| Objectives:1. To explore the risk factors of susceptibility of non-syndromic cleft lipwith or without cleft palate (NSCL/P) in Liuzhou City, Guangxi.2. To explore the variable contribution of the TaqI、BamHI and RsaI polymorphisms inTGFα gene to NSCL/P.3. To explore the variable contribution of rs142167(A/G) and rs3809857(G/T)polymorphisms in Wnt3gene to NSCL/P.4. To assess the gene-environment interaction on risk of NSCL/P.Methods: A matched case-control study was performed in this study. The studypopulation consisted of178cases with NSCL/P and178controls without any birth defectsborn in Guangxi between2007and2012. A questionnaire survey was carried out to detectthe information on maternal and paternal exposure before and during pregnancy. Thesamples of DNA were extracted from the peripheral blood of all children. The Genotypes ofTaqI, BamHI, RsaI in TGFα gene and rs142167, rs3809857in Wnt3gene of178pairssubjects were determined by polymerase chain reaction-based restriction fragment lengthpolymorphism (PCR-RFLP). McNemar test, univariate and multiple conditional logisticregression models were used to explore the association between environmental factors,different genotypes and the risk of NSCL/P. Additionally, the gene-environment interactionwas assessed by conditional logistic regression models. The odds ratio values (ORs) was calculated by using regression model to determine the addition effects among differentfactors and measure the interaction. All data analyses were performed using the statisticalsoftware package SPSS13.0(SPSS, Chicago, IL). A2-tailed P value <0.05was consideredstatistically significant.Results:1. In total,178pairs subjects with NSCL/P children as case and healthychildren as control were enrolled in this study. Among them,121pairs were boys and57pairs were girls. The cleft subtype ratio was1:1.49for cleft lip only with cleft lip and palate,and1:0.87for cleft lip only with cleft palate only.2. Risk factors in environmentThe results of multiple conditional logistic regression analysis indicated that living inrural area(OR:2.35;95%CI:1.10,5.05), keeping pets before six months to the early stagesof pregnancy (OR:4.46;95%CI:1.46,13.66), passive smoking before six months to theearly stages of pregnancy (OR:2.20;95%CI:1.28,3.77), threatened abortion (OR:20.84;95%CI:1.42,304.85), chronic disease history of mother (OR:31.84;95%CI:3.20,316.60), family history of birth defects (OR:11.14;95%CI:1.30,95.75) and father’soccupational exposure to physical adverse factors of father (OR:4.62;95%CI:1.10,19.47)were risk environment factors of NSCL/P. However, if supplement folic acid before sixmonths to the early stages of pregnancy (OR:0.30;95%CI:0.10,0.91) and the highereducational level of father (OR:0.14;95%CI:0.03,0.62), the risk of NSCL/P of theiroffsprings would decrease.3. Gene polymorphisms3.1The results suggested that TGFα gene TaqI polymorphism could be used as agenetic susceptibility marker for NSCL/P. Infants carrying the rarer C2allele showed a1.82-fold increase in risk for NSCL/P (OR:1.82;95%CI:1.13,2.91, P=0.013). C1C2orC2C2genotype was significantly associated with increased risk of NSCL/P compared withC1C1genotype (ORC1C2+C2C2vs C1C1:1.84;95%CI:1.10,3.10, P=0.020).3.2The results suggested that TGFα gene BamHI polymorphism could be used as a genetic susceptibility marker for NSCL/P. Infants carrying the rarer A1allele showed atwo-fold increase in risk for NSCL/P (OR:2.00;95%CI:1.30,3.06, P=0.002). A1A2orA1A1genotype was significantly associated with increased risk of NSCL/P compared withA2A2genotype (ORA1A1+A1A2vs A2A2:2.19;95%CI:1.37,3.50, P=0.001).3.3The results suggested that TGFα gene RsaI polymorphism could be used as agenetic susceptibility marker for NSCL/P. No association was found between the rarer A1allele and risk for NSCL/P in our data (OR:1.38;95%CI:0.89,2.14, P=0.149).Nevertheless, under a recessive genetic model, B1B1genotype was significantly associatedwith increased risk of NSCL/P compared with B1B2+B2B2genotype (ORB1B1vs B1B2+B2B2:3.42,95%CI:1.29,9.06, P=0.014).3.4The results suggested that Wnt3gene rs142167polymorphism could be used as agenetic susceptibility marker for NSCL/P. Infants carrying the rarer G allele showed a1.65-fold increase in risk for NSCL/P (OR:1.65;95%CI:1.15,2.34, P=0.006). Under arecessive genetic model, GG genotype was significantly associated with increased risk ofNSCL/P compared with AG or AA genotype (ORGG vs AG+AA:2.64;95%CI:1.03,6.76,P=0.043).3.5No significant association was detected when cases and controls were comparedwith the genotype for Wnt3gene rs3809857polymorphism in risk of NSCL/P.4. Gene-environment interaction between TGFα, Wnt3gene polymorphisms andenvironmental factors4.1The positive additive interactions were found between TGFα gene TaqIpolymorphism and passive smoking and alcohol use before six months to the early stages ofpregnancy, threatened abortion, family history of birth defects and father’s occupationalexposure to physical adverse factors. Similarly, a positive additive interaction was foundbetween TGFα gene BamHI polymorphism and keeping pets and no folic acid supplementbefore six months to the early stages of pregnancy and father’s occupational exposure tophysical adverse factors. Aslo, a positive additive interaction was found between TGFα gene RsaI polymorphism and alcohol use before six months to the early stages of pregnancy,threatened abortion and father’s occupational exposure to physical adverse factors.4.2The positive additive interactions were found between Wnt3gene rs142167polymorphism and no folic acid supplement before six months to the early stages ofpregnancy, alcohol use before six months to the early stages of pregnancy, threatenedabortion, family history of birth defects of mother and father’s occupational exposure tophysical adverse factors. Similarly, the positive additive interactions were found betweenWnt3gene rs3809857polymorphism and keeping pets, no folic acid supplement, passivesmoking before six months to the early stages of pregnancy, threatened abortion andfather’s occupational exposure to physical adverse factors.Conclusions:1. Our findings demonstrated that living in rural area, keeping petsbefore six months to the early stages of pregnancy, passive smoking before six months tothe early stages of pregnancy, threatened abortion, chronic disease history of mother, familyhistory of birth defects and father’s occupational exposure to physical adverse factors offather were risk environment factors of NSCL/P. However, supplement folic acid before sixmonths to the early stages of pregnancy and the higher educational level of father wereprotective factors of NSCL/P.2. Our findings support the contribution of TGFα gene TaqI, BamHI, RsaIpolymorphism and Wnt3gene rs142167polymorphism in the etiology of NSCL/P in thepopulation of Liuzhou City, Guangxi. And no association was found between the Wnt3gene rs3809857polymorphism and the risk of NSCL/P in our data. But these resultswarrant further investigation.3. There are obvious interactions between TGFα gene TaqI, BamHI and RsaIpolymorphisms and environmental factors such as passive smoking, alcohol use andkeeping pets before six months to the early stages of pregnancy, family history of birthdefects and father’s occupational exposure to physical adverse factors.4. There are obvious interactions between Wnt3gene rs142167and rs3809857 polymorphisms and environmental factors such as no folic acid supplement, passivesmoking, alcohol use, and keeping pets before six months to the early stages of pregnancy,threatened abortion, family history of birth defects and father’s occupational exposure tophysical adverse factors.5. NSCL/P is caused by the interactions between many minor genes andenvironmental risk factors. It is very important to study their correlation to classify the riskfactors and pathogenesis of NSCL/P. |
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