and the PE group.Logistic regression was used to calculate the OR value and the 95%confidence interval.Multivariate dimension reduction(MDR)was used to perform multifactor interaction analysis,and possible gene interactions in the pathogeneses of PE was determined.Results:There were statistical significances in prenatal BMI,urine protein,mean gestational weeks,and birth weights of newborns between the PE group and the control group(P<0.05),which were consistent with PE diagnostic criteria.Results of Hardy-Weinberg test showed that in the 27 loci in the control group,the frequencies of the alleles in the 10 SNP loci were not in line with Hardy-Weinberg equilibrium,thus these loci would not be included in subsequent statistical analysis.Pearson chi-square test was performed for the 17 SNP loci,and OR value as well as 95%confidence interval were calculated.The results demonstrated that the frequency distribution of the genotypes of rs 1800629 locus in TNF-alpha gene had a marginal statistical difference between the PE group and the control group(?2=3.729,P=0.053).The risk of PE was increased in people with GG genotype(OR=1.65);frequency distribution of the genotypes of rs1799724 locus in TNF-alpha gene was statistically significant between the PE group and the control group(?2=7.39,P=0.0065).The risk of PE was decreased for people with CC genotype(OR=0.57),and CC genotype was the protective factor;there was statistical difference in the frequency distribution of the genotypes of rsl 800896 locus in IL-10 gene between the PE group and the control group(?2=6.29,P=0.012),and the risk of PE was decreased for people with AA genotype(OR=0.53);there was statistical difference in the frequency distribution of the genotypes of rs2070744 locus in NOS3 gene between the PE group and the control group(?2=7.26,P=0.007),and the risk of PE was decreased for people with TT genotype(OR=0.13);there was statistical difference in the frequency distribution of the genotypes of rs47621ocus in AGT gene between the PE group and the control group(?2=4.693,P1=0.03),and the risk of PE was increased for people with CC genotype(OR=1.76);The frequency of alleles and the frequency distribution of genotypes in the other 12 SNP loci were not statistically significant.Results of MDR interaction analysis revealed that the optimal model included EPAP2(rs2549782),GSTP1(rsl695),AGT(rs4762),IL-10(rs1800896),APOE(rs7412),and TNF-alpha(rs1800629,rs1799724).Furthermore,the accuracy of the training sample was 0.7294,which was 0.5853 for the validation sample,while the cross-validation consistency was 10/10(P = 0.001).The combination of the seven factors provided the optimal accuracy of the validation sample and cross-validation consistency with statistical significance.The optimal models of the combinations of other factors were not statistically significant.Conclusion:rs1800629,rs1799724,rs1800896,rs2070744,and rs4762 polymorphic loci were correlated with the risk of PE in the Han population in ShenZhen;the interactions of EPAP2,GSTP1,AGT,IL-10,APOE,and TNF-alpha genes played an important role in the pathogenesis of PE.As a disease,PE has a strong genetic factor in its causes,and shows a complex process of the interactions of various factors.Study of PE using genetic polymorphism and genetic susceptibility from different views will help clarify the genetic basis for the pathogenesis of PE.