Association Of Genetic Variants Of Toll Like Receptor Key Genes With Lung Cancer Risk

Objectives Toll-like receptors(TLRs)are one of the pattern recognition receptors,and TLRs recognize specific molecules that activate the adaptive immune system to exacerbate the inflammatory response.Chronic inflammatory response is closely related to the development of cancer.Single nucleotide polymorphisms located in the TLRs promoter and 3’untranslated region may affect gene expression by affecting the activity of the promoter or regulating the binding of the gene to the miRNA.This study aimed to investigate the relationship between genetic variation of TLR receptor genes and susceptibility to lung cancer.Methods This case-control study included 700 non-small cell lung cancer patients(NSCLC)and 700 health controls.The 700 cases were collected from North China University of Science and Technology affiliated Tangshan Gongren Hospital and Tangshan Renmin Hospital in China from 2012 to 2014.Control individuals without a history of any cancer were recruited from the same region.The relevant literature was used to screen out cancer-associated TLRs genes:TLR3,TLR4,TLR5 and TLR7 genes.The dbSNP database and the Ensembl database were used to screen out the promoter region of the above genes and the SNP site of the 3’untranslated region in the Chinese Han population with a minor allele frequency(MAF)greater than 0.05.Functional prediction was carried out by using TRANSFAC and SNPinfo Web Serve software and finally SNPs affected by transcription factor binding or microRNA binding were screened.Genotyping was performed using Polymerase chain reaction-restriction fragment length polymorphism(PCR-RFLP)and Taqman probe methods.Statistical analysis of the data was performed using SPSS23.0.The analysis was performed using the?~2 test to analyze the distribution of the basic characteristics(gender,age,smoking status)of the subjects in the case group and the control group.The Hardy-Weinberg equilibrium uses the pearson fitting goodness test.Odds ratio(OR)and 95%confidence interval(95%CI)were estimated by unconditional logistic regression.The correction of multiple tests was performed using the False discovery rate(FDR)method.Results After screening by literature and bioinformatics,six TLRs(TLR3 rs5743303,TLR4rs1927914,rs11536891,rs7869402,TLR5rs1640816,TLR7 rs7873784)were screened to influence gene expression.Firstly,the basic characteristics of the subjects were analyzed.The frequency distribution of gender and age in the case group and the control group was consistent,and the P values were all greater than 0.05.The proportion of smokers in the case group(44.4%)was significantly higher than that in healthy controls.There was no significant difference in the cumulative smoking between the case group and the control group(P=0.773).We analyzed the relationship between these variants and susceptibility to non-small cell lung cancer and found that TLR4 rs7869402 C>T significantly reduced the risk of lung cancer.TLR3 rs5743303,TLR4 rs1927914,TLR4rs11536891,TLR5 rs1640816,TLR7 rs3853839 were not associated with the risk of lung cancer(P>0.05).Individuals with at least one T allele in TLR4 rs7869402 genetic variation were able to reduce the risk of lung cancer(OR=0.63,95%CI=0.45-0.89).Stratified analysis showed that males(OR=0.58,95%CI=0.38-0.87)and low age groups(OR=0.43,95%CI=0.27-0.69)who carried at least one T allele was associated with an decreased risk of NSCLC.Smoking stratification showed that smokers carrying at least one T allele reduced the risk of NSCLC(OR=0.49,95%CI=0.28-0.87)compared with CC genotype carriers,but not in smokers(OR=0.77,95%CI=0.50-1.19).Pathological type stratification showed that individuals with at least one T allele in the adenocarcinoma group were associated with risk of NSCLC(OR=0.62,95%CI=0.41-0.92)instead of squamous cell carcinoma(OR=0.71,95%CI=0.44-1.13)and other types of NSCLC(OR=0.23,95%CI=0.03-1.70).Haplotype analysis showed that the distribution of rs1927914G-rs7869402T-rs11536891T haplotype was statistically different between non-small cell lung cancer group and control group(P=0.001).Conclusions TLR4 rs7869402C>T genetic variation may reduce the susceptibility of lung cancer and rs1927914G-rs7869402T-rs11536891T haplotype may be a protective factor for lung cancer There was no correlation between TLR3 rs5743303,TLR4rs1927914,rs11536891,TLR5 rs1640816,TLR7 rs3853839 gene polymorphisms and the risk of lung cancer.Figure6;Table7;Reference 192...