Study On The Relationship Between MAP3k1 Snps And Susceptibility Of Esophageal Squamous Cell Carcinoma In Jiangsu Han Population

Objective:To study the possible contributions that MAP3k1 single nucleotide variations conferred to the susceptibility to Esophageal squamous cell carcinoma?ESCC?and further explore the interactions between MAP3k1 SNPs and exogenous risk factors in the process of tumorigenesis.Methods:In attempt to discover the possible relationships between MAP3k1 single nucleotide variants rs702688 A>G,rs702689 G>A,rs72644086A>Gand effects it induced in ESCC,a total of 1043 histologically-diagnosed ESCC patients and 1315 healthy,well-matched controls were recruited from the Affiliated People's Hospital of Jiangsu University?Zhenjiang,China?for a duration from October 2008 to January 2017 for this study.Genomic DNA was extracted from the sample with the QIAamp DNA Blood Mini Kit?Qiagen,Berlin,Germany?following the protocol provided.Sample DNA was amplified by PCR according to the manufacturer's protocol.Ligation Detection Reaction?LDR?method was deployed to genotype the samples with technical support from Biotechnology Inc.?Shanghai,China?.For quality control,10%of the total samples were randomly chosen for repeated analyses.Pilot linkage disequilibrium analyses were performed in the Chinese Han population to choose SNP loci with moderate correlation,and tagging SNPs were selected for further analyses.To evaluate the statistical differences based on the calculated genotype frequencies between case and control groups,Chi-square??²?test was applied.ORs with 95%CIs were used to assess the strength of association between the three MAP3K1 SNPs and ESCC risk.Further to estimate the overall risk of ESCC imparted by the synergistic effects between MAP3K1 SNPs and other exogenous factors such as smoking and drinking status,stratified analyses were performed to explore the possible interactions.Linkage disequilibrium along with haplotype analyses were utilized to further evaluate the genetic risks MAP3k1 SNPs inflicted in tumorigenesis of ESCC.Results:In our study,we found that only the heterozygote genotype of rs702689 AG?OR=1.272,95%confidence interval=1.061¹.525,p=0.009?is shown to be associated with increased risk of developing ESCC among all three single locus polymorphisms of MAP3k1.Moreover,stratification study revealed that MAP3k1rs702688,rs702689,rs72644086 loci variations were implicated in the altered susceptibility to ESCC when stratified based on selected environmental risk factors?age,gender,smoking drinking status included?.To elaborate on this,MAP3k1rs702688 AG+GG genotype increased male susceptibility to ESCC,while rs702689AG and AA+AG genotype increased susceptibility to ESCC in female cohort.rs702689 AG and AA+AG genotype increased the susceptibility to ESCC among people who were over 63y,contrarily in<63y subgroup,increased risk of ESCC was observed in rs72644086 AG and AG+GG genotype.rs702689 AG and AA+AG genotype increased susceptibility to ESCC in non-smoking subgroup.rs72644086 AG genotype more than doubled the risk among people who drank.Interestingly,in non-alcoholconsumption cohort,rs702689 AG and AA+AG genotype were found to be associated with higher risk for ESCC.Linkage disequilibrium?LD?analysis revealed that all three SNPs of MAP3k1 correlated with each other closely.Also,Haplotype analyses showed that MAP3k1 A_rs702688G_rs702689A_rs72644086 was the protective haplotype against ESCC?60.0%in controls and 55.9%in cases?.As compared with haplotype Ars702688Grs702689Ars72644086,it's safe to infer that MAP3k1 Grs702688Ars702689Ars72644086might facilitate tumorigenesis in ESCC.Conclusion:In this current study,we investigated the possible interaction and association between genetic polymorphisms in MAP3k1 with risk factors and the risk for the development of ESCC in the at-risk Chinese population.We discovered that the heterozygote genotype of MAP3k1 rs702689 AG?OR=1.272,95%confidence interval=1.061-1.525,p=0.009?showed significant association with increased risk for developing esophageal squamous cell cancer.Stratification studies also suggested with exposure to different risk factors?age,gender,smoking and drinking status?,susceptibility to ESCC was altered respectively.However,our findings need to be further validated in larger multi-center studies.Different ethnicity should also be a consideration in the verifying process of future study.Last but not least,the exact underlying mechanisms for the altered susceptibility aforementioned remain an enigma,functional experiments are in dire need to possibly target MAP3k1 therapeutically.