Association Between Single-nucleotide Polymorphisms In STING,MAVS And TRAF3 Genes And Cervical Precancerous Lesions

ObjectivesCervical cancer is the third most common cancer in women worldwide.In China,the prevalence of the cervical carcinoma goes up year by year and has the trend of younger.Persistent HPV infection is considered as a major cause of cervical cancer,moreover,a variety of environmental and host factors influence the development of cervical cancer.The prevalence of genital HPV infections in developing countries is very high in young women,but most of the infections regress without intervention.Pathway in innate immunity plays an important role in protecting against HPV infection.Therefore,the lack of effective immune response to HPV is a key factor in the occurrence of cervical cancer.Moreover,studying the mechanism how HPV affect immune function becomes increasingly important.In our study,the associations between Single nucleotide polymorphisms（SNPs）in STING,MAVS and TRAF3 gene and cervical precancerous lesions in the Chinese population were investigated.In addition,we also evaluated the potential interactions between environmental factors and these SNPs to further enriching the precancerous lesions and prevention strategies and key molecular biomarkers of cervical cancer.Methods1.This was a case-control study.The population included 164 subjects with the cervical precancerous lesions and 428 control subjects.Cervical specimens were collected for HPV genotyping and thinprep cytologic test.Furthermore,venous blood was collected for whole genomic DNA extraction.2.The general information of subjects and potential risk factors were collected with through epidemiological questionnaire.3.SNPs in the STING,MAVS and TRAF3 genes on human chromosomes were screened from the Hapmap database.Matrix assisted laser desorption ionization time of flight mass spectrometry was used to genotype all SNPs.4.SPSS 16.0,Haploview 4.0 Software,MDR and MDRpt were used to explore the relationship between the polymorphisms in STING,MAVS and TRAF3 genes,environmental factors and the susceptibility of cervical precancerous lesions.Results1.The univariate analysis showed that significant differences were found in age and high-risk HPV infection between the cervical precancerous lesions cases and controls.No significant differences in the body mass index（BMI）,number of term births,genital cleaning after each intercourse,age at menarche,the initial pregnancy of age and pregnant frequencies were found between the cases and controls.2.In this study,nine polymorphisms in three candidate genes,including the STING gene（rs7380272）,the MAVS gene（rs3746660,zx315,rs6116065,rs8116776 and rs914294）and the TRAF3 gene（rs7156191,rs8022180 and zh429）,were genotyped.The genotype distributions of these SNPs were observed to be in Hardy-Weinberg equilibrium.3.Compared with genotype CC of MAVS zx315,individual who carried genotype CA increased the risk of developing cervical precancerous lesions(OR_adjusted=1.47,P=0.046),after adjusting age and the initial pregnancy of age.And in the dominant genetic model,individuals carrying genotype CA/AA in zx315 has 1.46 times higher risk for developing cervical precancerous lesions than those carrying the CC genotype(CA/AA vs CC:OR_adjusted=1.46,P=0.040).In addition,we found that individuals with the TC genotype in TRAF3 zh429 had a33%decreased risk of cervical precancerous lesions(OR_adjusted=0.67,95%CI=0.16–0.98,P=0.045)compared with those with the wild-type CC,after adjusting age and the initial pregnancy of age.In the dominant genetic model,individual carrying genotype TC/TT has 0.69 times lower risk for developing cervical precancerous lesions than those carrying the CC genotype(TC/TT vs CC:OR_adjusted=0.69,P=0.049).While the other 7 SNPs were not observed to be relevant to the risk of cervical precancerous lesion.4.After adjusting age and the initial pregnancy of age,the associations between MAVS and TRAF3 haplotypes and the risk of cervical precancerous lesions were estimated.No haplotypes in STING,MAVS or TRAF3 gene was found to be significantly associated with risk of cervical precancerous lesions.5.Interactiona.We evaluated the interactive effects of HPV infection and each SNP based on an additive scale and multiplicative scale.According to the RERI,AP and S indexes,a significant synergistic interaction was found between MAVS zx315 and high-risk HPV infection(RERI_adjusted=3.1,95%CI:0.07-6.25;AP_adjusted=0.42,95%CI:0.14-0.71;S_adjusted=1.95,95%CI=1.04-3.67).Among high-risk HPV-infected individuals,women with carrying the minor A allele in MAVS zx315 had an increased risk of cervical precancerous lesions by 41.5%compared with individuals carrying wild type at zx315.While,multiplicative interaction analysis revealed no interaction between high-risk HPV infection and these 9 SNPs.b.MDR analysis identified a significant three-locus interaction model,involving in high-risk HPV infection,pregnancy outcome and rs6116065 in MAVS.Based on the MDR model,we further performed a risk analysis of different combinations among these three factors.We found that among high-risk HPV-infected individuals,women with normal pregnancy and,carrying the minor G allele in MAVS rs6116065 had a reduced risk of cervical precancerous lesions by 14%compared with individuals who were wild type at rs6116065.ConclusionOur study provides evidences that the MAVS zx315 polymorphism and TRAF3 zh429polymorphism influence the risk of cervical precancerous lesions.Moreover,our study also finds that two-way and three-way gene-environment interactions exist in the etiology of cervical precancerous lesions.This study provides new epidemiological clues about the role of STING,MAVS and TRAF3 which play a key role in innate immunity in cervical precancerous lesions and further insights into such interactions in the etiology of cervical precancerous lesions.