| On the basis of the population-based survey of intrauterine transmission of hepatitis B virus(HBV),we aimed to explore the genes with genetic susceptibility of HBV intrauterine transmission by candidate gene strategy,and the mechanism of HBV intrauterine transmission from the aspects of heredity,environment and their interaction,which could provide foundation for effective intervention and interruption of HBV mother-to-child transmission.Part I: Incidence and risk factors of intrauterine transmission among pregnant women with chronic hepatitis B virus infectionObjective: To identify the potential risk factors of hepatitis B virus(HBV)intrauterine transmission and investigate the incidence of HBV intrauterine transmission among HBsAg-positive pregnant women in Wuhan,China.Methods: From May 2012 to August 2017 at Wuhan Medical Care Center for Women and Children,Wuhan,China,HBsAg-positive pregnant women and their neonates were invited to participate this study.Multivariate unconditional logistic regression was used for data analysis.Result:(1)Finally,a total of 1506 mothers paired with 1532 neonates were enrolled,of which 128(8.35%)neonates were identified with intrauterine transmission.(2)The result of multivariate logistic regression showed that maternal hepatitis B e antigen(HBeAg)positivity(OR = 4.26,95% CI:2.60-6.98,P < 0.001),HBV DNA positivity in third trimester(OR = 1.67,95% CI:1.02-2.74,P = 0.041),and cesarean section(OR = 0.29,95% CI:0.19-0.44,P < 0.001)were associated with the risk of HBV intrauterine transmission.Conclusions: Our data confirmed that maternal HBeAg positivity and HBV DNA positivity in third trimester were the risk factors of HBV intrauterine transmission.However,cesarean section may be a protective factor of HBV intrauterine transmission.Part II: Study on the relationship between genetic variation of genes in RLR-MAVS and c GAS-STING signaling pathway and other genes with HBV intrauterine transmissionObjective: To explore the relationship between genetic variation of genes in RLR-MAVS and c GAS-STING signaling pathway and other genes with hepatitis B virus(HBV)intrauterine transmission.Methods: A case-control study was performed on HBsAg-positive pregnant women paired with neonates who delivered from January 2013 to August 2017 at Wuhan Medical Care Center for Women and Children,Wuhan,China.In total,1356 neonates born from HBs Ag-positive pregnant women were included into this study,which consisted of 107 neonates with HBV intrauterine infection and 1249 neonates without.Through literature review,RLR-MAVS and c GAS-STING signaling pathway related genes and IL10,IL12 A,IL12B,TLR3,TLR9,TNFSF14 were selected as candidate genes.Mass ARRAY gene detection system was used for genotyping.Multivariate unconditional logistic regression,cumulative effect analysis and multifactor dimensionality reduction were used for data analysis.Result: In RIG-I/MAVS signaling pathway,the risk of HBV intrauterine transmission in neonates with rs28413168 CC/CG genotype in INTS10 gene increased by 100% compared with those with GG genotype(OR = 2.00,95% CI: 1.26-3.19;P = 0.004).In c GAS-STING signaling pathway,the risk of HBV intrauterine transmission in neonates who carried GG/AG genotype in MB21D1 gene was significantly lower than that in neonates with AA genotype(OR = 0.48,95% CI: 0.30-0.78;P = 0.003).Compared with neonates with rs1800872 CC genotype in IL10 gene,the risk of HBV intrauterine transmission in neonates with AA genotype at this locus was significantly increased(OR = 3.01,95% CI: 1.02-9.84;P = 0.047).The polymorphism of TLR3 rs3775291 in newborns was also closely related to intrauterine transmission of HBV.Compared with newborns carrying rs3775291 CT/CC genotype in TLR3 gene,newborns with TT genotype had significantly increased risk of HBV intrauterine transmission(OR = 2.09,95% CI: 1.07-4.12;P = 0.032).Additionally,no significant association was found between other SNPs in neonates and the risk of HBV intrauterine transmission.In the unconditional logistic regression model,the risk of HBV intrauterine transmission in newborns with 5-8 risk alleles was 4.34 times higher than that in those with 0-2 risk alleles(95% CI: 1.44-13.09;P = 0.009)after adjustment for the age of delivery,parity,HBe Ag,HBV DNA in third trimester and mode of delivery.Conclusions: The genetic polymorphisms of INTS10 rs28413168,MB21D1 rs311678,IL10 rs1800872,TLR3 rs3775291 are closely related to the susceptibility of HBV intrauterine transmission.The more risk alleles a newborn carries,the higher the risk of HBV intrauterine transmission.Part III: Interactions between variation in candidate genes and environmental factors in HBV intrauterine transmissionObjective: To explore whether the genetic variations of INTS10 rs28413168,MB21D1 rs311678,IL10 rs1800872,TLR3 rs3775291 interact with environmental factors,including maternal HBe Ag,HBV DNA and delivery mode,to influence the occurrence of HBV intrauterine transmission.Methods: The subjects of study were the same as the second part.To evaluate interactions between INTS10 rs28413168,MB21D1 rs311678,IL10 rs1800872,TLR3 rs3775291 and HBe Ag,HBV DNA and delivery mode,multiplicative interactions were evaluated by a likelihood ratio test in the logistic regression model.The additive interaction analysis was performed using the excel sheet made by Andersson et al.Result:(1)Our study showed that there were additive interaction between genetic variation in INTS10 rs28413168 with maternal HBe Ag(AP = 0.54,95% CI: 0.21-0.86;SI = 2.57,95% CI: 1.06-6.25),and between IL10 rs1800872 with HBe Ag(AP = 0.57,95% CI: 0.10-1.04).(2)The interaction between gene polymorphism in MB21D1 rs311678 and maternal HBV DNA(AP = 0.41,95% CI: 0.07-0.75)was found.(3)There were additive interaction between variation of MB21D1 rs311678 and mode of delivery(RERI = 4.14,95% CI: 0.43-7.84;AP = 0.56,95% CI: 0.28-0.84;SI = 2.84,95% CI: 1.14-7.04),and between variation of IL10 rs1800872 and mode of delivery(AP = 0.58,95% CI: 0.24-0.92).Additionally,we observed multiplicative interaction between genetic variation in TLR3 rs3775291 and mode of delivery(P = 0.020).Conclusions: The study on gene-environmental interaction suggests that environmental factors such as maternal HBe Ag,HBV DNA during pregnancy and delivery mode may superimpose or amplify the genetic effect of HBV intrauterine transmission in newborns. |
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