遗传多态性、microRNA与肺癌、焦炉工氧化应激和遗传损伤的关联性研究
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摘要
肺癌是全世界发病率和死亡率最高的恶性肿瘤。大量研究表明，肺癌是由遗传因素与环境因素共同作用的结果。研究者们能够通过全基因组关联研究（genomewide association studies, GWAS）较为全面了解个体的遗传因素。目前肺癌GWAS研究已经在不同人种（包括中国汉族人群）中报道了多个肺癌易感性位点。然而，所确定的大多数易感性位点对肺癌发生的作用较小，仅能解释部分的肺癌发生，因此还需要继续寻找新的肺癌易感性位点。基因型填补能够对未分型的遗传变异进行预测，基于基因型填补的关联性研究有利于发现新的遗传易感性位点。细胞周期调节、凋亡、氧化应激和炎性免疫反应应答通路在吸烟所致肺癌中发挥了重要作用。然而目前仍不太清楚这些通路上的遗传变异肺癌易感性的关联。为此我们在第一部分中采用基于基因型填补的关联性研究策略，全面探索细胞周期调节、凋亡、氧化应激和炎性免疫应答通路的遗传多态性与肺癌易感性之间的关联。
大量研究表明，除遗传因素外，肺癌发生与环境因素密切相关。环境因素的暴露能够改变机体的表观基因组，进而改变基因的表达，影响疾病的发生发展。微小RNA（microRNA，miRNA）是表观遗传学调节的主要机制之一。众多研究表明，香烟烟雾的暴露能够改变机体的miRNA表达水平。然而，PAHs作为香烟烟雾中的一类重要的致癌物，目前很少有流行病学研究表明PAHs暴露能否影响miRNA表达水平。为此我们以肺癌高发性的、PAHs高暴露的职业性人群——焦炉工为研究对象，在第二部分的第一节中详细探讨了PAHs暴露对miRNA表达的影响。
氧化应激和遗传损伤是PAHs诱发肺癌的重要机制。PAHs在代谢过程中能产生大量活性自由基（reactive oxygen species，ROS）。ROS能攻击生物大分子，从而造成组织细胞损伤，是诱发肿瘤发生的重要起因。此外，PAHs经代谢后可生成二羟基环氧化物，可与DNA分子共价结合形成PAHs-DNA加合物，进而引起DNA链断裂、基因组不稳定和染色体损伤等遗传损伤。这些遗传损伤是肿瘤发生的早期生物学事件。miRNA可以通过调节氧化应激和DNA损伤应答中的重要靶基因，进而介导机体对氧化应激和遗传损伤的应答反应。然而目前尚无流行病学研究表明miRNA是否与PAHs引起的氧化应激和遗传损伤相关。为此，我们在第二部分的第二、三节中以焦炉工为研究对象，进一步探讨了PAHs相关性miRNA与氧化应激、遗传损伤的关联。
第一部分重要通路上的遗传多态性及其与吸烟的交互作用对肺癌易感性的影响
细胞周期调节、凋亡、氧化应激和炎性免疫应答在吸烟导致肺癌中发挥了重要作用。然而目前仍不太清楚这些通路上的遗传多态性与肺癌易感性之间的关联。中国汉族人群肺癌GWAS已经确定了多个肺癌易感性遗传位点，为了继续寻找新的肺癌易感性位点，我们采用基于基因型填补的关联性研究，探讨细胞周期调节、凋亡、氧化应激和炎性免疫应答信号通路上的单核苷酸多态性（single nucleotidepolymorphisms，SNPs）对肺癌易感性的影响。我们首先从中国汉族人群肺癌GWAS基因型填补后的数据库（2331例肺癌病例与3077例对照）中，选择了24042个相关通路上的SNPs，评价它们与肺癌易感性的关联，随后在另外两个人群中进行了验证（共4133例肺癌病例与4522例对照）。
两个SNPs（rs2282987与rs2706748）被成功验证出来。当我们合并三个阶段的结果后发现，rs2282987与肺癌易感性相关（OR=1.18，Padd=2.27×10-9）。与rs2282987GG携带者相比，rs2282987CC携带者的肺癌易感性显著增高（OR=1.37，Phomo=1.10×10-6）。rs2706748与肺癌易感性之间的正相关关系（OR=1.17，Padd=5.10×10-6）虽然未达到基于通路的显著性阈值（Padd>2.0×10-6），但由于它在三个阶段中的Padd均符合各个阶段的要求（GWAS阶段Padd=9.65×10-5；I期验证Padd=3.26×10-2；II期验证Padd=4.49×10-2），因此也纳入了后续的分析中。交互作用分析发现，在年龄为51-60岁之间的人群中，rs2282987和rs2706748与吸烟状态（rs2282987：Pinteraction=1.04×10-2；rs2706748：Pinteraction=3.03×10-2）和吸烟剂量（rs2282987：Pinteraction=1.21×10-2；rs2706748：Pinteraction=5.21×10-2）之间存在交互作用。遗传多态性与吸烟对肺癌易感性的联合效应分析表明，携带两个SNPs的危险等位基因的重度吸烟者的肺癌风险最高。
在本部分研究中我们最终确定了CDK6和SH3RF1基因上的两个肺癌易感性位点，进一步证明细胞周期和凋亡是肺癌发生的重要病因学机制。此外，我们发现在年龄为51-60岁的人群中，遗传多态性能够与吸烟交互作用，共同影响肺癌易感性，进一步强调了基因-环境交互作用是肺癌发生的重要机制。此外，联合效应分析有助于确定高危人群，以便进行肺癌的早期预防和筛查。
第二部分血浆中多环芳烃相关性microRNA及其与焦炉工氧化应激和遗传损伤的关联性
第一节焦炉工血浆microRNA表达谱情况及特征性microRNA的验证
暴露于环境因素后，机体的miRNA表达水平可发生改变。由于血浆miRNA是生理状态和疾病状态的稳定标记物，因此我们将采取两阶段研究策略，初步探讨职业性PAHs暴露对血浆miRNA表达情况的影响。我们以391名男性健康焦炉工作为研究对象，以尿羟基多环芳烃（monohydroxy polycyclic aromatic hydrocarbons，OH-PAHs）和血浆BPDE-白蛋白加合物作为PAHs内暴露指标。在发现阶段，我们根据焦炉工工作环境中PAHs的浓度水平，将工人分为对照组和暴露组，分别从两组中各选择了20名工人，采用Solexa测序法检测两组混合血浆的miRNA表达谱情况。在验证阶段，我们采用定量逆转录PCR（quantitative reverse transcriptasepolymerase chain reaction，qRT-PCR）验证了8个差异表达且可能相关的miRNA，采用多元线性回归，评价PAHs内暴露水平与miRNA表达量之间的剂量反应关系。
发现阶段中，在暴露筛查组中表达水平较低的miRNA中，有68个miRNA的表达水平在两组间存在五倍以上的差异；而在暴露筛查组中表达水平较高的miRNA中，仅有三个miRNA在两组间存在两倍以上的差异。我们选择了8个miRNA进行验证，最终发现miR-24-3p、miR-27a-3p、miR-142-5p、miR-28-5p和miR-150-5p与PAHs内暴露水平之间的关联与发现阶段的的表达趋势具有一致性。miR-24-3p、miR-27a-3p和miR-142-5p的表达水平与4-OHPHE浓度呈负相关关系（βstd<-0.115，P <0.030）；miR-24-3p与miR-28-5p的表达水平与血浆BPDE-白蛋白加合物浓度呈负相关关系（βstd<-0.165，P≤0.004）。mR-150-5p是发现阶段在暴露筛查组中表达量较高的miRNA，经qRT-PCR验证后，mR-150-5p的表达水平与1-OHNAP、2-OHNAP、2-OHPHE和ΣOH-PAHs的浓度呈正相关关系（βstd>0.120，P <0.030）。功能富集分析显示，这五个miRNA的靶基因主要参与外源性刺激的应答反应、酶活性调节以及代谢过程等。
本节研究首次探讨了PAHs暴露水平对miRNA表达谱的影响。发现阶段的结果表明，PAHs不同暴露组的miRNA表达谱存在差异，且大部分miRNA在暴露组中表达下调；验证阶段最终确定了四个与PAHs暴露呈负相关关系的miRNA和一个与PAHs暴露呈正相关关系的miRNA，这些miRNA可能参与了外源性刺激的应答反应、酶活性调节以及代谢过程。该部分研究结果提示PAHs暴露可能会影响miRNA的表达，从而来介导其有害效应。
第二节多环芳烃相关性microRNA与焦炉工氧化应激的关联性
8-羟基脱氧鸟苷（8-hydroxy-2’-deoxyguanosine，8-OHdG）与8-异前列腺素（8-isoprostane，8-iso-PG）可分别用来评价氧化性DNA损伤和脂质过氧化水平。miRNA可以通过调节氧化应激中的重要靶基因，进而介导机体的氧化应激应答反应。为此我们以第一节验证阶段的365名工人为研究对象，检测了尿8-OHdG和8-iso-PG的浓度，采用多元线性回归分析，评价了PAHs相关性miRNA与8-OHdG和8-iso-PG之间的剂量反应关系。
对于8-OHdG而言，这五个miRNA与8-OHdG的关联性在总人群中均无统计学意义。分层分析后发现，仅miR-142-5p与8-OHdG的正相关关联在非吸烟者中具有临界统计学意义（βstd=0.194，P=0.045）。对于尿8-iso-PG而言，miR-24-3p和miR-150-5p与8-iso-PG在总人群中呈负相关关联（βstd=-0.094，P <0.020），但均未达到Bonferroni多重校正的P值要求（P>0.010）。分层分析后发现，miR-24-3p、miR-142-5p和miR-28-5p与8-iso-PG在非吸烟者中呈显著的负相关关联（βstd<-0.185，P≤0.010），且经Bonferroni多重校正后，仍具有统计学意义，其中miR-28-5p与8-iso-PG的关联性最强（βstd=-0.234）。
本节研究我们发现，miRNA在总人群中与8-OHdG无相关性，而与8-iso-PG呈一定的负相关关联，在非吸烟者中这种负相关关联更加明显，表明miRNA可能在非吸烟者中影响了PAHs引起的脂质过氧化水平。
第三节多环芳烃相关性microRNA与焦炉工遗传损伤的关联性
PAHs-DNA加合物可诱发DNA链断裂、基因组不稳定和染色体损伤。研究表明，miRNA介导了细胞对致癌物引起的DNA损伤的应答反应。为此我们以第一节验证阶段的365名工人为研究对象，检测了工人淋巴细胞的DNA链断裂和染色体损伤情况，采用多元线性回归和多元Poisson回归分析，评价PAHs相关性miRNA与DNA链断裂水平和染色体损伤之间的剂量反应关系。
对于DNA链断裂指标而言，在总人群中，miR-142-5p与Tail DNA%和TM存在正相关性（βstd>0.110，P≤0.010），经Bonferroni多重校正后仍具有统计学意义。分层分析后发现，在吸烟者中，miR-142-5p与Tail DNA%呈正相关关系（βstd=0.125，P=0.006），经Bonferroni校正后仍具有统计学意义。对于染色体损伤指标而言，在总人群中，这五个PAHs相关性miRNA与微核率的正相关关联均具有统计学意义（FR>1.090，P≤0.002），且经Bonferroni校正后仍具有统计学意义，其中miR-24-3p与微核率的关联程度最强（FR=1.152）。分层分析后发现，在吸烟者，miR-24-3p、miR-27a-3p、miR-28-5p和miR-150-5p均与与微核率呈正相关关联（FR>1.095，P≤0.005），且经Bonferroni校正后仍具有统计学意义，其中miR-24-3p与微核率的关联程度最强（FR=1.190）;在年龄为41-60岁之间的工人中，miR-24-3p和miR-28-5p与微核率之间具有正相关关联（FR>1.165，P <2.0×10-4），且经Bonferroni校正后仍具有统计学意义，其中miR-24-3p与微核率的关联程度最强（FR=1.174）。
本节结果表明，miRNA可能影响了PAHs所致的遗传损伤水平，尤其是染色体损伤，而miRNA对染色体损伤的影响在吸烟者和年龄为41-60岁之间的工人体内更加显著。
综上所述，本研究探索了遗传多态性、miRNA与肺癌易感性及PAHs所致早期健康损伤的关联。我们在第一部分首先探索了四大重要通路上的遗传多态性及其与吸烟的交互作用对肺癌易感性的影响。新发现了CDK6和SH3RF1基因上的两个肺癌易感性位点，进一步证明细胞周期和凋亡是肺癌发生的重要病因学机制。我们也发现在年龄为51-60岁的人群中，遗传多态性能够与吸烟交互作用，共同影响肺癌易感性，强调了基因-环境交互作用在肺癌发生中的重要作用。随后为了研究表观遗传因素在环境有害因素致肺癌中的作用，我们以广泛存在的PAHs为环境因素的代表，以PAHs高暴露的焦炉工为研究对象，采用两阶段研究策略首次探讨了职业性PAHs暴露对miRNA表达的影响，发现不同PAHs暴露组间miRNA的表达谱情况存在差异，我们最终确定了五个PAHs相关性miRNA，且这五个miRNA也与PAHs所致的氧化应激水平和遗传损伤水平之间的存在一定的关联，从而表明miRNA可能介导了机体对PAHs的应答反应，可能是PAHs导致氧化应激和遗传损伤中的重要机制。
Lung cancer is the most commonly diagnosed cancer and the leading cause ofcancer deaths worldwide. Accumulating evidence shows that genetic factors may interactwith environmental factors to contribute to lung cancer development. Researchers canunderstand the genetic basis underlying lung cancer development through genome-wideassociation studies (GWAS). Recent GWAS in different populations (including Chinesepopulations) have identified multiple lung cancer susceptibility loci. However, mostidentified loci have small effects and thus only explain a fraction of lung cancersusceptibility variation, suggesting that additional lung cancer susceptibility loci remainto be explored. Genotype imputation can make predictions of the ungenotyped variations,and imputation-based association analyses can facilitate us to further discover the novelassociations. Cell cycle regulation, apoptosis, oxidative stress, and inflammationresponse play critical roles in the development of smoking-induced lung cancer. However,it is still not well known whether their genetic variants are associated with lung cancersusceptibility. Therefore, in the first part of our study, we took imputation-based association analyses to investigate the associations of genetic variants in the pathways ofcell cycle regulation, apoptosis, oxidative stress and inflammation response with lungcancer susceptibility.
Many studies show that besides of genetic factors, the development of lung cancer isalso closely associated with environmental factors. Exposure to environmental factorshas been sown to alter the epigenome to change the gene expression and influence thedevelopment of diseases. microRNAs (miRNAs) are one of the main mechanisms ofepigenetic regulation. Many studies showed that cigarette smoke exposure can alter themiRNA expression levels. PAHs are an important class of carcinogens in cigarettesmoke; however, few epidemiological studies have shown that whether PAHs exposurecan affect the miRNA expression levels. Therefore, we enrolled coke oven workers whoare high-risk populations of lung cancer and are continuously exposed to highconcentrations of PAHs, and discussed the impacts of PAHs exposure on miRNAexpression in the first section of the second part.
Oxidative stress and genetic damages are important mechanisms of PAHs-inducedlung cancer. During the metabolic process, PAHs can produce a large number of reactiveoxygen species (ROS) which can attack biological macromolecules, resulting in tissuedamages, and thus are important cause of carcinogenesis. Besides, after metabolism,PAHs can be transformed into dihydroxy epoxide which can covalently combine withDNA to form PAHs-DNA adducts, causing genetic damages, such as DNA strand breaks,genomic instability and chromosomal damage. These genetic damages are the earlyevents of carcinogenesis. miRNAs can regulate the important target genes involved inoxidative stress and DNA damage response to mediate the response to oxidative stressand genetic damages. However, no epidemiological studies have shown that whether miRNAs were associated with PAHs-induced oxidative stress and genetic damage.Therefore, in the second and the third sections of the second part, we used coke ovenworkers to further investigate the associations of PAHs-associated miRNAs withoxidative stress and genetic damages.
Part I. Effects of genetic variants in important pathways and theirinteractions with smoking on lung cancer susceptibility
Cell cycle regulation, apoptosis, oxidative stress, and inflammation response playcritical roles in the development of smoking-induced lung cancer. However, it is still notwell known whether the genetic variants on these pathways are associated with lungcancer susceptibility. Lung cancer GWAS in Chinese populations have identifiedmultiple lung cancer susceptibility loci. In order to further discover new lung cancersusceptibility loci, we took imputation-based association analyses to investigate theinfluence of single nucleotide polymorphisms (SNPs) in the pathways of cell cycleregulation, apoptosis, oxidative stress and inflammation response on lung cancersusceptibility. We first selected24042SNPs in these pathways from the imputed datasetof lung cancer GWAS of Chinese Han (2331lung cancer cases and3077controls) toevaluate their associations with lung cancer susceptibility, and then conducted additionaltwo-stage validations (a total of4133lung cancer cases and4522controls).
Two SNPs (rs2282987and rs2706748) were successfully validated. When wecombined the results of all three stages, rs2282987was associated with lung cancer risk(OR=1.18, Padd=2.27×10-9). The lung cancer risk for carriers with rs2282987CC wassignificantly higher when compared with the carriers of rs2282987GG (OR=1.37, Phomo=1.10×10-6). The positive association for rs2706748with lung cancer risk (OR=1.17, Padd=5.10×10-6) did not reach the pathway-based significance (Padd>2.0×10-6), but itsPaddin each stage had reached the corresponding requirements (GWAS: Padd=9.65×10-5;validation I: Padd=3.26×10-2; and validation II: Padd=4.49×10-2), and thus was alsoincluded into further analyses. Interaction analyses showed in the subjects aged between51-60years old, rs2282987and rs2706748interacted with smoking status (rs2282987:Pinteraction=1.04×10-2; rs2706748: Pinteraction=3.03×10-2) and smoking dose (rs2282987:Pinteraction=1.21×10-2; rs2706748: Pinteraction=5.21×10-2). The analyses of combined effectsof genetic variants with smoking showed that the OR for heavy smokers with risk allelesof these two SNPs was the highest.
In this part, we have identified two new lung cancer susceptibility variants locatedin CDK6and SH3RF1, further underscoring the etiology role of cell cycle regulation andapoptosis in lung cancer development. Furthermore, we identified that genetic variantsmay interact with smoking to affect lung cancer susceptibility in subjects aged51-60years, further highlighting gene-environment interactions in lung cancer etiology. Finally,the analyses of combined effects may help to identify high-risk individuals for theprevention and screening of lung cancer.
Part II. Identification of polycyclic aromatic hydrocarbons-associatedmicroRNAs in plasma and their associations with oxidative stress andgenetic damages in coke oven workers
Section I. microRNA expression profiles in plasma of coke oven workersand validation of microRNA signatures.
The expression levels of miRNAs can be altered by exposure to environmentalpollutants. Circulating miRNAs in plasma have the potential to be served as stable blood-based biomarkers for both physiological and pathological conditions, thus weperformed a two-stage study to investigate whether occupational PAHs exposure mayaffect the expressions of miRNAs in plasma. In this section, we enrolled391healthymale coke oven workers as our study subjects. Urinary monohydroxy-PAHs (OH-PAHs)and plasma BPDE-albumin adducts were used as the PAHs internal exposure biomarkers.In discovery stage, we divided coke oven workers in to control group and exposed groupaccording to the airborne concentrations of PAHs in their working environment, and thenwe selected20workers from each group. We used Solexa sequencing to detect themiRNA expression profiles in two plasma pools of these two groups. In the validationstage, we used quantitative reverse transcriptase polymerase chain reaction (qRT-PCR) tovalidate eight differentially expressed and potentially related miRNAs, and used multiplelinear regression models to evaluate the dose-response associations between PAHsexposure and miRNA expression levels.
In discovery stage, among the miRNAs with lower expression levels in exposedgroup, there were68miRNAs with at least five-fold differential expression between thetwo groups; among the miRNAs with higher expression levels in exposed group, onlythree miRNAs showed at least two-fold differential expression between the two groups.We selected8miRNAs for validation, and eventually identified that miR-24-3p,miR-27a-3p, miR-142-5p, miR-28-5p, and miR-150-5p showed similar associations withPAHs exposure levels as those in the discovery stage. The expression levels ofmiR-24-3p, miR-27a-3p and miR-142-5p were negatively associated with urinary4-OHPHE (βstd<-0.115, P <0.030); miR-24-3p and miR-28-5p showed negativeassociations with plasma BPDE-albumin adducts (βstd<-0.165, P≤0.004). miR-150-5pwas the miRNA showing higher expression level in exposed group in the discovery stage. By qRT-PCR validation, the expression level of miR-150-5p was positively associatedwith1-OHNAP,2-OHNAP,2-OHPHE, and ΣOH-PAHs (βstd>0.120, P <0.030).Function enrichment analysis showed that the target genes of these five miRNAs weremainly involved in response to exogenous stimuli, regulation of enzyme activity andmetabolic processes.
In this section, we explored the influence of PAHs exposure on miRNA expressionprofiles for the first time. The results of the discovery stage showed that different PAHsexposure groups had different miRNA expression profiles, and most of the differentiallyexpressed miRNAs were down-regulated in the exposed group; in validation stage, weeventually identified four negatively associated miRNAs and one positively associatedmiRNA. These miRNAs may be involved in the response to exogenous stimuli,regulation of enzyme activity and metabolic processes. The results in this sectionsuggested that PAHs exposure may affect the expressions of miRNA to mediate theirharmful health effects.
Section II. Associations of polycyclic aromatic hydrocarbons-associatedmicroRNAs with oxidative stress in coke oven workers.
8-hydroxy-2’-deoxyguanosine (8-OHdG) and8-isoprostane (8-iso-PG) can be usedto evaluate the oxidative DNA damage level and lipid peroxidation level, respectively.miRNAs may mediate the response to oxidative stress through regulating the importanttarget genes involved in oxidative stress. Therefore, we used365workers in thevalidation stage of the first section as the study subjects, and detected the concentrationsof urinary8-OHdG and8-iso-PG. We used multiple linear regression models to evaluatethe dose-response relationship of the expression levels of PAHs-associated miRNAs with8-OHdG and8-iso-PG.
For8-OHdG, none of the five PAHs-associated miRNAs were significantlyassociated with8-OHdG in the general population. In stratification analysis, we onlyfound a marginally significant association between miR-142-5p and8-OHdG innon-smokers (βstd=0.194, P=0.045). For8-iso-PG, miR-24-3p and miR-150-5p werenegatively associated with8-iso-PG in the general population (βstd=-0.094, P <0.020),but these associations didn’t reach the significance threshold of Bonferrioni correction (P>0.010). In stratification analysis, we found that miR-24-3p, miR-142-5p, andmiR-28-5p were significantly associated with8-iso-PG in non-smokers (βstd<-0.185, P≤0.010), even after Bonferrioni correction. The magnitude of the association betweenmiR-28-5p and8-iso-PG was higher (βstd=-0.234).
In this section, we found that these five miRNAs were not associated with8-OHdGin the general population, but were negatively associated with8-iso-PG in some extent,especially in non-smoking workers. Our study suggested that miRNAs may affect thelevel of PAHs-induced lipid peroxidation in non-smoking workers.
Section III. Associations of polycyclic aromatic hydrocarbons-associatedmicroRNAs with genetic damages in coke oven workers.
PAHs-DNA adducts can induce DNA strand breaks, genomic instability andchromosomal damage. Studies have shown that miRNAs can mediate the cellularresponses to the carcinogen-induced DNA damage. Therefore, we used365workers inthe validation stage of the first section as the study subjects, and detected the levels ofDNA strand breaks and chromosome damages in lymphocytes. We used multiple linearregression and Poisson regression models to evaluate the dose-response relationships ofthe expression levels of PAHs-associated miRNAs with DNA strand breaks andchromosome damages.
For the biomarkers of DNA strand breaks, miR-142-5p was positively associatedwith Tail DNA%and TM (βstd>0.110, P≤0.010) in the general population, even afterBonferroni correction. In stratification analysis, miR-142-5p was positively associatedwith Tail DNA%in smokers (βstd=0.125, P=0.006), even after Bonferroni correction.For the biomarker of chromosome damage, these five PAHs-associated miRNAs were allsignificantly positively associated with MN frequency in the general population (FR>1.090, P≤0.002), even after Bonferroni correction. The magnitude of the association formiR-24-3p and MN frequency was relatively higher (FR=1.152). In stratificationanalysis, miR-24-3p, miR-27a-3p, miR-28-5p, and miR-150-5p were positivelyassociated with MN frequency in smokers (FR>1.095, P≤0.005), even after Bonferronicorrection. The magnitude of the association for miR-24-3p and MN frequency was stillrelatively higher (FR=1.190). miR-24-3p and miR-28-5p showed positive associationswith MN frequency in workers aged between41-60years old (FR>1.165, P <2.0×10-4),even after Bonferroni correction. The magnitude of the association for miR-24-3p andMN frequency was still relatively higher (FR=1.174).
In this section, we found that miRNA may affect the levels of PAHs-induced geneticdamages, especially chromosomal damage, and the associations between miRNAsexpression and chromosomal damage were more prominent in smokers and workers agedbetween41-60years old.
In summary, our study explored the associations of genetic variants and miRNAswith lung cancer risk and PAHs-related early health damages. In the first part, weexplored the impact of genetic variants of four major pathways and their interactionswith smoking on lung cancer susceptibility. We found two new susceptibility variants in CDK6and SH3RF1, further underscoring the etiology role of cell cycle regulation andapoptosis in lung cancer development. We also found that genetic variation interactedwith smoking in the subjects aged between51-60years old to contribute to lung cancersusceptibility, further highlighting the importance of gene-environment interactions inlung cancer development. Then, in order to study the roles of epigenetic factors in theharmful environmental factors-induced lung cancer, we used PAHs as the representativeenvironmental factors, and used coke oven workers who were highly exposed to PAHs asour study subjects. We performed a two-stage study to explore the effects of occupationalPAHs exposure on miRNA expression for the first time, and found that the miRNAexpression profiles were different in different PAHs exposure groups. We eventuallyidentified five PAHs-related miRNAs and found that there were a certain associations ofthe five PAHs-associated miRNA with PAHs-induced oxidative stress and geneticdamage levels, suggesting that miRNA maybe an important mechanism that mediates thePAHs response and PAHs-induced oxidative stress and genetic damages.
大量研究表明，除遗传因素外，肺癌发生与环境因素密切相关。环境因素的暴露能够改变机体的表观基因组，进而改变基因的表达，影响疾病的发生发展。微小RNA（microRNA，miRNA）是表观遗传学调节的主要机制之一。众多研究表明，香烟烟雾的暴露能够改变机体的miRNA表达水平。然而，PAHs作为香烟烟雾中的一类重要的致癌物，目前很少有流行病学研究表明PAHs暴露能否影响miRNA表达水平。为此我们以肺癌高发性的、PAHs高暴露的职业性人群——焦炉工为研究对象，在第二部分的第一节中详细探讨了PAHs暴露对miRNA表达的影响。
氧化应激和遗传损伤是PAHs诱发肺癌的重要机制。PAHs在代谢过程中能产生大量活性自由基（reactive oxygen species，ROS）。ROS能攻击生物大分子，从而造成组织细胞损伤，是诱发肿瘤发生的重要起因。此外，PAHs经代谢后可生成二羟基环氧化物，可与DNA分子共价结合形成PAHs-DNA加合物，进而引起DNA链断裂、基因组不稳定和染色体损伤等遗传损伤。这些遗传损伤是肿瘤发生的早期生物学事件。miRNA可以通过调节氧化应激和DNA损伤应答中的重要靶基因，进而介导机体对氧化应激和遗传损伤的应答反应。然而目前尚无流行病学研究表明miRNA是否与PAHs引起的氧化应激和遗传损伤相关。为此，我们在第二部分的第二、三节中以焦炉工为研究对象，进一步探讨了PAHs相关性miRNA与氧化应激、遗传损伤的关联。
第一部分重要通路上的遗传多态性及其与吸烟的交互作用对肺癌易感性的影响
细胞周期调节、凋亡、氧化应激和炎性免疫应答在吸烟导致肺癌中发挥了重要作用。然而目前仍不太清楚这些通路上的遗传多态性与肺癌易感性之间的关联。中国汉族人群肺癌GWAS已经确定了多个肺癌易感性遗传位点，为了继续寻找新的肺癌易感性位点，我们采用基于基因型填补的关联性研究，探讨细胞周期调节、凋亡、氧化应激和炎性免疫应答信号通路上的单核苷酸多态性（single nucleotidepolymorphisms，SNPs）对肺癌易感性的影响。我们首先从中国汉族人群肺癌GWAS基因型填补后的数据库（2331例肺癌病例与3077例对照）中，选择了24042个相关通路上的SNPs，评价它们与肺癌易感性的关联，随后在另外两个人群中进行了验证（共4133例肺癌病例与4522例对照）。
两个SNPs（rs2282987与rs2706748）被成功验证出来。当我们合并三个阶段的结果后发现，rs2282987与肺癌易感性相关（OR=1.18，Padd=2.27×10-9）。与rs2282987GG携带者相比，rs2282987CC携带者的肺癌易感性显著增高（OR=1.37，Phomo=1.10×10-6）。rs2706748与肺癌易感性之间的正相关关系（OR=1.17，Padd=5.10×10-6）虽然未达到基于通路的显著性阈值（Padd>2.0×10-6），但由于它在三个阶段中的Padd均符合各个阶段的要求（GWAS阶段Padd=9.65×10-5；I期验证Padd=3.26×10-2；II期验证Padd=4.49×10-2），因此也纳入了后续的分析中。交互作用分析发现，在年龄为51-60岁之间的人群中，rs2282987和rs2706748与吸烟状态（rs2282987：Pinteraction=1.04×10-2；rs2706748：Pinteraction=3.03×10-2）和吸烟剂量（rs2282987：Pinteraction=1.21×10-2；rs2706748：Pinteraction=5.21×10-2）之间存在交互作用。遗传多态性与吸烟对肺癌易感性的联合效应分析表明，携带两个SNPs的危险等位基因的重度吸烟者的肺癌风险最高。
在本部分研究中我们最终确定了CDK6和SH3RF1基因上的两个肺癌易感性位点，进一步证明细胞周期和凋亡是肺癌发生的重要病因学机制。此外，我们发现在年龄为51-60岁的人群中，遗传多态性能够与吸烟交互作用，共同影响肺癌易感性，进一步强调了基因-环境交互作用是肺癌发生的重要机制。此外，联合效应分析有助于确定高危人群，以便进行肺癌的早期预防和筛查。
第二部分血浆中多环芳烃相关性microRNA及其与焦炉工氧化应激和遗传损伤的关联性
第一节焦炉工血浆microRNA表达谱情况及特征性microRNA的验证
暴露于环境因素后，机体的miRNA表达水平可发生改变。由于血浆miRNA是生理状态和疾病状态的稳定标记物，因此我们将采取两阶段研究策略，初步探讨职业性PAHs暴露对血浆miRNA表达情况的影响。我们以391名男性健康焦炉工作为研究对象，以尿羟基多环芳烃（monohydroxy polycyclic aromatic hydrocarbons，OH-PAHs）和血浆BPDE-白蛋白加合物作为PAHs内暴露指标。在发现阶段，我们根据焦炉工工作环境中PAHs的浓度水平，将工人分为对照组和暴露组，分别从两组中各选择了20名工人，采用Solexa测序法检测两组混合血浆的miRNA表达谱情况。在验证阶段，我们采用定量逆转录PCR（quantitative reverse transcriptasepolymerase chain reaction，qRT-PCR）验证了8个差异表达且可能相关的miRNA，采用多元线性回归，评价PAHs内暴露水平与miRNA表达量之间的剂量反应关系。
发现阶段中，在暴露筛查组中表达水平较低的miRNA中，有68个miRNA的表达水平在两组间存在五倍以上的差异；而在暴露筛查组中表达水平较高的miRNA中，仅有三个miRNA在两组间存在两倍以上的差异。我们选择了8个miRNA进行验证，最终发现miR-24-3p、miR-27a-3p、miR-142-5p、miR-28-5p和miR-150-5p与PAHs内暴露水平之间的关联与发现阶段的的表达趋势具有一致性。miR-24-3p、miR-27a-3p和miR-142-5p的表达水平与4-OHPHE浓度呈负相关关系（βstd<-0.115，P <0.030）；miR-24-3p与miR-28-5p的表达水平与血浆BPDE-白蛋白加合物浓度呈负相关关系（βstd<-0.165，P≤0.004）。mR-150-5p是发现阶段在暴露筛查组中表达量较高的miRNA，经qRT-PCR验证后，mR-150-5p的表达水平与1-OHNAP、2-OHNAP、2-OHPHE和ΣOH-PAHs的浓度呈正相关关系（βstd>0.120，P <0.030）。功能富集分析显示，这五个miRNA的靶基因主要参与外源性刺激的应答反应、酶活性调节以及代谢过程等。
本节研究首次探讨了PAHs暴露水平对miRNA表达谱的影响。发现阶段的结果表明，PAHs不同暴露组的miRNA表达谱存在差异，且大部分miRNA在暴露组中表达下调；验证阶段最终确定了四个与PAHs暴露呈负相关关系的miRNA和一个与PAHs暴露呈正相关关系的miRNA，这些miRNA可能参与了外源性刺激的应答反应、酶活性调节以及代谢过程。该部分研究结果提示PAHs暴露可能会影响miRNA的表达，从而来介导其有害效应。
第二节多环芳烃相关性microRNA与焦炉工氧化应激的关联性
8-羟基脱氧鸟苷（8-hydroxy-2’-deoxyguanosine，8-OHdG）与8-异前列腺素（8-isoprostane，8-iso-PG）可分别用来评价氧化性DNA损伤和脂质过氧化水平。miRNA可以通过调节氧化应激中的重要靶基因，进而介导机体的氧化应激应答反应。为此我们以第一节验证阶段的365名工人为研究对象，检测了尿8-OHdG和8-iso-PG的浓度，采用多元线性回归分析，评价了PAHs相关性miRNA与8-OHdG和8-iso-PG之间的剂量反应关系。
对于8-OHdG而言，这五个miRNA与8-OHdG的关联性在总人群中均无统计学意义。分层分析后发现，仅miR-142-5p与8-OHdG的正相关关联在非吸烟者中具有临界统计学意义（βstd=0.194，P=0.045）。对于尿8-iso-PG而言，miR-24-3p和miR-150-5p与8-iso-PG在总人群中呈负相关关联（βstd=-0.094，P <0.020），但均未达到Bonferroni多重校正的P值要求（P>0.010）。分层分析后发现，miR-24-3p、miR-142-5p和miR-28-5p与8-iso-PG在非吸烟者中呈显著的负相关关联（βstd<-0.185，P≤0.010），且经Bonferroni多重校正后，仍具有统计学意义，其中miR-28-5p与8-iso-PG的关联性最强（βstd=-0.234）。
本节研究我们发现，miRNA在总人群中与8-OHdG无相关性，而与8-iso-PG呈一定的负相关关联，在非吸烟者中这种负相关关联更加明显，表明miRNA可能在非吸烟者中影响了PAHs引起的脂质过氧化水平。
第三节多环芳烃相关性microRNA与焦炉工遗传损伤的关联性
PAHs-DNA加合物可诱发DNA链断裂、基因组不稳定和染色体损伤。研究表明，miRNA介导了细胞对致癌物引起的DNA损伤的应答反应。为此我们以第一节验证阶段的365名工人为研究对象，检测了工人淋巴细胞的DNA链断裂和染色体损伤情况，采用多元线性回归和多元Poisson回归分析，评价PAHs相关性miRNA与DNA链断裂水平和染色体损伤之间的剂量反应关系。
对于DNA链断裂指标而言，在总人群中，miR-142-5p与Tail DNA%和TM存在正相关性（βstd>0.110，P≤0.010），经Bonferroni多重校正后仍具有统计学意义。分层分析后发现，在吸烟者中，miR-142-5p与Tail DNA%呈正相关关系（βstd=0.125，P=0.006），经Bonferroni校正后仍具有统计学意义。对于染色体损伤指标而言，在总人群中，这五个PAHs相关性miRNA与微核率的正相关关联均具有统计学意义（FR>1.090，P≤0.002），且经Bonferroni校正后仍具有统计学意义，其中miR-24-3p与微核率的关联程度最强（FR=1.152）。分层分析后发现，在吸烟者，miR-24-3p、miR-27a-3p、miR-28-5p和miR-150-5p均与与微核率呈正相关关联（FR>1.095，P≤0.005），且经Bonferroni校正后仍具有统计学意义，其中miR-24-3p与微核率的关联程度最强（FR=1.190）;在年龄为41-60岁之间的工人中，miR-24-3p和miR-28-5p与微核率之间具有正相关关联（FR>1.165，P <2.0×10-4），且经Bonferroni校正后仍具有统计学意义，其中miR-24-3p与微核率的关联程度最强（FR=1.174）。
本节结果表明，miRNA可能影响了PAHs所致的遗传损伤水平，尤其是染色体损伤，而miRNA对染色体损伤的影响在吸烟者和年龄为41-60岁之间的工人体内更加显著。
综上所述，本研究探索了遗传多态性、miRNA与肺癌易感性及PAHs所致早期健康损伤的关联。我们在第一部分首先探索了四大重要通路上的遗传多态性及其与吸烟的交互作用对肺癌易感性的影响。新发现了CDK6和SH3RF1基因上的两个肺癌易感性位点，进一步证明细胞周期和凋亡是肺癌发生的重要病因学机制。我们也发现在年龄为51-60岁的人群中，遗传多态性能够与吸烟交互作用，共同影响肺癌易感性，强调了基因-环境交互作用在肺癌发生中的重要作用。随后为了研究表观遗传因素在环境有害因素致肺癌中的作用，我们以广泛存在的PAHs为环境因素的代表，以PAHs高暴露的焦炉工为研究对象，采用两阶段研究策略首次探讨了职业性PAHs暴露对miRNA表达的影响，发现不同PAHs暴露组间miRNA的表达谱情况存在差异，我们最终确定了五个PAHs相关性miRNA，且这五个miRNA也与PAHs所致的氧化应激水平和遗传损伤水平之间的存在一定的关联，从而表明miRNA可能介导了机体对PAHs的应答反应，可能是PAHs导致氧化应激和遗传损伤中的重要机制。
Lung cancer is the most commonly diagnosed cancer and the leading cause ofcancer deaths worldwide. Accumulating evidence shows that genetic factors may interactwith environmental factors to contribute to lung cancer development. Researchers canunderstand the genetic basis underlying lung cancer development through genome-wideassociation studies (GWAS). Recent GWAS in different populations (including Chinesepopulations) have identified multiple lung cancer susceptibility loci. However, mostidentified loci have small effects and thus only explain a fraction of lung cancersusceptibility variation, suggesting that additional lung cancer susceptibility loci remainto be explored. Genotype imputation can make predictions of the ungenotyped variations,and imputation-based association analyses can facilitate us to further discover the novelassociations. Cell cycle regulation, apoptosis, oxidative stress, and inflammationresponse play critical roles in the development of smoking-induced lung cancer. However,it is still not well known whether their genetic variants are associated with lung cancersusceptibility. Therefore, in the first part of our study, we took imputation-based association analyses to investigate the associations of genetic variants in the pathways ofcell cycle regulation, apoptosis, oxidative stress and inflammation response with lungcancer susceptibility.
Many studies show that besides of genetic factors, the development of lung cancer isalso closely associated with environmental factors. Exposure to environmental factorshas been sown to alter the epigenome to change the gene expression and influence thedevelopment of diseases. microRNAs (miRNAs) are one of the main mechanisms ofepigenetic regulation. Many studies showed that cigarette smoke exposure can alter themiRNA expression levels. PAHs are an important class of carcinogens in cigarettesmoke; however, few epidemiological studies have shown that whether PAHs exposurecan affect the miRNA expression levels. Therefore, we enrolled coke oven workers whoare high-risk populations of lung cancer and are continuously exposed to highconcentrations of PAHs, and discussed the impacts of PAHs exposure on miRNAexpression in the first section of the second part.
Oxidative stress and genetic damages are important mechanisms of PAHs-inducedlung cancer. During the metabolic process, PAHs can produce a large number of reactiveoxygen species (ROS) which can attack biological macromolecules, resulting in tissuedamages, and thus are important cause of carcinogenesis. Besides, after metabolism,PAHs can be transformed into dihydroxy epoxide which can covalently combine withDNA to form PAHs-DNA adducts, causing genetic damages, such as DNA strand breaks,genomic instability and chromosomal damage. These genetic damages are the earlyevents of carcinogenesis. miRNAs can regulate the important target genes involved inoxidative stress and DNA damage response to mediate the response to oxidative stressand genetic damages. However, no epidemiological studies have shown that whether miRNAs were associated with PAHs-induced oxidative stress and genetic damage.Therefore, in the second and the third sections of the second part, we used coke ovenworkers to further investigate the associations of PAHs-associated miRNAs withoxidative stress and genetic damages.
Part I. Effects of genetic variants in important pathways and theirinteractions with smoking on lung cancer susceptibility
Cell cycle regulation, apoptosis, oxidative stress, and inflammation response playcritical roles in the development of smoking-induced lung cancer. However, it is still notwell known whether the genetic variants on these pathways are associated with lungcancer susceptibility. Lung cancer GWAS in Chinese populations have identifiedmultiple lung cancer susceptibility loci. In order to further discover new lung cancersusceptibility loci, we took imputation-based association analyses to investigate theinfluence of single nucleotide polymorphisms (SNPs) in the pathways of cell cycleregulation, apoptosis, oxidative stress and inflammation response on lung cancersusceptibility. We first selected24042SNPs in these pathways from the imputed datasetof lung cancer GWAS of Chinese Han (2331lung cancer cases and3077controls) toevaluate their associations with lung cancer susceptibility, and then conducted additionaltwo-stage validations (a total of4133lung cancer cases and4522controls).
Two SNPs (rs2282987and rs2706748) were successfully validated. When wecombined the results of all three stages, rs2282987was associated with lung cancer risk(OR=1.18, Padd=2.27×10-9). The lung cancer risk for carriers with rs2282987CC wassignificantly higher when compared with the carriers of rs2282987GG (OR=1.37, Phomo=1.10×10-6). The positive association for rs2706748with lung cancer risk (OR=1.17, Padd=5.10×10-6) did not reach the pathway-based significance (Padd>2.0×10-6), but itsPaddin each stage had reached the corresponding requirements (GWAS: Padd=9.65×10-5;validation I: Padd=3.26×10-2; and validation II: Padd=4.49×10-2), and thus was alsoincluded into further analyses. Interaction analyses showed in the subjects aged between51-60years old, rs2282987and rs2706748interacted with smoking status (rs2282987:Pinteraction=1.04×10-2; rs2706748: Pinteraction=3.03×10-2) and smoking dose (rs2282987:Pinteraction=1.21×10-2; rs2706748: Pinteraction=5.21×10-2). The analyses of combined effectsof genetic variants with smoking showed that the OR for heavy smokers with risk allelesof these two SNPs was the highest.
In this part, we have identified two new lung cancer susceptibility variants locatedin CDK6and SH3RF1, further underscoring the etiology role of cell cycle regulation andapoptosis in lung cancer development. Furthermore, we identified that genetic variantsmay interact with smoking to affect lung cancer susceptibility in subjects aged51-60years, further highlighting gene-environment interactions in lung cancer etiology. Finally,the analyses of combined effects may help to identify high-risk individuals for theprevention and screening of lung cancer.
Part II. Identification of polycyclic aromatic hydrocarbons-associatedmicroRNAs in plasma and their associations with oxidative stress andgenetic damages in coke oven workers
Section I. microRNA expression profiles in plasma of coke oven workersand validation of microRNA signatures.
The expression levels of miRNAs can be altered by exposure to environmentalpollutants. Circulating miRNAs in plasma have the potential to be served as stable blood-based biomarkers for both physiological and pathological conditions, thus weperformed a two-stage study to investigate whether occupational PAHs exposure mayaffect the expressions of miRNAs in plasma. In this section, we enrolled391healthymale coke oven workers as our study subjects. Urinary monohydroxy-PAHs (OH-PAHs)and plasma BPDE-albumin adducts were used as the PAHs internal exposure biomarkers.In discovery stage, we divided coke oven workers in to control group and exposed groupaccording to the airborne concentrations of PAHs in their working environment, and thenwe selected20workers from each group. We used Solexa sequencing to detect themiRNA expression profiles in two plasma pools of these two groups. In the validationstage, we used quantitative reverse transcriptase polymerase chain reaction (qRT-PCR) tovalidate eight differentially expressed and potentially related miRNAs, and used multiplelinear regression models to evaluate the dose-response associations between PAHsexposure and miRNA expression levels.
In discovery stage, among the miRNAs with lower expression levels in exposedgroup, there were68miRNAs with at least five-fold differential expression between thetwo groups; among the miRNAs with higher expression levels in exposed group, onlythree miRNAs showed at least two-fold differential expression between the two groups.We selected8miRNAs for validation, and eventually identified that miR-24-3p,miR-27a-3p, miR-142-5p, miR-28-5p, and miR-150-5p showed similar associations withPAHs exposure levels as those in the discovery stage. The expression levels ofmiR-24-3p, miR-27a-3p and miR-142-5p were negatively associated with urinary4-OHPHE (βstd<-0.115, P <0.030); miR-24-3p and miR-28-5p showed negativeassociations with plasma BPDE-albumin adducts (βstd<-0.165, P≤0.004). miR-150-5pwas the miRNA showing higher expression level in exposed group in the discovery stage. By qRT-PCR validation, the expression level of miR-150-5p was positively associatedwith1-OHNAP,2-OHNAP,2-OHPHE, and ΣOH-PAHs (βstd>0.120, P <0.030).Function enrichment analysis showed that the target genes of these five miRNAs weremainly involved in response to exogenous stimuli, regulation of enzyme activity andmetabolic processes.
In this section, we explored the influence of PAHs exposure on miRNA expressionprofiles for the first time. The results of the discovery stage showed that different PAHsexposure groups had different miRNA expression profiles, and most of the differentiallyexpressed miRNAs were down-regulated in the exposed group; in validation stage, weeventually identified four negatively associated miRNAs and one positively associatedmiRNA. These miRNAs may be involved in the response to exogenous stimuli,regulation of enzyme activity and metabolic processes. The results in this sectionsuggested that PAHs exposure may affect the expressions of miRNA to mediate theirharmful health effects.
Section II. Associations of polycyclic aromatic hydrocarbons-associatedmicroRNAs with oxidative stress in coke oven workers.
8-hydroxy-2’-deoxyguanosine (8-OHdG) and8-isoprostane (8-iso-PG) can be usedto evaluate the oxidative DNA damage level and lipid peroxidation level, respectively.miRNAs may mediate the response to oxidative stress through regulating the importanttarget genes involved in oxidative stress. Therefore, we used365workers in thevalidation stage of the first section as the study subjects, and detected the concentrationsof urinary8-OHdG and8-iso-PG. We used multiple linear regression models to evaluatethe dose-response relationship of the expression levels of PAHs-associated miRNAs with8-OHdG and8-iso-PG.
For8-OHdG, none of the five PAHs-associated miRNAs were significantlyassociated with8-OHdG in the general population. In stratification analysis, we onlyfound a marginally significant association between miR-142-5p and8-OHdG innon-smokers (βstd=0.194, P=0.045). For8-iso-PG, miR-24-3p and miR-150-5p werenegatively associated with8-iso-PG in the general population (βstd=-0.094, P <0.020),but these associations didn’t reach the significance threshold of Bonferrioni correction (P>0.010). In stratification analysis, we found that miR-24-3p, miR-142-5p, andmiR-28-5p were significantly associated with8-iso-PG in non-smokers (βstd<-0.185, P≤0.010), even after Bonferrioni correction. The magnitude of the association betweenmiR-28-5p and8-iso-PG was higher (βstd=-0.234).
In this section, we found that these five miRNAs were not associated with8-OHdGin the general population, but were negatively associated with8-iso-PG in some extent,especially in non-smoking workers. Our study suggested that miRNAs may affect thelevel of PAHs-induced lipid peroxidation in non-smoking workers.
Section III. Associations of polycyclic aromatic hydrocarbons-associatedmicroRNAs with genetic damages in coke oven workers.
PAHs-DNA adducts can induce DNA strand breaks, genomic instability andchromosomal damage. Studies have shown that miRNAs can mediate the cellularresponses to the carcinogen-induced DNA damage. Therefore, we used365workers inthe validation stage of the first section as the study subjects, and detected the levels ofDNA strand breaks and chromosome damages in lymphocytes. We used multiple linearregression and Poisson regression models to evaluate the dose-response relationships ofthe expression levels of PAHs-associated miRNAs with DNA strand breaks andchromosome damages.
For the biomarkers of DNA strand breaks, miR-142-5p was positively associatedwith Tail DNA%and TM (βstd>0.110, P≤0.010) in the general population, even afterBonferroni correction. In stratification analysis, miR-142-5p was positively associatedwith Tail DNA%in smokers (βstd=0.125, P=0.006), even after Bonferroni correction.For the biomarker of chromosome damage, these five PAHs-associated miRNAs were allsignificantly positively associated with MN frequency in the general population (FR>1.090, P≤0.002), even after Bonferroni correction. The magnitude of the association formiR-24-3p and MN frequency was relatively higher (FR=1.152). In stratificationanalysis, miR-24-3p, miR-27a-3p, miR-28-5p, and miR-150-5p were positivelyassociated with MN frequency in smokers (FR>1.095, P≤0.005), even after Bonferronicorrection. The magnitude of the association for miR-24-3p and MN frequency was stillrelatively higher (FR=1.190). miR-24-3p and miR-28-5p showed positive associationswith MN frequency in workers aged between41-60years old (FR>1.165, P <2.0×10-4),even after Bonferroni correction. The magnitude of the association for miR-24-3p andMN frequency was still relatively higher (FR=1.174).
In this section, we found that miRNA may affect the levels of PAHs-induced geneticdamages, especially chromosomal damage, and the associations between miRNAsexpression and chromosomal damage were more prominent in smokers and workers agedbetween41-60years old.
In summary, our study explored the associations of genetic variants and miRNAswith lung cancer risk and PAHs-related early health damages. In the first part, weexplored the impact of genetic variants of four major pathways and their interactionswith smoking on lung cancer susceptibility. We found two new susceptibility variants in CDK6and SH3RF1, further underscoring the etiology role of cell cycle regulation andapoptosis in lung cancer development. We also found that genetic variation interactedwith smoking in the subjects aged between51-60years old to contribute to lung cancersusceptibility, further highlighting the importance of gene-environment interactions inlung cancer development. Then, in order to study the roles of epigenetic factors in theharmful environmental factors-induced lung cancer, we used PAHs as the representativeenvironmental factors, and used coke oven workers who were highly exposed to PAHs asour study subjects. We performed a two-stage study to explore the effects of occupationalPAHs exposure on miRNA expression for the first time, and found that the miRNAexpression profiles were different in different PAHs exposure groups. We eventuallyidentified five PAHs-related miRNAs and found that there were a certain associations ofthe five PAHs-associated miRNA with PAHs-induced oxidative stress and geneticdamage levels, suggesting that miRNA maybe an important mechanism that mediates thePAHs response and PAHs-induced oxidative stress and genetic damages.
引文
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