Correlation Between Genetic Polymorphisms Of Cytotoxic T Lymphocyte-Associated Antigen-4 Gene And Susceptibility To Esophageal Cancer

Backgroud and ObjectivesEsophageal cancer is one of the common cancer. The incident and mortality rate of esophageal cancer were the highest in the world. Numerous studies on the etiology of esophageal cancer have been performed but no confirmative results were concluded. Some high penetrance predisposing genes were associated with esophageal cancer. Cytotoxic T Lymphocyte-Associated Antigen-4, an important negative regulator in the activation of T cell, played an critical role in anti-cancer immunity. Some certain polymorphism positions of CTLA gene influencing the function of CTLA4 have also been found. Therefore, this study was to explore whether the polymorphisms of CTLA4 gene were related to the susceptibility and biological behaviors charactor of esophageal cancer.MethodsA total of 237 esophageal cancer patients and 408 health individuals were included in the grouped case-control study. To controlling confounds better,205 esophageal cancer patients and 205 gender-, age-matched health individuals were selected to perform a matched case-control study. Genomic DNA were extracted from peripheral blood of every individuals. PCR-RFLP and direct sequencing method were used to detect the genotype of three tagSNPs in CTLA4 gene and the linkage disequilibrium was estimated by Haploview 4.1 software. Unconditional logistic regression and conditional logistic regression were used to analyze the effects of the polymorphisms on the susceptibility of esophageal cancer in grouped and matched case-control study, respectively. PHASE 2.1 software based on Bayesian algorithm was used to construct haplotypes and then conditional logistic regression was used to analyze the association between haplotypes of CTLA4 and risk of esophageal cancer.χ2 test or Fisher exact probabilities was used to analyze the effect of three tagSNPs on TNM staging of esophageal cancer.ResultsAnalyzed in grouped case-control study, an association was observed between the rs231775 AG and AA genotype, with regard to an increased risk of ESCC, with adjusted OR 1.823 (95%CI:1.233-2.693) and adjusted OR 2.053 (95%CI:1.277-3.298), respectively. Additionally, a significant correlation was also found between the rs4553808 AG genotype and ESCC (adjusted OR=2.267,95%CI:1.589-3.233, P<0.001). Moreover, the distributions of rs4553808 genotypes were significantly different in different group of TNM staging(P=0.002).In matched case-control study, a strong association was observed between the rs231775AG and AA genotype, with regard to an increased risk of ESCC, with adjusted OR 2.280(95%CI:1.433-3.629) and adjusted OR 2.192(95%CI:1.229-3.911), respectively. Additionally, a significant correlation was also found between the rs4553808 AG genotype and ESCC (adjusted OR=1.848,95%CI:1.220-2.800, P=0.004). The polymorphisms of rs231775, rs4553808 and rs733618 clustered in one block and were in tight LD in the population (0.5<D'<0.8).Eight haplotypes were subsequently identified by PHASE 2.1 software. The tightly linked AAG-containing haplotype conferred a five-fold higher risk to susceptibility of ESCC (adjusted OR=5.035,95%CI:1.599-15.860, P=0.005). In contrast, lower susceptibility to ESCC was found to be associated with the GAA haplotype (all were wild type alleles; adjusted OR= 0.413,95%CI:0.251-0.680, P=0.001).ConclusionThe current research demonstrated that significant correlation between genotypes of rs231775 or rs4553808 of CTLA4 gene and the risk of ESCC. The tightly linked AAG-containing haplotype conferred a higher risk to susceptibility of ESCC. In contrast, a lower susceptibility to ESCC was found to be associated with the GAA haplotype. Moreover, CTLA4 gene rs4553808 genotypes were related to the TNM staging of esophageal cancer.