| BackgroundCigarette smoking is the most important environment risk-factor of lung cancer. During cigarette smoking, more than 60 kinds of carcinogens are produced and some of them such as polycyclic aromatic hydrocarbon compounds, benzene, arsenic, propylene, nicotine (nicotine), carbon monoxide, and tobacco tar can contribute to the occurrence of lung cancer. By different mechanisms, those carcinogens may result in the DNA damage of bronchial epithelial cell, the activation of oncogenes, and the mutation and inactivation of tumor suppressor genes, thus leading to the development of lung cancer. Many studies have shown that over 80% of lung cancers are tobacco related. However, less than 20% of smokers develop lung cancer. These indicate that genetic susceptibility plays a key role in lung cancer.Nicotine is the major addictive substrate of tobacco which makes smoker be addicted to tobacco and thus increases the danger of smoking, though its direct carcinogenesis is still controversial. Moreover, it's reported that nicotine can specially active the Akt signals pathway via its interaction with nicotinic acetylcholine receptor and then inhabit the cell apoptotic signal, which eventually leads to the development of tumor or cancer. Nicotinic acetylcholine receptor family locates at chromosome 15q25. These receptors expression in the key regions of the brain are related to tobacco addictive behavior, and those distribute in epithelial cells of the lung are involved in vivo signal transduction via binding to nicotine and NNK, resulting in cell proliferation and neoplastic transformation. In 2008, Nature magazine reported several genetic variants in nicotinic acetylcholine receptor family genes were associated with a significantly increased risk of lung cancer in smokers in European population. Since then, American and Japanese studies reported the same results. Simultaneously, sever studies demonstrated that the genetic variants in nicotinic acetylcholine receptor family genes can significantly affect the number of cigarettes smoked per day and thus gave a hypothesis that the association between the genetic variants and lung cancer risk is indirect, deriving from association of the same locus with smoking habit, since nicotine is not carcinogenic, available data do not provide plausibility of the association between the nicotinic locus and lung cancer pathogenesis. The negative data of the genetic variants in never-smokers from the studies in American and Englishmen supported this hypothesis; however, the positive conclusions in European and Japanese population were not in agreement with the suggestion. All these supported that large prospective with diverse ethnics and mechanic studies are warranted.By examining the HapMap data and using the Hapview 4.1 software, however, we found that the distribution of SNPs and the haplotype block vary considerably among different ethnic groups and the risk SNPs, rs8034191, rs1051730, and rs16969968 identified in previous GWAS are extremely rare in Asians, suggesting that there must be other risk variants in susceptibility to lung cancer in Chinese populations. Recently, one study in Chinese population identified a functional genetic variant (rs6495309 T>C) in the CHRNA3 gene which is a member of the Nicotinic acetylcholine receptor gene family. It was unique, of high frequency, and increased the risk of lung cancer significantly in Chinese population, especially in current smokers and never-smokers, however, not in former smokers. The recent meta-analysis of four reported results in never-smoking groups demonstrated that the two high association genetic variations had nothing to do with lung cancer, suggesting that the conclusion of our population maybe achieved by chance and still need to be further validated in the population.Passive smoking group is a class of people who never smoke but often exposure to the tobacco smog. Cigarette smoking also brings risk to those people, but they were often neglected in previous studies. Thus, we supported that the inconsistent conclusion between the different ethnics may be due to the different frequency of passive smoking group in non-smokers. So in this case-control based study, we investigated the association between the genetic variant in CHRNA3 promoter and lung cancer risk of the southern Chinese population, especially in smokers, passive smoking population and non-smokers. We then performed meta-analysis to summarize the latest research findings to explore the major positive genetic variation in CHRNA3 gene and the risk of lung cancer both in smokers and never-smokers.Objective:In order to investigate the association between the genetic variant in CHRNA3 promoter and the risk of lung cancer in a southern Chinese population, especially in smokers, passive smoking population and non-smokers., and to analyze the gene-environment interaction on the lung cancer risk.Methods:In current study, we performed a case–control study of 1056 lung cancer cases and 1056 age- and sex frequency– matched cancer-free controls in a southern Chinese population to investigate the common polymorphism rs6495309(T>C)in the risk of lung cancer. CHRNA3 genotype was determined by PCR-RFLP analysis and SAS 9.13 was used to analyze the genetic variant and lung cancer risk through non-conditional logistic regression. Moreover, according to the principles and norms of systematic reviews, PubMed database was used to search the standard case-control studies of CHRNA3 genetic variants and lung cancer, and then we used the Stata 10.0 software to perform meta-analysis.Result:This study included 1056 lung cancer patients and 1056 cancer-free controls. Of the 1056 cases, there were 384 (36.4%) cases of adenocarcinoma, 369 (34.9%) squamous cell carcinoma, 43 (4.1%) large cell carcinoma, 128 (12.1%) small cell lung cancer, and 132 (12.5%) mixed-cell or undifferentiated carcinoma. According to the IASLC staging classifications, there were 154 (14.5%) cases of stage I, 94 (8.9%) stage II, 333 (31.5%) stage III, and 475 (45.0%) stage IV. The difference in distributions of overall drinkers between the cases and controls were not statistically significant (P=0.9158), but it seemed that cases were more apt to abjure drinking in response to the early symptoms of the terrible cancer, just as the table I shown(current drinker:15.6% versus 17.6;former drinker: 6.1 % versus 3.9%, P=0.0429).Otherwise, more current smokers and former smokers were found among the cases than the controls (current smokers: 37.3% versus 34.7%; former smokers: 19.6% versus 16.7%; P=0.0283). The controls had a higher BMI compared to the cases (P<0.0001). Moreover, we didn't find the significant association between family history of cancer and lung cancer (P=0.9417).The observed genotype frequency of rs6495309 (T>C) was in agreement with the Hardy-Weinberg equilibrium in the control subjects (P=0.2677) and was significantly difference among case and control(P = 0.0003). Compared with the TT genotypes, the CT heterozygotes (adjusted OR=1.27; 95%CI=1.01-1.62; P=0.046), the CC homozygote (adjusted OR=1.64; 95%CI=1.67- 2.12; P=0.001) and the increased risk of lung cancer was statistically significant. The carriers of variant (risk) alleles (rs6495309C) were associated with significantly increased risk of lung cancer (adjusted OR=1.41; 95%CI=1.13-1.76; P=0.003).There was a significant trend for an allele dose effect on risk of lung cancer (Ptrend =0.0001).Stratification analysis showed the increase risk of lung cancer was obvious in population that older than age 60, male, smokers, passive smoking population. We further analyzed the source of passive smoking and found that the observed genotype frequency of rs6495309 (T>C) was only significantly difference among case and control whose passive smoking was from parents. Moreover, Meta-analysis revealed that the reported high association SNPs in CHRNA3 gene and the risk of lung cancer were more significantly in smoker (combined OR = 1.42, 95% CI = 1.34-1.51; P <0.0001). But in never-smokers, because of the existence of heterogeneity between each publications, we performed stratification analysis by ethics, the results showed that the genetic variations in CHRNA3 gene were associated with the risk of lung cancer in Asian group (combined OR = 1.40, 95% CI = 1.21-1.62; P <0.0001), but not in Caucasian group (combined OR = 0.89, 95% CI = 0.76-1.04; P = 0.082).Conclusion:The CHRNA3 promoter variant rs6495309 (T>C) can significantly increase the risk of lung cancer in southern Chinese population, especially in population that older than age 60, male, smokers, passive smokers. For the passive smokers, the carriers of variant alleles (rs6495309C) whose parents were smokers get a high lung cancer risk. In smokers, the reported high association SNPs in CHRNA3 gene and the risk of lung cancer were more significantly. In never-smokers, the genetic variations in CHRNA3 gene were associated with the risk of lung cancer in Asian group, while not in Caucasian group. |
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