Associations Between Single Nucleotide Polymorphisms In Nicotinic Acetylcholine Receptor Genes And DNA Damage Levels Of Coke Oven Workers

The abundant polycyclic aromatic hydrocarbons (PAHs) have been confirmed to be the main cause of DNA damage for coke-oven workers. PAHs were formed and released during the coke process. Numerous occupational epidemiological studies demonstrated that DNA damage levels may be different even under similar environments, suggesting that genetic heterogeneity may play a role in determining the individual's genetic toxicity when exposing to carcinogenic PAHs. Determination of the genetic background and DNA damage levels of the occupational PAHs exposed coke-oven workers will provide us with a good model for analyzing the"genotype-phenotype"relationship.With the development of technology and the widely use of genome wide association studies (GWAS), researches of complex diseases, such as lung cancer achieved great success. Recently several GWAS have identified a novel susceptibility region at 15q25, nicotinic acetylcholine receptors (nAChRs) subunit CHRNA3-CHRNB4-CHRNA5 (cholinergic receptor, nicotinic,α3,β4 andα5) gene cluster, which was strongly associated with lung cancer in Caucasian population in the beginning of 2008. This association was subsequently confirmed by another independent GWAS also based on Caucasian population in the end of 2008. Then, Pillai.et al indicates that this gene cluster was associated with FEV1 and COPD in 2009.Coke oven workers are exposed to coke oven emissions (COE) that contain a wide variety of polycyclic aromatic hydrocarbons (PAHs), which are carcinogenic and mutagenic to humans. To investigate whether polymorphisms of CHRNA3-CHRNB4-CHRNA5 gene cluster play a major role in DNA damage in coke oven workers, which was an important early biological event in carcinogenesis, we select three SNPs in the CHRNA3-CHRNB4- CHRNA5 gene cluster and detected the association between these SNPs and DNA damage level in the coke oven workers.In this study, we recruited 309 workers from a steel plant in Taiyuan, northern China. After adjustment for BPDE-Alb adduct levels, age, work years, smoking status and drink, our results showed that the lymphocytes olive tail moment (OTM) of high exposure group (1.23±1.05) was significantly higher than that of low exposure group (0.80±1.07). We genotyped the SNPs (rs667282, rs12910984, rs2036534) which in CHRNA3-CHRNB4- CHRNA5 gene cluster and evaluated their associations with the DNA damage levels of 309 workers. In the high exposure group, subjects with the rs667282 CT and TT+CT genotype had marginally or significantly lower OTM values (0.95±0.13, 1.09±0.11) than subjects with the rs667282 CC genotype (1.64±0.17), P=0.002, 0.008, respectively. We also found that the OTM in carriers of rs12910984 AG and AG+AA genotype (0.92±0.13 and 0.47±0.12) was significantly lower than that of the GG genotype carriers (1.60±0.17) in high expose people, P=0.002, 0.010, respectively. However, there were no significance was found in the association between polymorphisms in CHRNA3-CHRNB4-CHRNA5 gene cluster and the DNA damage levels in the low exposure group.The diplotype results showed that, the CG/CG diplotype carriers had the highest OTM (1.64±0.17), which is significantly higher compared with the most widely distributed TA/CG diplotype (0.89±0.13) in the high exposure group, P=0.001. We also found that the OTM of TA/TA diplotype carriers (1.35±0.17) was higher compared with that of the most widely distributed TA/CG diplotype in the high exposure group, P=0.035. No significance was found in the association between diplotype and the DNA damage levels in the low exposure group.The results showed that workers carriers of rs667282 CC and rs12910984 GG had higher DNA damage levels when exposed to exogenous cytotoxic factors like PAHs, while the OTM increased in subjects carriers of CG/CG and TA/TA diplotype.In summary, we selected three SNPs in the CHRNA3-CHRNB4-CHRNA5 gene cluster and detected the associations between these SNPs and DNA damage levels in the coke oven workers. Our results indicated that CHRNA3-CHRNB4-CHRNA5 gene cluster variations may moderate DNA damage levels in the high PAHs exposure group coke oven workers. However, the sample size of our study was small, which may lead to the insufficient power, so the association between SNPs in the CHRNA3-CHRNB4-CHRNA5 gene cluster and DNA damage levels should be validated by additional large population studies. Moreover, we should evaluate the biological mechanisms for PAHs induced DNA damage in the further studies.