Association Of BTLA Polymorphisms With The Susceptibility To Esophageal Squamous Cell Carcinoma In The Eastern Chinese Han Population

Background:The pathogenesis of esophageal squamous cell carcinoma(ESCC)is complex,where the interrelationship between environmental exposures and individual genetic mutations may promote the occurrence and development of ESCC.As an essential member of immune cooperative signaling molecules,co-inhibitory receptor B and T lymphocyte attenuator(BTLA)plays a vital role in T cell tolerance and tumor specific immune response.Recently,growing evidence has suggested that BTLA single nucleotide polymorphisms(SNPs)changed the susceptibility to a variety of cancers.Nevertheless,whether the variations in the BTLA gene associating with ESCC risk remain unknown.Objective:Regarding the significant value of co-signaling molecules in anti-tumor therapy,we conducted this case-control study to clarify the exact relationship between the four BTLA SNPs and the risk of ESCC in the Eastern Chinese Han population.Methods:A total of 721 sporadic ESCC patients and 1,208 matched non-cancer controls were included in this research,and four tagging BTLA polymorphisms(rs2171513 G>A,rs3112270 A>G,rs1982809 G>A and rs16859629 T>C)were selected and genotyped using SNPscan TM Assays.In this study,Student’s t-test and Chi-square test(χ~2)were performed to evaluate the continuous variables and categorical variables,respectively.The Hardy-Weinberg equilibrium(HWE)was assessed using theχ~2for each genotyped SNP among the control cases.The haplotype of BTLA was analyzed by online software SHESIS,and the potential associations between BTLA variants and ESCC risk and the risk of lymph node metastasis were examined by the multivariate logistic regression analyses after adjustment for age,gender,BMI,and environmental factors,and described by crude odds ratios(OR)with 95%confidence interval(CI).A two-sided P value<0.05 was deemed as statistically significant.Results:The results of the four BTLA SNPs were consistent with the HWE(all P>0.05),meaning that the control group could represent the Chinese.We found that BTLA rs2171513 G>A,rs3112270 A>G,and rs1982809 G>A SNPs were not correlated with the susceptibility to the entire cohorts(all P>0.05).Nevertheless,we showed that the BTLA rs16859629 T>C SNP significantly decreased the risk of ESCC(TC vs.TT:OR=0.75,95%CI=0.57-0.99,P=0.044;TC+CC vs.TT:OR=0.75,95%CI=0.57-0.98,P=0.035).However,the statistical significance of BTLA rs16859629 T>C distribution disappeared after adjusting for the confounding factors,including age,sex,smoking,and alcohol status(P>0.05).When stratified by these factors,and taking BTLA rs2171513 GG wild homozygous genotype as a reference,BTLA rs2171513 GA/AA genotype reduced the risk of ESCC in the drinking subgroup(GA+AA vs.GG:adjusted OR=0.62,95%CI=0.39-0.97,P=0.037).And when using BTLA rs3112270 AA genotype as a reference,results demonstrated that the genotype of AG in BTLA rs3112270 lowered the ESCC risk in the male population(AG vs.AA:adjusted OR=0.78,95%CI=0.61-0.99,P=0.042).Furthermore,in the ever drinking subgroup,we found a similar decreased effect of rs3112270 AG genotype on the risk of ESCC(AG vs.AA:adjusted OR=0.61,95%CI=0.38-0.97,P=0.037).When stratified by BMI,analyses showed that the rs3112270 A>G variant decreased the genetic susceptibility to ESCC in the BMI<24kg/m~2subgroup(AG vs.AA:adjusted OR=0.72,95%CI=0.55-0.93,P=0.012;AG+GG vs.AA:adjusted OR=0.77,95%CI=0.60-0.98,P=0.032).But in the BMI≥24kg/m~2population,the outcome of this SNP conferred an opposite effect on the development of ESCC(GG vs.AA:adjusted OR=1.91,95%CI=1.02-3.59,P=0.045).In addition,we showed that BTLA rs2171513 G>A,rs3112270 A>G,rs16859629 T>C and rs1982809 G>A genotype distribution frequency did not significantly affect the risk of lymph node metastasis in the ESCC patients(all P>0.05).And the BTLA haplotypes did not significantly change the risk of ESCC(all P>0.05).Conclusion:Taken together,this case-control study preliminarily confirmed that the representative two variants of rs3112270 A>G and rs2171513 G>A in BTLA gene might influence the risk of ESCC in the Eastern Chinese Han population,which is the first study for the involvement of the co-inhibitory BTLA gene with the susceptibility to ESCC to our knowledge.However,due to the limitation of recruited sample sizes,more studies with larger samples are worth to elucidate these works as well as the molecular function of BTLA polymorphisms in diverse ethnic patients diagnosed with ESCC.