The Association Study Of Single Nucleotide Polymorphisms In DNA Repair And Folate Metabolism Genes And Lung Cancer Susceptibility In A Chinese Population

Lung cancer is the leading cause of cancer-related death in the world,and tobacco smoking has long been established as the predominant risk factor for it. Tobacco-related carcinogens cause a variety of DNA damage that is repaired by different enzymatic pathways.There are mainly four DNA repair pathways in cell.Of them,NER plays a critical role in repairing DNA damage induced by smoking.Based on the pathway candidate strategy,total 298 SNPs in 24 genes were genotyped by the Illumina genotyping platform among 500 incident lung cancer patients and 517 age- and gender-matched controls.After eliminating the SNPs that genotyping rate <90%or minor allele frequency <0.05,total 99 SNPs were selected as TagSNP for the remains based on the principle of R square equal to 0.8.Significantly association were found between ten SNPs and lung cancer risk during the single locus analysis.Positive association were still remained for two locus that MNAT1-rs973063 and PCNA-rs25406 and lung cancer risk even after 1000 times permutation test.During the stratified analysis,we revealed that that several genes in the NER pathway could interact with age,gender,family cancer history and smoking status.Haplotypes in PCNA and RPA1 were found significantly associated with lung cancer susceptibility.Combined multiple locus analysis were conduced for the ten SNPs after grouping them by their effect to lung cancer risk.The results showed that there exists significantly allele number dependence dose-effect(p=0.001;p=0.003)for the two group.A three-factor model were showed to have lowest prediction error after analysis by MDR.The model was consist by CSB-rs4253038,RPA1-rs1131636, ERCC1-rs2336219.In conclusion,we analyzed for the first time the association between genes in NER and lung cancer risk on the pathway level,and we revealed that several SNPs in the pathway may contribute to the risk of lung cancer.And the interaction between combined effect of risk alleles and lung cancer susceptibility showed a dose-effect relation. Among the four DNA repair pathways,BER is also essential for the repair of damage caused by smoking.Based on the same strategy with partⅠ,Total 226 SNPs were genotyped in 20 genes,and 60 SNPs were choose as TagSNP.Six SNPs showed significant association with lung cancer risk.But no one remained after the multiple adjust.Four interaction pairs were found as for LIG3-age, LIG1-fmc,PNKP-fmc,and MBD1-culumative smoking dose.However no significant interactions were found for SNPs in BER and smoking status.Haplotypes in MBD1, MBD4 and REV3L were found significantly associated with lung cancer susceptibility.Combined multiple locus analysis were conduced among the five SNPs that showed protective effect for lung cancer risk.The results showed that there exists significantly allele number dependence dose-effect(p=0.00005)between the five SNPs and lung cancer risk.A three-factor model were revealed to have lowest prediction error after analysis by MDR.The model was consist by APEX2_rs3136820,TDG_rs4135042, MPG_rs2541623.In conclusion,we analyzed for the first time the association between genes in BER and lung cancer risk on the pathway level,and we revealed several SNPs that may be contribute to the risk of lung cancer.And the interaction between combined effect of risk alleles and lung cancer susceptibility showed a dose-effect relation. There are few studies on the association of DSBR and lung cancer risk,because no evidence showed that direct association exists between DSBR and DNA damage caused by smoking.However,double-strands breakage is fatal for cells which often result in carcinogenesis.We investigated the association between SNPs in DSBR genes and lung cancer risk because the important role for DSBR in carcinogenesis.Based on the same strategy with partⅠ,total 318 SNPs in 22 genes were genotyped and 91 SNPs were selected as TagSNP.Significantly association were found between seven SNPs and lung cancer risk during the single locus analysis.Positive association were still remained for three SNPs in two genes after multiple tests.These SNPs include RAD52-rs11571378(p= 0.002),RAD52-rs1051672(p=0.04)and XRCC5-rs2241321(p=0.005).During the stratified analysis,we revealed that that several genes in the DSBR pathway could interact with age,gender,and family cancer history.No significant interaction were found between SNPs in DSBR and smoking status.Haplotypes in RAD52 and XRCC5 were also found significantly associated with lung cancer susceptibility.Combined multiple locus analysis were conduced for the ten SNPs after grouping them by their effect to lung cancer risk.The results showed that there exists significantly allele number dependence dose-effect(p=3×10^-6;p=0.02)for the two group.No significant interaction model were found during the MDR analysis.In conclusion,we analyzed for the first time the association between genes in DSBR and lung cancer risk on the pathway level,and we also revealed several SNPs that may be contribute to the risk of lung cancer.And the interaction between combined effect of risk alleles and lung cancer susceptibility showed a dose-effect relation. PartsⅣPolymorphisms in Folate Metabolism Genes and Susceptibility to Lung CancerEpidemiologic studies have provided evidence that smoking is the primary risk factor for lung cancer.However people who had quit smoking still have higher risk of lung cancer than those who had never smoking.And adequate folate intake could reduced the risk of getting lung cancer for ever those ever smokers.It's also established that lack of folate can increase the risk of lung cancer.Lack of folate or disturbance in this pathway may lead to aberrant DNA synthesis and repair and DNA methylation.Polymorphism in folate metabolism related genes may contribute to the disturbance.Based on the hypothesis,we determined the association between SNPs mainly in four key folate metabolism genes with lung cancer risk among 500 incident lung cancer patients and 517 age- and gender-matched cancer-free controls.Among older individuals(>60 years),an increased risk was suggested for the variant allele carriers of MTHFR rs17037396[Odds ratio(OR)=2.18,95% confidence interval(CI):1.25-3.80]and rs3753584(OR=2.53,95%CI=1.36-4.73), compared with subjects with wild homozygote,Haplotype analysis revealed that MTHFR"ACCACC"haplotype may contribute to the risk of lung cancer(OR=1.49, 95%CI:1.03-2.14,local test p value 0.032).A data mining method,multifactor dimensionality reduction(MDR),predicted a four-factor interaction model (rs1801133,rs4659731,rs2273029 and rs699517)with the lowest average prediction error(45.08%,p<0.001).These findings suggest that genetic variants in one-carbon metabolizing genes might modulate the risk of lung cancer by interaction with environmental factor or genes in the same pathway.