Our current study revealed that the SNP rs6495309T>C in the CHRNA3 gene was associated with an increased risks and poor prognosis of both COPD and lung caner in Chinese populations. The rs6495309C variant genotypes (CC or CT/CC) interacted with smoking on increasing risks of both diseases, and potentially with passive smoking on risk of lung cancer and COPD. The reporter assays showed that nicotine and NNK, but not B(a)P could induce a higher promoter activity of the rs6495309C allele than T allele. However, for the SNP rs1051730G>A, no significant association was observed for neither COPD nor lung cancer. To best of our knowledge, this is the first study to reveal the SNP in the CHRNA3 gene was associated with both COPD and lung cancer risks and prognosis.
The biological function of the rs6495309C variant genotypes on increasing lung cancer risk had been described previously 
. Here, we showed that the rs6495309T>C variation contributed to a reduction in the spirometric phenotypes. The rapid decline of FEV1 is a marker for airflow obstruction and used to assess the severity of the airflow obstruction 
, this is consistent with our finding that the rs6495309CC genotype was correlated with worse COPD stages. Studies have shown that CHRNA3 associated with smoking addiction through the high expression of CHRNA3 in the key regions of the brain 
, the rs6495309CC genotype carriers may consume more cigarettes, thus leading to more damage in pulmonary function 
. Consistently, lung cancer patients with the rs6495309C genotypes had poor survival, because smoking is always associated with a decreased survival of lung cancer 
, and CHRNA3 functions to promote chemotherapy resistance through the Akt-dependent proliferation and the NF-kappaB-dependent survival pathways under the stimulation of NNK 
. Taken together, we supported that the rs6495309T>C polymorphism is a available indicator of prognosis of both COPD and lung cancer.
By experimentally exposing the transfected cells with the plasmids to the tobacco related chemical components, we found that nicotine induced a higher level of promoter activity of CHRNA3
under the control of the promoter with the rs6495309C allele than that with the T allele. Therefore, those rs6495309C allele carriers are more susceptible to be nicotine- dependence. Intriguingly, we also found that NNK conferred an increased transcript activity particularly for the CHRNA3
promoter with the rs6495309C allele. Because CHRNA3
is also a receptor of NNK, we could assume that NNK modulates the adverse genetic effect of rs6495309C genotypes on increasing lung diseases risk because NNK can cause gene mutation, DNA damage, activation of oncogenes and tumor-related signal pathways 
In stratification analysis, the associations between the rs6495309C variant genotypes and COPD as well as lung cancer risk were all significant in smokers but not in never smokers; they were also significant for lung cancer risk, and borderline significant for COPD risk in passive smokers, which was novel findings. The CHRNA3 SNPs are associated with smoking behavior 
; it’s conceivable that the rs6495309C variant genotypes interacted with ever smoking on increasing COPD and lung cancer risk, and between the variant genotypes and passive smoking on increasing lung cancer risk, because of the modulating of tobacco smoking on CHRNA3. Furthermore, those individuals being passive smokers in childhood (passive smoking from parents) with rs6495309C genotypes would face a more noticeable high risk of lung cancer as well as COPD, reflecting a hazard risk of parents’ smoking on children’s healthy. Previous studies had controversial results of the association between CHRNA3
SNPs and lung diseases risk in never smokers 
, mainly due to the bias from different passive smoking status. Here, we showed that the association was significant in passive smoker but not in smoke avoider, suggesting that the CHRNA3 SNPs may only exert their genetic effect in smoking-related population.
As we know, COPD and lung cancer are the most striking smoking-related diseases, and COPD is considered to be an important risk factor of lung cancer 
. Here, this functional causal SNP rs6495309T>C shared by COPD and lung cancer, supported an intrinsic linkage of smoking’s effect on these diseases. Furthermore, COPD cases with rs6495309C genotypes would suffer an intuitively higher risk of lung cancer, indicating a possible predisposition of COPD patients to development of lung cancer in those genotypes carriers. Yet, studies deeply into investigating and verifying those indicated genetic markers to predict the lung cancer risk in COPD patients are essential.
The present study has several strengths. In previous lung cancer case-control studies, the controls were cancer-free subjects without excluding the COPD patients 
, and thus these studies could not avoid the possible confounding bias on evaluating the association between the genetic variants and lung cancer risk. Here, in our designed case-control study, the controls were all cancer-free and with normal pulmonary function, which allowed us to simultaneously compare the COPD and lung cancer groups with the same control group. Such a study design helped us to unravel the intrinsic linkage between COPD and lung cancer. Furthermore, our study had high statistical power for both COPD and lung cancer association analysis (98.3% for lung cancer, 94.5% for COPD). However, there were also some limitations because this was a hospital-based case-control study, there must be selection bias or information bias. In addition, because the controls were age (±5 years) and sex frequency matched with COPD patients, significant deviation in age distribution was observed between lung cancer cases and controls, which may lead to some confounding.
In conclusion, our data revealed a shared susceptible SNP rs6495309T>C and its interaction with smoking or passive smoking in association with the risk and prognosis for both COPD and lung cancer in Chinese populations. The SNP rs6495309T>C, once validated by others would be a useful biomarker to predict the risk and prognosis of COPD and lung cancer.