Characterization Of Genetic And Epigenetic Mechanism Underlying Smoking Behaviors And Nicotine Dependence

Smoking behaviors are seriously harmful to individuals’ health.Smoking is a well-documented risk factor for various diseases,such as cancers.Approximately 6 million deaths worldwide each year are attributable to smoking.Currently,many of us are facing an immense public health challenge from tobacco smoking,thus,more smoking-related studies are greatly needed.Due to smoking behaviors are influenced by both genetic and environmental factors,we conducted three individual studies from epidemiological,genetic and epigenetic perspectives to reveal the mechanisms underlying smoking and its harmful consequences.Although several studies have documented the higher prevalence of smoking among Chinese adults,none has examined the prevalence of nicotine dependence(ND)in China.To address this issue,we conducted a large-scale,cross-sectional study of tobacco use among adults by employing a well-accepted standardized questionnaire.From 2012 to 2014,a total of 17,057 adult subjects consisting of 13,476 males and 3,581 females were recruited.We found that the prevalence of male smoking was 66.1%,whereas female smoking rate only 3.2%.Among male smokers,18.2%were classified as high ND and 39.8%were low-to-moderate ND,which has significant difficulties quitting without treatment.Further,we found that the degree of ND was highly correlated with age,educational level,and annual family income.The social-environmental factors conveyed increased risk for smoking initiation,which is particularly true for the influence of friends’ smoking.Furthermore,current smokers had a significantly higher risk of achieving respiratory and digestive symptoms.To explore the effect of genetics on smoking cessation,we integrated 22 reported studies(N = 11,075)on the association between DRD2/ANKK1 Taq1A polymorphism with smoking abstinence to carry out a meta-analysis.Among cross-sectional and longitudinal studies,we detected that Taq1A A1/*genotype was significantly associated with smoking cessation.Through combining studies with different designs,we revealed the association of TaqlA A1/*genotype with smoking cessation became more signifCcant(p = 3.9 × 10-5)and no evidence of betweel-Study heterogeneity or publication bias exists.DNA methylation plays a very important role in cancer pathogenesis.Previous epigenome-wide association studies(EWASs)have revealed a large number of DNAm loci associated with smoking.Thus,we tested the hypothesis that abnormal DNAm loci associated with smoking are enriched in genes and pathways that convey a risk of cancer by determining whether smoking-related methylated genes led to enrichment in cancer-related pathways.We analyzed two sets of smoking-related methylated genes from 28 studies originating from blood and buccal samples(N = 18,677).By analyzing 320 methylated genes from 26 studies on blood samples,we found 57 enriched pathways associated with different types of cancer(FDR<0.05).Of these,11 were also significantly replicated in the 661 methylated genes from two studies of buccal samples(p<0.05).Furthermore,we constructed a subnetwork of genes important for smoking-attributable cancer from the 48 non-redundant genes in the 11 oncogenic pathways.Of these genes,such as DUSP4 and AKT3,are well documented as being involved in smoking-related lung cancer.Taken together,we first performed a large-scale study to investigate the prevalence of smoking and level of ND in China.By using meta-analytic approach,we found TaqlA.polymorphism plays an important role in smoking cessation and smokers with homozygous A2 allele have a 22%higher probability of smoking cessation.Finally,we provide systematic and robust evidence in support of smoking could induce cancer pathogenesis via altering DNA methylation.