The Epidemiological Study On The Association Of Lifestyle Factors、 Genetic Polymorphisms In NOD2Mediated Immune Inflammatory Pathways And Related MiRNA With The Risk Of Lung Cancer

[Objective]To provide scientific evidence for the prevention and control of lung cancer, weconducted an epidemiological study to investigate the lifestyle factors and geneticpolymorphisms in NOD2mediated immune inflammatory pathways with the risk oflung cancer. To explore the expression level and clinical significance of miRNA-107in lung cancer.[Methods]1. A case-control study was conducted, including1312newly diagnosed cases withlung cancer and1556healthy control subjects frequently matched by gender and age(±2year). Epidemiological data were collected by in-person interviews using astandard questionnaire. The adjusted odds ratios (ORs) and corresponding95%confidence intervals (CIs) were estimated by fitting multivariate unconditionallogistic regression models that included potential confounding factors. The interactioneffects and population attributable risk analysis of lifestyle-related factors on lungcancer were also investigated in our analysis.2.5ml blood sample was collected from each patients and saliva was collected fromeach control by The OrageneTMDNA self-collection kit. The genomic DNA wereextracted from all blood and saliva samples. The genotypes of polymorphisms weredetermined by Multiplex SNaPshot technology. The unconditional logistic regressionwas used to identify the independence and interacted effects of geneticpolymorphisms in NOD2mediated immune inflammatory pathways andenvironmental facts to the development of lung cancer.3. The expression of miRNA-107in43matched lung cancer tissues and adjacentnon-tumor lung tissues was measured by qRT-PCR.Then, to analyze the relationship between the expression level and clinicopathologic features.[Results]1. Compared with non-smokers, former smokers and current smokers were linkedto a significantly increased risk of male lung cancer with adjusted OR of4.763（95%CI：3.539～6.411）and4.472（95%CI：3.456～5.786）,respectively．The risksof lung cancer obviously elevated with increased of cigarettes smoked per day, thedulation, pack-year of smoking and ages started, as well as depth of inhalation. Therisks of lung cancer among adult men who quit for more than ten years（OR=0.68,95%CI:0.49～0.96）was lower compared with current smokers. Cigarettesmoking was associated with elevated risk of adenocarcinoma and Squamous cellcarcinoma, the adjusted OR was2.910（95%CI:2.144～3.952） and7.502（95%CI:4.848～11.609）, respectively．2. No statistical significant association was found between alcohol drinking andlung cancer in our analysis. Compared with non-smokers and non-alcohol drinkers,The adjusted OR of lung cancer in smokers and alcohol drinkers was4.666（95%CI:3.552～6.129）, which was higher than the smokers but not-alcohol drinkers（OR=4.108,95%CI:3.140～5.374）.3. Compared with non-tea drinkers, tea drinking significantly decreased the risk oflung cancer（OR=0.655，95%CI:0.547～0.785）. A protective effect of tea drinkingon risk of lung cancer was observed for non-smokers with adjusted OR of0.452（95%CI:0.347～0.588）and the risks decreased with increased years of tea drinking.The inverse associations were also observed between frequency, concentration,consumption, types and risk of lung cancer among non-smokers. Tea drinking wasassociated with decreased risk of lung cancer for those smokers with drinking tea <3times/week,<250g/month and low concentration, with the adjusted OR of0.452（95%CI:0.290～0.706）,0.548（95%CI:0.366～0.819）and0.631（95%CI:0.428～0.932, respectively.4. Stratified analyses indicated that NOD2rs3135500GA/AA variant genotype hadsignificantly increased the risk of lung cancer among history of pulmonary disease （OR=2.309,95%CI:1.205～4.421） compared with the GG genotype. RIPK2rs2906766GA/AA variant genotype carrier had significantly decreased the risk oflung cancer among males （OR=0.788,95%CI:0.673～0.923）,smokers（OR=0.764,95%CI:0.639～0.914）and alcohol drinkers（OR=0.679,95%CI:0.535～0.863）. Compared with CC genotype, RIPK1rs17548629CT/TT variant genotypehad protective effect among non-tea drinkers（OR=0.752,95%CI:0.586～0.964）andhistory of pulmonary disease （OR=0.464,95%CI:0.253～0.850）. IL8rs1126647AT/TT variant genotype carrier was associated with a significantly decreased lungcancer risk among tea-drinkers（OR=0.751,95%CI:0.579～0.976）. However, nosignificant association was found between RIPK1rs77736895and NF-КBIArs2273650C/T genotypes and lung cancer risk.5. The expression level of miRNA-107were upregulated in lung cancer tissuescompared with adjacent non-tumor lung tissues（P=0.01）.The expression level ofmiRNA-107was related to lymphatic metastasis，while was not related to age，gender，tumor size, TNM stage, smoking history and family history of cancer.[Conclusions]1. Our findings provide further evidence that smoking is a mainly risk factor formale lung cancer, and quits moking will reduce the risk.2. Alcohol drinking may not be the risk factor for lung cancer, but may enhancesthe risk of smoking.3. The protective effect of tea drinking was observed on the risk of lung cancer,especially for non-smokers.4. Genetic polymorphisms in NOD2mediated immune inflammatory pathwaysmay modulate the risk of lung cancer in the Chinese population. However, furtherstudies with functional evaluation of the SNP are warranted to replicate and extendthe significance of the findings.5. miRNA-107was overexpressed in lung cancer tissues. miRNA-107may haverelatiovship with lymphatic metastasis and could be considered as a new marker ofmalignant degree of lung cancer.