A Case-control Study On The Association Between Genetic Polymorphisms Of CYP2A13, MPO, GSTP1 And Lung Cancer Susceptibility In Han-Chinese

Lung cancer is the most common malignant tumor all over the world. With the development of the industry and urbanization process in Chian, we also face the more and more serious state to control and prevent the tumor. It is very intersting for the control and prevention of cancer to deal with lung cancer in the 21 century. It has been well established that lung caner is an enviroment-associated disease caused by mainly tabacco smoking and air pollution. Otherwise, it also indicate that variant susceptibility exist between individuals in the common carcinogen-enviroment exposure by the epidemiologic study. With the complement of human genomic project, the study on the single neucleotide polymorphism (SNP), which can reflect the variance between individuals, was think highly of one most important post-genomic project. To research the candidated gene and look for the SNPs associated with lung caner susecptibility on the basis of information of SNP database is a valid method.The carcinogenesis and process of lung cancer is an multi-step caused by multitude factors. The carcinogens such as tobacco smoking,will go through complex process by a series of carcinogen-metabolizing enzymes. It has been found that the polymorphisms of some metabolizing enzymes, such as glutathione-S-transferase PI (GSTP1), Myeloperoxidase(MPO) can effect the metabolazing for the tobacco carcinogens. So, it can be infered that The genetic variations at carcinogen-metabolizing enzymes may lead to interindividual differences at the level of internal carcinogenic dose and lead to differential risk in the individuals with similar exposures, and especially in the initial step, the variations may play an important role. In the light of common disease-common variant hypothesis, we hypothesis also that, there is association between the common polymorphisms of some metabolazing enzymes gene and lung cancer susceptibility, and the common gene polymorphisms may be the candidated biomarkers for the scan of the risk individuals.To validat the hypothesis, we select the metabolizing enzyme gene GSTP1, MPO and cytochrome P450 2A13(CYP2A13) as the candidated gene which play an important role in tobacco carcinoges metabolization and expressed in human lung tissue, to investigate the association between common polymorphisms and lung cancer risk in Chinese population, using a case-control analysis of 266 subjects with lung cancer and 307 controls with no personal history of the disease. With the process of International HapMap project, we can retrieve a lot of information for the research on Chinese gene polymorphisms. We analysed the 3 gene thoroughly according to the SNP data retrieved from the database and select the SNPs to study using the sequence-based and HapMap-based method syntheticly. The tagSNPs rs7208693 for MPO, tagSNPs rs1645690 and rs8192789 for CYP2A13, and the haplotype-tagging SNPs rs1695, rs4891, rs762803, rs749174 for GSTP1 were selected, these SNPs can reflect the common polymorphisms of the 3 genes. Taqman assays was used to genotype the the genetic polymorphisms for the 266 patients and 307 controls, and the genotyping method was validated by TA cloning and sequencing. Unconditional logistic regression method was used to evaluate the distribution of the genetic polymorphisms between the 2 groups and the association with lung cancer after adjusting for confounders. We evaluated the relationship between MPO G-463A, GSTP1 rs1695 and lung cancer risk by Meta analysis.We found the interference caused by homologous sequences during the study for the rs8192789 of CYP2A13, so we furtherly researched the interfering effect to CYP2A13 SNP study caused by homologous sequences using TA cloning and sequencing method.The frequency of the 6 SNPs we tested was consistent with the data of Han-Chinese of Beijing released by HapMap database. The tagSNPs rs1645690 of CYP2A13 showed association between lung caner risk and non-smokers(adjust OR =0.448,95%CI 0.208～0.967,p=0.041), not the tagSNPs rs7208693 of MPO. The all 4 Haplotype-tagging SNPs, rs1695, rs4891, rs762803 and rs749174, showed association with lung cancer susceptibility in the smokers. Phase 2 sofrware was used to reconsrtuct the haplotype for GSTP1, and the haplotype(CACA) showed an increased risk of lung cancer among the smokers(adjust OR=1.53,95% CI 1.04～2.25,p=0.033). Furthermore, the diplotype analyses also demonstrated the significant association beween the risk haplotype and lung cancer. The risk haplotypes cosegregate with one or more biologically functional polymorphisms and it corresponds to a recessive inheritance mode. The results of Meta analysis indicate that the polymorphisms of MPO G-463A and GSTP1 rs1695 were not significantly associated with lung cancer risk. We cloned and sequenced the sequence of CYP2A13 gene, and the outcome indicate that the homologous sequences may interfere with the SNP study and some published SNPs in dbSNPs may not exist.In conclusion, our study firstly investigated the association between the common polymorhpisms of the 3 candidated genes and lung cancer risk according to the SNPs information published. We found a risk SNPs of CYP2A13 and a risk haplotype of GSTP1 ssociated with lung caner, and these polymorphisms may be candidated SNP markers for lung cancer susceptibility in Chinese, which can be defined lung cancer risk SNPs...