An Epidemiology Study On The Associations Between Gene Polymorphisms Of TNF-α And Environmental Factors With Preterm Delivery

Objective: Preterm delivery(PTD) is a major cause of perinatal death, accounts for 5%-15% of total deliveries.The etiology and pathogenesis of PTD has not yet been completely understood. Many researchers agreed that now the incidence of PTD associated with the interaction of genetic factors and environmental factors.The purpose of this study is to provide epidemilolgical and genetic clues for etiological of PTD, and to provide a theoretical basis for clinical prevention and treatment by investigating the relationship between G238A,G308A,G488A single nucleotide polymorphisms (SNP) in tumor necrosis factor-α(TNF-α) gene and PTD in Han ethnic group of Chinese women in southern China, as well as the interaction of the polymorphism of gene and related risk factors of PTD.Methods:The case-control study was used to this study. The objects of the study were the maternal who delivered in Guangdong Women and Children Hospital during June 2009 to June 2010. The pregnant women with 28 to unreached 37 gestational weeks were selected as a case group, and the pregnant women with 37 to 42 gestational weeks were selected as a control group. The face-to-face interview was used to gather data by a structured questionnaire, which included demographic characteristics, personal habits and health factors. In addition, 89 cases of PTD and 110 normal controls were draw 3 ml venous blood in the permission to detect TNF-αgene-238, - 308, +488 polymorphism by using polymerase chain reaction - high-resolution melting curve (PCR-HRM) combined with sequencing. Chi-square test and unconditional Logistic regression were use to find the main risk factors for PTD, and unconditional logistic regression analysis was use to calculate the odds ratios(ORs) with 95% confidence intervals (95% CIs), and to estimate the association between certain genotypes and PTD by adjusting the possible confounders as well as the interaction of risk factors.Results: 1.The mothers with premature rupture of membranes,vaginal infections during pregnancy,placental abnormalities, family history of PTD,history of previous PTD,low educational level and household income were significantly associated with PTD(P<0.05). Multivariate Logistic regression analysis showed that the OR and 95%CI of family history of PTD were 18.868 and 1.831-194.386; the OR and 95%CI of vagina infect during pregnancy were 5.378 and 1.188-24.348; the OR and 95%CI of premature rupture of membranes were 28.732 and 7.445-110.880; the OR and 95%CI of placental abnormalities were 28.021 and 2.871 -273.506 respectively.2.(1)TNF-αgene -238,-308 genotypes frequencies and allele frequency distribution showed that there were not statistical difference between case and control(P>0.05).+488 locus A allele, GA(AA)genotype distribution in the case was significantly higher frequencies than that of the control, and the difference was significant(χ2=10.036,P=0.002,χ2=11.235,P=0.004). The results indicated that who carry TNF-αgene +488 locus A genotype(GA/AA) has risk of PTD than who carry wild genotype(GG)of 2.911 times(95%CI=1.474-5.748), and individuals with carrying the GA genotype also increased the risk of PTD (OR=2.815, 95%CI =1.402-5.654) by adjusting income, education and other demographic characteristics.(2)TNF-αgene G-238A and G-308A polymorphisms were in strong linkage disequilibrium (D '= 1.000, r2 = 0.513), the composition of two single -238G/-308A and -238G/-308G haplotype frequency was beyond 0.03, accounting for 98.2% of haplotypes. The frequencies of two haplotypes in Han ethnic group of Chinese women in southern China were 7.7% and 90.5% respectively; there were not statistical difference, and unrelated to the incidence of PTD in distributions of the haplotypes between the PTD group and the control group. Multivariate non-conditional Logistic regression analysis was used to analyze the interactions of the gene - gene, TNF-αgene +488, -238 and -308 wild genotype is protective factors of PTD, while +488 A/-238G/-308G genotype significantly increased the risk ofPTD(OR=3.116; 95% CI:1.679 -5.784). 3. Multivariate logistic regression analysis was used to analyze the interactions of the gene- environment, the results showed that environmental exposure factors'OR value were higher than mutant gene, this indicated that the family history of PTD, vagina infect during pregnancy, premature rupture of membranes and placental abnormalities play an important role in effects.The result of the interactions between gene and environment suggested -238 and -308 GA + AA genotype could strengthen the effect of BV, and could be a positive effect(r>1),+488 GA + AA genotype could reduce the effect of the BV,and could be negative effects (r<1); -238,-308 and +488 GA+AA genotype could strengthen the effect of premature rupture of membranes, and could be a positive effect(r>1);-308,+488 genotype could strengthen the effect of placental abnormalities, and could be a positive effect(r>1); +488 GA+AA genotype could strengthen the effect of placental abnormalities, and could be a positive effect(r>1).Conclusions: 1. The family history of PTD, vaginal infections during pregnancy, premature rupture of membranes, placental abnormalities were the main risk factors for PTD.2. TNF-αgene +488 polymorphisms was significant susceptibility to PTD in sole or associated with other sites. It could significantly increase the risk of PTD, while -238, -308 polymorphism were not significant susceptibility to PTD. 3. There were complex interactions between gene-gene or gene-environment. The family history of PTD,BV,placental abnormalities and premature rupture of membranes could significantly increase the risk of PTD; TNF–α-238, -308 and the +488 GA + AA genotype could strengthen or weaken the effect of the environment.